Neonatal and Pediatric Liver and Metabolic Diseases: Clinical Casebook [1st ed.] 9789811592300, 9789811592317

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Neonatal and Pediatric Liver and Metabolic Diseases: Clinical Casebook [1st ed.]
 9789811592300, 9789811592317

Table of contents :
Front Matter ....Pages i-xii
Neonatal and Pediatric Liver Diseases (Manoj K. Ghoda)....Pages 1-36
Case 1: A 20-Month-Old Child Who Returned to the Clinic After a Lapse of 12 Months and a 20-Month-Old Child with Recurrent Convulsions (Manoj K. Ghoda)....Pages 37-45
Case 2: A 9-Year-Old Boy Presenting with Hepatitis, Epistaxis, and Bleeding from Gums (Manoj K. Ghoda)....Pages 47-50
Case 3: Lightning Strikes at One Place Thrice! (Manoj K. Ghoda)....Pages 51-54
Case 4: A Worried Couple with a Child Having Jaundice (Manoj K. Ghoda)....Pages 55-59
Case 5: A 2-Year-Old Child Who Had Recurrent Hematemesis and Bleeding per Rectum (Manoj K. Ghoda)....Pages 61-64
Case 6: A Child Who Had Lost Appetite and Interest (Manoj K. Ghoda)....Pages 65-68
Case 7: A Year-Old Child with Chronic Diarrhea and Severe Failure to Thrive (Manoj K. Ghoda)....Pages 69-72
Case 8: A 3-Year-Old Male with Recurrent Diarrhea and Chest Infection That Made His Mother Go Back to Her Parents (Manoj K. Ghoda)....Pages 73-76
Case 9: A 11-Month-Old Pair of Twins Who Made Everyone in the Family Cry for 5 Months (Manoj K. Ghoda)....Pages 77-83
Case 10: A Child with Recurrent Diarrhea That Made the Family Measurable (Manoj K. Ghoda)....Pages 85-87
Case 11: A 3-Month-Old Child with Recurrent Fever, Diarrhea, Failure to Thrive, and Electrolyte Disturbances (Manoj K. Ghoda)....Pages 89-91
Case 12: A 13-Year-Old Girl with Chronic Abdominal Pain and Vomiting (Manoj K. Ghoda)....Pages 93-99
Case 13: A 6-Month-Old Child with Neonatal Cholestasis and Generalized Edema (Manoj K. Ghoda)....Pages 101-103
Case 14: A 6-Week-Old Child Who Had Progressive Jaundice and Creamy White Stools (Manoj K. Ghoda)....Pages 105-109
Case 15: Milk by Any Other Name Could Also Be Milk (Manoj K. Ghoda)....Pages 111-115
Case 16: An 8-Year-Old Son of a Lady Executive Who Was a Keen “Net” Searcher (Manoj K. Ghoda)....Pages 117-123
Case 17: Neo Rich Parents Who Wanted the Best for Their Child! (Manoj K. Ghoda)....Pages 125-130
Case 18: A Case of “Crigler–Najjar Syndrome” (Manoj K. Ghoda)....Pages 131-134
Case 19: A Pleasant Child Who Developed Prolonged Jaundice (Manoj K. Ghoda)....Pages 135-138
Case 20: Prolonged Neonatal Jaundice and Cardiac Defects (Manoj K. Ghoda)....Pages 139-143
Case 21: Neonatal Jaundice in a Child with Ocular Problem (Manoj K. Ghoda)....Pages 145-148
Case 22: A 3-Year-Old Girl with Unexplained Vomiting and Failure to Thrive (Manoj K. Ghoda)....Pages 149-153
Case 23: A 3-Year-Old Boy with Failure to Thrive and Progressively Stiffening Muscles (Manoj K. Ghoda)....Pages 155-157
Case 24: A 2-Month-Old Child with Neonatal Ascites (Manoj K. Ghoda)....Pages 159-164
Case 25: A Patient with Sickle Cell Anemia with Sudden Onset of Jaundice (Manoj K. Ghoda)....Pages 165-168
Case 26: A 7-Year-Old Boy with Recurrence of Jaundice (Manoj K. Ghoda)....Pages 169-172
Case 27: An 8-Year-Old Boy with Recurrent Jaundice (Manoj K. Ghoda)....Pages 173-175
Case 28: A 3-Year-Old with Huge Liver and Abnormal Liver Functions (Manoj K. Ghoda)....Pages 177-181
Case 29: A 15-Year-Old Boy with Prolonged Jaundice (Manoj K. Ghoda)....Pages 183-186
Case 30: A Young Girl with Recurrent Jaundice and Vague RUQ Mass (Manoj K. Ghoda)....Pages 187-189
Case 31: A Young Boy with Ascites (Manoj K. Ghoda)....Pages 191-194
Case 32: Two Cases of Recurrence of Jaundice (Manoj K. Ghoda)....Pages 195-196
Case 33: A 12-Year-Old Boy with “Obstructive Jaundice” (Manoj K. Ghoda)....Pages 197-199
Case 34: 11-Year-Old Boy with Jaundice and Bleeding PR (Manoj K. Ghoda)....Pages 201-202
Case 35: A Young Boy with Failed Renal Transplant and Sudden Onset of Ascites (Manoj K. Ghoda)....Pages 203-206
Case 36: A 2-Year-Old Boy with Diarrhea, Failure to Thrive, and Hepatomegaly (Manoj K. Ghoda)....Pages 207-210
Case 37: A Child with “Recurrent Attacks of Asthma” (Manoj K. Ghoda)....Pages 211-214
Case 38: A 3-Year-Old Boy with Recurrent Jaundice and Severe Iron Deficiency Anemia (Manoj K. Ghoda)....Pages 215-216
Case 39: 3-Year-Old Boy with Huge Liver (Manoj K. Ghoda)....Pages 217-218
Case 40: A Case of Neonatal Liver Failure (Manoj K. Ghoda)....Pages 219-226
Case 41: A Case of Acute Hepatitis and... Something More (Manoj K. Ghoda)....Pages 227-229
Case 42: A Case of Neonatal Hepatitis and Failure to Thrive (Manoj K. Ghoda)....Pages 231-234
Case 43: An Infant with Sudden Onset of Unilateral Ptosis and Jaundice (Manoj K. Ghoda)....Pages 235-238
Case 44: A Neonate with Rapidly Deteriorating Liver Functions (Manoj K. Ghoda)....Pages 239-241
Case 45: A 6-Month-Old Child with Hematemesis (Manoj K. Ghoda)....Pages 243-246
Case 46: A Young Child with Persistent Elevation of SGOT/SGPT (Manoj K. Ghoda)....Pages 247-248
Case 47: An Infant with Persistent Vomiting (Manoj K. Ghoda)....Pages 249-251
Case 48: A Case of Fever and Jaundice (Manoj K. Ghoda)....Pages 253-254
Case 49: A Neonate with Jaundice and Enlarged Liver (Manoj K. Ghoda)....Pages 255-259
Case 50: A Case of Huge Hepatomegaly but No Hypoglycemia (Manoj K. Ghoda)....Pages 261-263
Case 51: Pregnant Lady with HBsAg Positivity: A Pediatrician’s Perspective (Manoj K. Ghoda)....Pages 265-266

Citation preview

Neonatal and Pediatric Liver and Metabolic Diseases Clinical Casebook Manoj K. Ghoda

123

Neonatal and Pediatric Liver and Metabolic Diseases

Manoj K. Ghoda

Neonatal and Pediatric Liver and Metabolic Diseases Clinical Casebook

Manoj K. Ghoda Gujarat Super Speciality Clinic Ahmedabad India

ISBN 978-981-15-9230-0    ISBN 978-981-15-9231-7 (eBook) https://doi.org/10.1007/978-981-15-9231-7 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2021 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore

This book is written for postgraduate pediatric students and practicing pediatricians in a case record format to make this formidable looking subject easy to understand. Medical science keeps progressing and therefore understanding and interpretation of many things discussed here could change over time so the reader is requested to update himself with current theories and practices. This book is dedicated to my daughter late Shivani, my son Atit, and my wife Hemakshi and all my patients who gave me the opportunity to learn this difficult subject.

Preface

Neonatal and pediatric liver, liver-related metabolic diseases, and pancreatic disease pose a formidable challenge in their diagnosis and management. Many diverse etiologies have a similar phenotype, making things difficult. Investigating them is difficult, time-consuming, and expensive and at times unreliable. Only careful evaluation and meticulous diagnostic workup will pinpoint the underlying problem. To make these difficult problems a little bit easier for the practitioners, we have collected some interesting cases of these conditions and tried to take the reader through the journey we took in a simple language for easy understanding and hope these principles could be applied in their practice. On a positive note, molecular biology is advancing at a very rapid pace and, without doubt, will replace cumbersome and time-consuming algorithms with a single or at the most a few reliable and cost-­ effective tests. We hope the reader enjoys this book as much as we have enjoyed it writing. Ahmedabad, India August 15, 2020

Manoj K. Ghoda

vii

Contents

1 Neonatal and Pediatric Liver Diseases����������������������������������������������������   1 1.1 Neonatal and Pediatric Liver Diseases Are Unique����������������������������   1 1.2 Neonatal and Pediatric Liver Diseases Are Different from Adult Liver Diseases for the Following Main Reasons��������������   1 1.3 Liver Function Tests����������������������������������������������������������������������������   9 1.4 Investigating a Case of Neonatal Jaundice������������������������������������������  11 1.4.1 Suggested Protocol�����������������������������������������������������������������  11 1.5 Treatment in the Case of Conjugated Hyperbilirubinemia till a Definitive Diagnosis Is Made ����������������������������������������������������  13 1.6 Basic Understanding of Inborn Errors of Metabolism and Metabolic Disorders ��������������������������������������������������������������������  13 1.6.1 Introduction����������������������������������������������������������������������������  13 1.7 Next Generation Sequencing in Neonatal, Infantile and Pediatric Liver, and Metabolic Diseases��������������������������������������  30 1.8 Conclusion������������������������������������������������������������������������������������������  36 2 Case 1: A 20-Month-Old Child Who Returned to the Clinic After a Lapse of 12 Months and a 20-Month-Old Child with Recurrent Convulsions ����������������������  37 2.1 What Are Your Working Diagnoses? What Would You Do Next in Each of These Two Cases? ����������������������������������������������  38 2.1.1 Analyzing a Case of Hypoglycemia ��������������������������������������  38 2.2 Understand Various Types of GSDs Affecting the Liver in a Significant Way����������������������������������������������������������������������������  43 2.2.1 GSD Type-I ����������������������������������������������������������������������������  43 2.2.2 GSD Type-III��������������������������������������������������������������������������  44 2.2.3 GSD Type-IV��������������������������������������������������������������������������  44 3 Case 2: A 9-Year-Old Boy Presenting with Hepatitis, Epistaxis, and Bleeding from Gums ��������������������������������������������������������  47 3.1 Would a Liver Biopsy Help?��������������������������������������������������������������  48 4 Case 3: Lightning Strikes at One Place Thrice!��������������������������������������  51 4.1 What Is Your Differential Diagnosis? What Additional Tests Would You Do?��������������������������������������������������������������������������  52 4.2 Clinical Features ��������������������������������������������������������������������������������  53 ix

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5 Case 4: A Worried Couple with a Child Having Jaundice ��������������������  55 5.1 Do You Agree with Our Suspicion? What Other Investigations Would You Do?����������������������������������������  56 5.1.1 Crigler–Najjar Syndrome (CN Syndrome) ����������������������������  56 5.1.2 Phototherapy ��������������������������������������������������������������������������  58 6 Case 5: A 2-Year-Old Child Who Had Recurrent Hematemesis and Bleeding per Rectum��������������������������������������������������  61 6.1 Why Do You Think She Has Bled?����������������������������������������������������  61 7 Case 6: A Child Who Had Lost Appetite and Interest����������������������������  65 7.1 What Is Your Working Diagnosis? What Further Tests You Would Do Now?�����������������������������������������������������������������  66 8 Case 7: A Year-Old Child with Chronic Diarrhea and Severe Failure to Thrive ��������������������������������������������������������������������  69 9 Case 8: A 3-Year-Old Male with Recurrent Diarrhea and Chest Infection That Made His Mother Go Back to Her Parents��������������������������������������������������������������������������������������������  73 10 Case 9: A 11-Month-Old Pair of Twins Who Made Everyone in the Family Cry for 5 Months����������������������������������������������������������������  77 10.1 What Should We Do Now? ��������������������������������������������������������������  78 10.2 What Next? ��������������������������������������������������������������������������������������  78 10.3 Progressive Familial Intrahepatic Cholestasis����������������������������������  79 11 Case 10: A Child with Recurrent Diarrhea That Made the Family Measurable������������������������������������������������������������������������������  85 12 Case 11: A 3-Month-Old Child with Recurrent Fever, Diarrhea, Failure to Thrive, and Electrolyte Disturbances��������������������  89 12.1 How Will You Explain These Abnormalities in His Blood Gas Picture?����������������������������������������������������������������  90 12.1.1 What Is Your Diagnosis?������������������������������������������������������  90 13 Case 12: A 13-Year-Old Girl with Chronic Abdominal Pain and Vomiting��������������������������������������������������������������������������������������  93 13.1 What Is Your Diagnosis, What Sort of Clinical Course You Predict, and What Is Your Expected Outcome for This Patient?��������������������������������������������������������������������������������  93 14 Case 13: A 6-Month-Old Child with Neonatal Cholestasis and Generalized Edema���������������������������������������������������������������������������� 101 14.1 What Is Your Line of Thinking? What Is Your Diagnosis?�������������� 102

Contents

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15 Case 14: A 6-Week-Old Child Who Had Progressive Jaundice and Creamy White Stools�������������������������������������������������������������������������� 105 15.1 What Is Your Working Diagnosis for Convulsions?������������������������� 105 15.2 What Further Tests Would You Like to Do? ������������������������������������ 106 15.3 Extra Hepatic Biliary Atresia������������������������������������������������������������ 107 16 Case 15: Milk by Any Other Name Could Also Be Milk������������������������ 111 16.1 How Will You Proceed Now?������������������������������������������������������������ 112 16.2 What Could This Be?������������������������������������������������������������������������ 112 17 Case 16: An 8-Year-Old Son of a Lady Executive Who Was a Keen “Net” Searcher ������������������������������������������������������������ 117 17.1 What Should I Do Now?������������������������������������������������������������������ 118 18 Case 17: Neo Rich Parents Who Wanted the Best for Their Child!������������������������������������������������������������������������������������������ 125 18.1 What Is Your Thinking?�������������������������������������������������������������������� 126 19 Case 18: A Case of “Crigler–Najjar Syndrome”������������������������������������ 131 19.1 What Do You Think Is Happening? What Precautions You Would Take Before Labelling Any Child with “Crigler–Najjar Syndrome”?���������������������������������������������������� 132 20 Case 19: A Pleasant Child Who Developed Prolonged Jaundice���������� 135 21 Case 20: Prolonged Neonatal Jaundice and Cardiac Defects���������������� 139 22 Case 21: Neonatal Jaundice in a Child with Ocular Problem �������������� 145 23 Case 22: A 3-Year-Old Girl with Unexplained Vomiting and Failure to Thrive �������������������������������������������������������������������������������� 149 24 Case 23: A 3-Year-Old Boy with Failure to Thrive and Progressively Stiffening Muscles ������������������������������������������������������ 155 25 Case 24: A 2-Month-Old Child with Neonatal Ascites �������������������������� 159 26 Case 25: A Patient with Sickle Cell Anemia with Sudden Onset of Jaundice���������������������������������������������������������������� 165 27 Case 26: A 7-Year-Old Boy with Recurrence of Jaundice���������������������� 169 28 Case 27: An 8-Year-Old Boy with Recurrent Jaundice�������������������������� 173 29 Case 28: A 3-Year-Old with Huge Liver and Abnormal Liver Functions���������������������������������������������������������������� 177 30 Case 29: A 15-Year-Old Boy with Prolonged Jaundice�������������������������� 183

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Contents

31 Case 30: A Young Girl with Recurrent Jaundice and Vague RUQ Mass�������������������������������������������������������������������������������� 187 32 Case 31: A Young Boy with Ascites���������������������������������������������������������� 191 33 Case 32: Two Cases of Recurrence of Jaundice�������������������������������������� 195 34 Case 33: A 12-Year-Old Boy with “Obstructive Jaundice”�������������������� 197 35 Case 34: 11-Year-Old Boy with Jaundice and Bleeding PR������������������ 201 36 Case 35: A Young Boy with Failed Renal Transplant and Sudden Onset of Ascites �������������������������������������������������������������������� 203 37 Case 36: A 2-Year-Old Boy with Diarrhea, Failure to Thrive, and Hepatomegaly ������������������������������������������������������������������������������������ 207 38 Case 37: A Child with “Recurrent Attacks of Asthma” ������������������������ 211 39 Case 38: A 3-Year-Old Boy with Recurrent Jaundice and Severe Iron Deficiency Anemia���������������������������������������������������������� 215 40 Case 39: 3-Year-Old Boy with Huge Liver���������������������������������������������� 217 41 Case 40: A Case of Neonatal Liver Failure���������������������������������������������� 219 42 Case 41: A Case of Acute Hepatitis and... Something More������������������ 227 43 Case 42: A Case of Neonatal Hepatitis and Failure to Thrive �������������� 231 44 Case 43: An Infant with Sudden Onset of Unilateral Ptosis and Jaundice���������������������������������������������������������������������������������������������� 235 45 Case 44: A Neonate with Rapidly Deteriorating Liver Functions������������������������������������������������������������������������������������������ 239 46 Case 45: A 6-Month-Old Child with Hematemesis�������������������������������� 243 47 Case 46: A Young Child with Persistent Elevation of SGOT/SGPT������������������������������������������������������������������������������������������ 247 48 Case 47: An Infant with Persistent Vomiting������������������������������������������ 249 49 Case 48: A Case of Fever and Jaundice �������������������������������������������������� 253 50 Case 49: A Neonate with Jaundice and Enlarged Liver ������������������������ 255 51 Case 50: A Case of Huge Hepatomegaly but No Hypoglycemia������������ 261 52 Case 51: Pregnant Lady with HBsAg Positivity: A Pediatrician’s Perspective���������������������������������������������������������������������� 265

1

Neonatal and Pediatric Liver Diseases

1.1

Neonatal and Pediatric Liver Diseases Are Unique

I started in this field some 25 years ago. Everything looked intimidating but perseverance and reading and a large pool of patients eventually worked for me and what was very intimidating then started making sense. Why these diseases look so intimidating? The reason as I see is that there are no gross clues and the neonate or infant cannot talk, so you have to look for finer clues and piece everything together, then it is not that difficult in a majority of the cases. I would suggest use your common sense and things will become very easy if very easy looks like exaggeration, at least easy is a genuine belief. Let us first have a basic understanding of Neonatal and pediatric liver diseases and see what is unique about them. If you are an adult physician dealing with pediatric or neonatal patients with jaundice as well, you must first understand that adult and neonatal and pediatric liver diseases have only yellowness in common; apart from this these are 180-degree apart. The reason being, they have totally different etiologies and different presentations, different evolution, different sets of investigations, and different treatments. Likewise neonatal and pediatric liver diseases are also two distinct entities. This understanding removes much of the confusion and avoids what may appear as haphazard approach to these diseases.

1.2

 eonatal and Pediatric Liver Diseases Are Different N from Adult Liver Diseases for the Following Main Reasons

• Firstly, there are in utero infections by hepatotropic viruses, which are transmitted to the fetus, thus newborn has a liver disease from birth itself.

© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2021 M. K. Ghoda, Neonatal and Pediatric Liver and Metabolic Diseases, https://doi.org/10.1007/978-981-15-9231-7_1

1

2

1  Neonatal and Pediatric Liver Diseases

• Secondly, there are anatomical abnormalities which, at times, are so gross that the child has jaundice at or soon after birth and at times does not survive into adulthood and hence these diseases are not seen in adults. Some inborn errors of metabolism (IEM) are so gross that the child develops jaundice soon after birth due to toxic effects of metabolic derangement and at times does not survive infancy and hence again these diseases also are not seen in adulthood. Then there is accumulation of certain metals like iron and copper, which starts damaging the liver around 3–5 years of age and by the time they reach adulthood most of them are moribund. Now, I think, it is easy to understand why some liver diseases are seen only or predominantly in newborns or infants. From the above, it is also clear to a motivated reader like you, why neonatal and pediatric liver diseases, also differ clearly in their etiology, presentation, evolution, and management!! Not only this, you will soon start realizing that even neonatal jaundice is not one homogenous entity! Do you find it confusing? Not at all; by further compartmentalizing we can reduce the differential diagnosis in each category. So try to see positive side of everything! It could be divided into the causes that present fulminantly with the newborn becoming critically ill in first few hours of life; or becoming acutely ill in the first few weeks or remaining jaundiced with grumbling illness for several months. This understanding is crucial as with this knowledge you can prioritize your scarce resources and reach the diagnosis much earlier. In the beginning, for me, the difficult part of evaluating any case of neonatal jaundice was that they all appeared the same and most of the time it was impossible to tell, without detailed history taking, detailed examination, and most of all doing elaborate tests, as to what could be the reason for jaundice in any given case. However, with experience and knowing various scenarios of etiology and their time of expression and natural history, I, and so will you, learnt to obtain certain important clues from the clinical work-up, which helped me to narrow down the diagnostic possibilities and hence cut down on the tests and thereby expenses and the delay. This attainment increases your confidence and it definitely reflects on how you deal with relatives, they will find you knowledgeable, someone who can treat their child. In my experience, this is less daunting in pediatric liver diseases. Various liver diseases do start differing from each other in pediatric age group and one can do a limited number of tests and the diagnosis may be reached.

Neonatal and Pediatric liver diseases are two distinct entities although seen by the same specialist.

1.2  Neonatal and Pediatric Liver Diseases Are Different from Adult Liver Diseases…

3

Neonatal Jaundice Here jaundice is present in neonatal period. It could be present at birth or it could develop later on; it could have rapid fulminant course, or an acute course, or an indolent course. It all depends upon the underlying etiology. Etiology of neonatal jaundice could be broadly summarized as: • Intrauterine infections: Generally, these infections are of TORCH group, but occasionally a neonate may contract parvovirus or even hepatitis B or C, syphilis, and the like, but these are rare these days. HBV and HCV infections are not strictly intra uterine but they are acquired at the time of delivery. In TORCH group, the liver is generally not the only organ affected but CNS, blood and bone marrow, and eyes are also affected and their pathology may dominate clinical picture. These infections are present at birth and therefore liver dysfunction, even though mild, could be picked up early on. A cautionary note for CMV infection, which is so common on serological testing that every effort should be made to confirm the diagnosis by PCR testing for CMV DNA and looking for CMV virus in urine. • Developmental abnormalities: During organogenesis, for genetic or infectious causes; the biliary tree is malformed, hampering the smooth flow of bile. It is seen that organs developing simultaneously with the biliary tree are also affected thus raising the possibility of a “hostile environment.” Infectious, metabolic, or some unknown factors may be operating at that point in the developmental process. A prime example of this type of defect is Extra Hepatic Biliary Atresia (EHBA). This is an important cause of neonatal jaundice but to be honest; in our practice its nowhere near 25% of all cases of neonatal jaundice as quoted in Western literature. There are other causes also like non-syndromic bile duct paucity, Alagille syndrome, and Choledochal cysts. Presentation is generally at birth or soon after with features of cholestasis and pale, creamy stool. Although in Choledochal cysts, the clinical presentation could be quite late. • Inherited metabolic diseases: This could be from: –– Toxic metabolite accumulation that is highly toxic to the liver parenchyma or severe impairment of crucial metabolic processes, which are essential for carrying out critical liver functions. These diseases produce jaundice soon after birth. The affected child becomes seriously ill and decompensates early on.

4

1  Neonatal and Pediatric Liver Diseases

–– Gradual accumulation of metabolic products, which are toxic to the liver. Here, the affected child remains healthy for a while; say a few years in Wilson’s disease or hemochromatosis (not of neonatal variety) or in some forms of Glycogen Storage Diseases, till the liver reserves are overwhelmed. These diseases then are present at birth but might not become manifest till in pediatric age group. –– Accumulation of metabolic products which are not toxic to the liver and thus do not impair critical liver functions. Various storage disorders are prime examples of this category. Here the liver may progressively enlarge due to accumulation of retained products and may show some mild enzyme elevation but there may not be any critical liver function derangement. There is one more category, disorders of bilirubin metabolism, where there could be presence of jaundice from birth, but it is not detrimental to the liver. Crigler-­ Najjar syndrome, Dubin Johnson syndrome, and Gilbert syndrome are some of the disorders in this category. So Categories 1 and 4 would be present in neonatal period, but categories 2 and 3 would only be present later on and strictly not the cause of neonatal jaundice. This understanding is crucial as it is often seen that Ceruloplasmin is requested in a case of neonatal jaundice!!

Neonatal Jaundice

Infection from mother

Structural defects

Inborn metabolic diseases

Yet unknown

TORCH

Extra Hepatic

Galactosemia

Idiopathic Neonatal

Hep B

Biliary Atresia

Tyrosinemia

Hepatitis

Hep C

Syndromic

Mitochondrial diseases

Syphills

Bile duct paucity

Glycogen storage diseases Others

HIV

Choledochal cysts

others

Parvo virus

Spontaneous perforation of bile duct

1.2  Neonatal and Pediatric Liver Diseases Are Different from Adult Liver Diseases…

5

Does Neonatal Jaundice from Diverse Etiologies Be Present in the Same Way? From the above discussion, you will agree with me, that the answer is no! The above conditions do not present homogenously. There are distinct patterns, which, if recognized, allow you to narrow down your differential diagnosis further. Important features you should look for, to easily differentiate the various causes of neonatal jaundice are: • Conjugated or unconjugated hyperbilirubinemia? • Sick child or non-sick child? • Persistently creamy stool from birth or intermittently creamy or yellow stool from birth? • Presence of other organ damage? • History of fetal insult during pregnancy? • Timing of onset of jaundice? These points are of extreme importance for general pediatricians and should be answered in every case. If you do not pay attention to these points mentioned above, your and your patients’ life may become measurable later on! I will discuss this in more detail as we go along. • Conjugated and unconjugated hyperbilirubinemia are two entirely different entities and therefore this has to be differentiated at the beginning itself. • Sickness: If the liver is grossly damaged or if the underlying metabolic abnormality occupies a strategic place in metabolic pathway, the neonate becomes sick. How to recognize sickness? You may ask me…. Features of sicknesses are: • Irritability, lethargy, drowsiness, coma, refusal to be fed, failure to thrive. • Gross metabolic disturbances in the form of acidosis, alkalosis, hypoglycemia, hyperammonemia, and renal failure. • Respiratory distress and apnea. • Evidence of decompensation like edema, ascites, and persistently elevated prothrombin time. If these are present then almost certainly the neonate has metabolic liver disease.

6

1  Neonatal and Pediatric Liver Diseases

Conjugated hyperbilirubinemia

Sick child

Fulminant or Hyperacute

Subacute onset with progression

onset and relentless progress with metabolic

Galactosemia

disturbances and liver failure

Tyrosinemia

Child not sick

Persistantly pale stool

Intermittent pale and yellow stool

Persistantly collapsed GB

GB visualized

CBD not Visualized

CBD visualized

EHBA very likely

EHBA very unlikely

Fatty acid oxidation disorders Mitochondrial liver diseases

Urea cycle disorders

Zellweger’s syndrome

Hereditory Fructose intolerance

Neonatal hemochromatosis

(if fructose is introduced in diet) TORCH, Alagille syndrome

Herpes simplex hepatitis

Idiopathic neonatal hepatitis etc

• Stool color: Again, this is basic but people do not pay attention to this simple observation!! Biliary atresia should produce persistently creamy stool. It may or may not be from birth, but once it takes pale color there is no way you would see yellow color again and in my experience at this point, you will be able to rule in or rule out EHBA. In severe cholestasis, you may still get creamy stool but more often than not you will get history of yellow stool for a period before creamy stool or intermittently yellow and creamy stool; when we hear this we have never found biliary atresia. • Multiorgan involvement would suggest either genetic or infective etiology. • Fetal insult during pregnancy: This could be in the form of IUGR, prematurity, or oligohydramnios. This favors mostly neonatal hemochromatosis if subsequently the newborn has liver involvement. • Timing of development and progress also gives you an important clue as to the underlying etiology: • Onset during the first few days of life with evidence of sickness or decompensation: Jaundice may be present at birth or develops soon after. Here hepatomegaly may or may not be very prominent and splenomegaly also may not be present initially because there is no enough time for them to get enlarged, but there is moderate-to-­ severe hepatocellular dysfunction. Usually, but not always, this is due to metabolic disease. Common metabolic conditions seen in India are: • Galactosemia: There is progressive hyperbilirubinemia; initially even unconjugated hyperbilirubinemia may be seen. There may be hemolytic anemia and sepsis, especially with Escherichia coli. Cataract may form if the course of the disease is not very fast although it is not very common in our practice.

1.2  Neonatal and Pediatric Liver Diseases Are Different from Adult Liver Diseases…

7

• Hepatorenal Tyrosinemia: Prominent coagulopathy and very high alpha-­ fetoprotein. Succinyl acetone in urine is diagnostic. • Neonatal hemochromatosis: Severe hepatocellular dysfunction, high ferritin, and high transferrin saturation. IUGR may be present. • Peroxisomal disorders: Developmental delay, failure to thrive, seizures, hypotonia. • Mitochondrial disorders: Severe Hepatocellular dysfunction, myopathy, lactic acidosis, and multisystem involvement. • Onset during first few days of life without evidence of sickness or decompensation: Here obviously the tempo of development of jaundice is slower and the child may remain reasonably well with only mild failure to thrive and none of the other features of sickness. Decompensation does occur but it is a late feature. Here: • It is usually hepatosplenomegaly. • Associated cardiovascular or nervous system or hematological involvement may be present. Examples in this category are: 1 . Extra-hepatic biliary atresia (EHBA). 2. Neonatal Idiopathic Hepatitis. –– Alagille syndrome or non-syndromic bile duct paucity. –– Choledochal cysts. –– Onset later in infancy or early childhood or pediatric age: –– Here hepatocellular dysfunction may or may not be severe but Hepato+/− splenomegaly may be prominent. –– Hereditary fructose intolerance (HFI): Appears with introduction of fructose, usually around 6 months of age. The patient may have hypoglycemic attacks, lactic acidosis, and hyperuricemia. –– GSD type-III: Skeletal myopathy and moderate hepatomegaly. –– Gaucher type III: Massive hepatosplenomegaly. –– Wilson’s disease: Hemolysis and cirrhosis. –– Niemann-Pick type-III: Hepatosplenomegaly and neurodegenerative diseases. –– Carnitine Palmitoyl Transferase-I (CPT-1) deficiency: Hypoketotic hypoglycemia and elevated plasma carnitine levels. Remember this classification if you are a general pediatrician as it helps in narrowing down your differential diagnosis significantly and scarce resources are better targeted. Moreover, if the patient moves to the higher center, they will make a mental note that the person looking after this patient has some logic!! So, what appears confusing initially should become clearer to you now.

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1  Neonatal and Pediatric Liver Diseases

Summary So let us go through this again; while trying to make some sense in a case of neonatal jaundice some important points you may want to know are: • Find out if hyperbilirubinemia is conjugated or unconjugated. • Any rise in conjugated bilirubin, more than 2  mg, is suggestive of liver parenchymal disease. • Always obtain alkaline phosphatase (ALP), Gamma GT (GGT), prothrombin time, and serum albumin and globulin to get an idea about the extent of liver failure. • Very high ALP suggests cholestasis. But remember, ALP could also be coming from bone, especially with prolonged cholestasis resulting in vitamin D deficiency, producing rickets. In such circumstances, GGT could help. GGT will only be raised in liver diseases and not in bone diseases. • Significant parenchymal disease will always be accompanied by anorexia, nausea, vomiting, and failure to thrive; the severity will be dependent on the severity of the liver illness. • Purely mechanical cause of jaundice, as in Extra Hepatic Biliary Atresia (EHBA), will rarely produce anorexia, nausea or vomiting. There will not be any major failure to thrive. • Ascites, gross metabolic disturbances or more broadly speaking, decompensation early on in the disease history, is highly suggestive of metabolic disease of the liver. All structural diseases like extra hepatic biliary atresia or bile duct paucity syndrome, etc. will produce late decompensation. • Large molecule diseases or storage diseases, as they are popularly known, may produce impressive hepatomegaly but may not produce disturbances in critical functioning of the liver and usually liver function tests show mild abnormality only. • Any sepsis associated with liver failure must alert you to the possibility of Galactosemia. But do remember, sepsis could cause cholestasis or inflammation, which disappears with infection. • Changing color of stool from creamy to yellow generally goes against biliary atresia, where there is constant creamy stool. In such cases cholestasis is a strong possibility. • Associated cardiac, neurological, or ocular symptoms narrow down the possibility to a few diseases like Alagille syndrome, toxoplasma, rubella, cytomegalovirus infection, etc.

1.3  Liver Function Tests

9

Neonatal jaundice Unconjugated Evidence of hemolysis?

Conjugated

No Evidence of hemolysis

Stool + USG for GB and

Lap cholangiogram with

biliary tree on fasting state

possibility of Kasai’s portoenterostomy

Falling Hb

Prematurity

High retics

Physiological jaundice

High lactate

Breast milk jaundice

Look for Rh incompatibility

PERSISTENTLY

GB collapsed and CBD not

Biliary atrsia very very

CREAMY

detected

likely

Involve pediatric hematologist

INTERMITTENT

GB normal and CBD

Biliary atresia unlikely to

CREAMY AND

identified

very unlikely

YELLOW

Follow next algorithm

Non sick child Stool persistanly creamy

Stool intermittently or persistantly yellow

Ultrasonography

Ultrasonography

Non visualization of CBD with collapsed GB

Persistanly collapsed GB and bile ducts not

EHBA

Bile duct and GB normal looking

Bile duct abnormality Surgical opinion if appropriate

visualized repeatedly TORCH

Operative

Liver biopsy

cholangiogram with preparation to

Bile salt disosrders

Viral titres

Suggestive

Not suggestive of EHBA

Coxsackie

TMS

Parvo virus Citrin deficiency

Urine organic acid

of EHBA

or specific abnormality found

Milder versions of

Liver biopsy

Galactosemia, Tyrosinemia,

Eye check up

Fatty acid oxidation

2 D ECHO

disorder, Urea cycle

X ray spine

proceed for Kasai’s portoenterostomy

Allagille

No EHBA

GAL1T

disorders

1.3

Liver Function Tests

These are a set of biochemical parameters used to identify and characterize the type and extent of the liver damage. They are broadly classified as structural/ non-­synthetic and synthetic functions. Anatomical functions generally define the type of injury and synthetic functions generally define the severity of the damage. Prothrombin time and albumin are the most crucial synthetic functions.

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1  Neonatal and Pediatric Liver Diseases

Non-synthetic or structural functions: • The aminotransferases include ALT/SGPT and AST/SGOT. –– ALT is a cytosolic enzyme, whereas AST is present as both cytosolic and mitochondrial isoenzyme, therefore ALT is more specific of the two. Elevation suggests liver parenchymal damage, more specifically in case of ALT. –– Rarely, as in myositis elevation of both AST and ALT may reflect muscle disease or injury. –– AST/ALT ratio may be useful in differential diagnosis. In most forms of acute liver injury, this ratio is less than or equal to 1, but in acute Wilson’s disease and alcoholic hepatitis the ratio is characteristically >2. In nonalcoholic steatohepatitis (NASH), the AST/ALT ratio is almost always less than or equal to 1 in the absence of cirrhosis. –– The degree of elevation correlates poorly with the extent of hepatocyte necrosis and has no prognostic value on its own. –– A rapid fall in levels in association with a rising bilirubin and prothrombin time suggests a poor prognosis in patients with acute liver failure. –– Levels are frequently normal or nearly normal in patients with advanced cirrhosis in the absence of significant ongoing liver injury. –– Uremia gives falsely a lower serum AST concentration. • Alkaline Phosphatase: Bone and liver are the major sources of serum Alkaline Phosphatase (ALP). –– Levels of ALP up to three times normal are relatively nonspecific and occur in various liver diseases. –– Striking elevations of ALP are seen predominantly with infiltrative hepatic disorders or biliary obstruction, either within the liver as in bile duct paucity syndromes or in the extrahepatic biliary tree as in atresia or Choledochal cyst. Granulomatous liver diseases including tuberculosis could produce disproportionately raised ALP. • Gamma Glutamyl Transpeptidase: –– As it is not found in appreciable quantities in the bone, it is helpful in confirming the hepatic origin of an elevated AP level. • Bilirubin: –– Unconjugated/indirect hyperbilirubinemia results from either increased bilirubin production due to hemolysis or inherited or acquired defects in hepatic uptake or conjugation, e.g., Crigler-Najjar syndrome or Gilbert’s syndrome. –– Conjugated/direct hyperbilirubinemia occurs as a result of inherited or acquired defects in hepatic excretion.

1.4  Investigating a Case of Neonatal Jaundice

11

Synthetic liver functions: • Prothrombin time (PT): –– It is vitamin K dependent and disturbed in vitamin K deficiency. –– It is a sensitive test for the severity of liver damage provided that there is no vitamin K deficiency. Progressively increasing PT with falling ALT is a bad prognostic sign. • Albumin: –– It reflects liver functioning and decreasing level is a bad prognostic sign provided there is no leak as in nephrotic syndrome or dietary deficiency.

1.4

Investigating a Case of Neonatal Jaundice

1.4.1 Suggested Protocol Unconjugated hyperbilirubinemia: • • • • • • • •

Hb. Reticulocyte count. If evidence of Hemolysis then hemolysis screen. Urine routine, microscopy, and culture. *Reducing substances in Urine. *Glucose and total galactose. *Neonatal TSH. *Marked etiologies can rarely be present with unconjugated hyperbilirubinemia.

Workup of Unconjugated Hyperbilirubinemia Evidence of hemolysis?

• Falling HB • High reticulocyte count • High LDH

No hemolysis?

• Prematurity • Physiological • Breast milk jaundice • Criggler Najjar syndrome

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1  Neonatal and Pediatric Liver Diseases

Unconjugated Hyperbilirubinemia In neonatal age: Physiological jaundice; should disappear after a week Breast milk jaundice; child is thriving well and when breast milk is interrupted there is rapid clearance Criggler Najjar syndrome; depending upon the enzyme deficiency, bilirubin could be moderately raised to very high and there may be failure to thrive. Interrupting breast feeding will not produce any significant decrease. In Adults: Hemolysis or ineffective erythropoesis; Hb is low or falling and high reticulocyte count. Gilbert’s syndrome; seen in around 5% of the population. LFTs are normal and so is CBC. Increase with fasting or illness.

Conjugated Hyperbilirubinemia The following steps help you to select investigations: • Color of stool you yourself see? • Is there a reducing substance, other than glucose, in urine? Are there any ketones in urine? • Any evidence of decompensation, i.e., ascites, edema feet, and uncorrectable coagulopathy. • What do the gall bladder and other biliary structures look like in a 4-h fasted child? If the gall bladder is collapsed on two properly done sonographies and stool is creamy from birth, consider biliary atresia. Proceed for liver biopsy and HIDA scan. Or proceed for laparoscopic liver biopsy and operative cholangiogram. If the gall bladder is collapsed but the stool color keeps changing or is not creamy from birth, then consider severe cholestasis. If this is associated with recurrent sepsis or hepatocellular dysfunction, presume that the patient has Galactosemia and stop Galactose till the diagnosis is refuted. Once these two diagnoses are ruled out consider: • TORCH titer and neonatal TSH and all other tests. • If this is negative we go for a detailed metabolic work-up. This will require urine metabolic screening and TMS blood. • Liver biopsy may be very useful, if you have a very experienced pathologist, if you take adequate samples and you have the means to do enzyme studies in the biopsy sample. Most of the places have neither of the three and hence the patient may not benefit from liver biopsy as expected.

1.6  Basic Understanding of Inborn Errors of Metabolism and Metabolic Disorders

1.5 • • • • • • • • •

13

 reatment in the Case of Conjugated T Hyperbilirubinemia till a Definitive Diagnosis Is Made

Avoid lactose-containing products. IV/oral dextrose, if vomiting or failure to thrive is significant. Blind antibiotics. Ursodeoxycholic acid 20–25 mg./Kg. IV vitamin K. Fat-soluble vitamins. Oral calcium. High-calorie diet. Oral phenobarbitone 3–5 mg./Kg. till decision to do HIDA scan is made.

Evidence of hemolysis? • could start early in neonatal period and worsen further but worsen at a slower rate than metabolic diseases. • liver may be enlarged • spleen is late to enlarge • apart from jaundice, the patient may not have any other symptoms • coagulopathy is correctable with vitamin K • Decompensation is late in the history of illness • in many instances sonography is diagnostic

1.6

No hemolysis? • could start very early in neonatal period and worsen further • liver may be enlarged • spleen may or may not be enlarged • there may be failure to thrive and other systemic symptoms • coagulopathy may not be correctable with vitamin K • Decompensation may be early in the disease history • Sonography is not diagnostic

 asic Understanding of Inborn Errors of Metabolism B and Metabolic Disorders

1.6.1 Introduction What Is Inborn Errors of Metabolism and Metabolic Diseases? To sustain the process of evolution, a living cell or an organism, has to devise ways to survive and progress to its potential and beyond. It has to adapt to its environment, get nutrition from it, and dispose of the waste. This basic process is called “metabolism.” It has to remember the pathways taken to carry out the metabolism and remember how to synthesize the necessary chemicals, the enzymes, and their facilitators, so that its progeny does not have to “reinvent the circle” and could move “beyond.”

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1  Neonatal and Pediatric Liver Diseases

This is achieved by incorporating requisite information in the “genetic code,” which is copied faithfully down the generations. Only infrequently, this code is defectively copied and things go haywire. In clinical terms, we call this phenomenon as “mutation” and the resultant effect on a living being as metabolic or genetic disorder. Thus, metabolic process starts from conception, to development of a life form, to being able to carry out all the functions of survival, right from breaking down the “essential life sustaining nutrients” to ultimately its safe disposal. If this “chain” is broken, there is accumulation of chemicals, “metabolites,” before the “obstacle,” and lack of “downstream” metabolites. The upstream metabolite/s may find an alternative way to “by-pass” the block, or may keep on accumulating producing a disease. The failure to complete the chain reaction could have a minimal effect or it could have devastating effects on the smooth functioning of a life form or even its death. It all depends upon the “position” of that particular “chain” in the “global” functioning of a cell/life form. What are “small molecular and large molecule” diseases? The level at which there is a block decides if the accumulated metabolite is small or large. Depending upon the size of the accumulated metabolite, we label the disorders as a “small molecule disorder” or a “large molecular” disorder. Generally, as a reader would expect, earlier the block in the chain reaction, smaller is the size of an accumulated metabolite. As you move down the chain, the size of the molecule gets bigger and nearer the “disposal” of the molecule as a waste (lysosomal storage disorders) or accumulation as a storage material (glycogen), larger is the size of the molecule. Of course, there are plenty of exceptions, for example, if glycogen has a problem with breaking down, then obviously earlier the block, larger is the upstream molecule. By and large, the large molecule disorders cause physical problems due to their sheer size, on top of other biochemical problems. Why Should we Bother to Look for these Diseases? Recent advances in the diagnosis and treatment of inborn errors of metabolism have improved substantially due to newer investigating modalities, like tandem mass spectroscopy and molecular genetics, and increased awareness; and consequently the prognosis for many of these conditions has improved significantly and still will continue to improve to an extent that these diseases could be cured in foreseeable future with the advent of molecular genetics. This makes it essential that the practicing pediatrician is familiar, at least, with the clinical presentation of these disorders. A clinical approach to the recognition of IEM in the young infant, even at a rural level with very basic facilities available only, is presented in this book. Indications for specific laboratory studies are discussed. Guidelines are provided for the stabilization and emergency treatment of critically-ill infants till they are safely taken to a competent center specializing in this field. This approach will identify those infants who will benefit from additional evaluation and specific treatment.

1.6  Basic Understanding of Inborn Errors of Metabolism and Metabolic Disorders

15

What Are the Common Metabolic Markers? • Many of the inborn errors of metabolism, including organic acidemia, urea cycle defects, and certain disorders of amino acid metabolism, present in the young infant with symptoms of an acute or chronic metabolic encephalopathy. Typical symptoms include: Lethargy. Poor feeding and failure to thrive. Apnea or tachypnea. Recurrent, unexplained, and vomiting. Metabolic acidosis and/or hyperammonemia are observed in many of these conditions. Therefore, appropriate laboratory testing for metabolic disorders should be performed in any infant who exhibits these findings. Although sepsis may be the initial consideration in a neonate with these symptoms, inborn errors of metabolism should always be in the differential diagnosis, particularly in a full-term infant with no specific risk factors. • Hypoglycemia may be the predominant finding in a number of inborn errors of metabolism, including glycogen storage disorders, defects in gluconeogenesis, and fatty acid oxidation defects. The latter disorders, among the most commonly encountered, exhibit marked clinical variability and also may present as a sudden death, a Reye’s-like episode, or a cardiomyopathy. • Jaundice or other evidence of hepatic dysfunction is the mode of presentation of another important group of inborn errors of metabolism including Galactosemia, hereditary tyrosinemia, neonatal hemochromatosis, and a number of other conditions. • A subset of lysosomal storage disorders may be present very early with coarse facial features, organomegaly, or even hydrops fetalis. Specific patterns of dysmorphic features and congenital anomalies characterize yet another group of inherited metabolic disorders, such as Zellweger syndrome and the Smith– Lemli–Opitz syndrome. Each of these symptom complexes, and the appropriate evaluation of the affected infants, is discussed in more detail in this review. • • • • •

The number, complexity, and varied clinical presentation of inborn errors of metabolism present a formidable challenge to the practicing pediatrician. Yet, in many cases, prevention of death or permanent neurologic sequelae in patients with these disorders is dependent on early diagnosis and institution of appropriate therapy irrespective of underlying etiology. It is therefore a must for the pediatrician to be familiar with the major signs and symptoms of inborn errors of metabolism and with the basic laboratory studies necessary to arrive at an initial diagnosis. Although a pediatrician may rarely be the sole provider of long-term care to these patients, he may well be responsible for the emergency care and stabilization of the infants and children affected and should be familiar with the fundamental aspects of such care.

16

1  Neonatal and Pediatric Liver Diseases

Clinical Presentation of IEM 1. Acute metabolic encephalopathy. 2. Vomiting. 3. Acid–Base imbalance. 4. Hypoglycemia. 5. Jaundice. 6. Hepatosplenomegaly. 7. Respiratory distress or apnea. 8. Abnormal odor. 9. Dysmorphic features. 10. Abnormal eye findings. Let us look into these in little more detail. 1. Acute Metabolic Encephalopathy: • Several groups of inherited metabolic disorders, most notably the organic acidemia, urea cycle defects, and certain disorders of amino acid metabolism, are typically present with acute life-threatening symptoms of an encephalopathy. • Because most of these metabolites cross the placenta and are cleared by the mother during gestation, affected infants usually appear normal at birth. • The interval between birth and onset of clinical symptoms ranges from hours to months. • The initial findings are usually those of lethargy and poor feeding, as seen in almost any sick infant. • Although sepsis is often the first consideration in infants who present in this way, these symptoms in a full-term infant with no specific risk factors strongly suggest a metabolic disorder. • Infants with inborn errors of metabolism may become debilitated and septic rather quickly, and it is therefore important that the presence of sepsis must ring alarm bells for underlying metabolic abnormality, especially if there is no definite focus or that the sepsis is a recurrent phenomenon. • If untreated, the lethargy associated with these conditions may progress into a coma. • Other signs of CNS dysfunction, such as seizures and abnormal muscle tone, also may be noted. Evidence of cerebral edema may be observed, and intracranial hemorrhage occasionally occurs. • An infant with inborn errors of metabolism who presents more abruptly or in whom the lethargy and poor feeding go unnoticed may first come to attention because of apnea or respiratory distress. • The apnea is typically central in origin and a symptom of the metabolic encephalopathy, but tachypnea may be a symptom of an underlying metabolic acidosis, as occurs in the organic acidemias. • Infants with urea cycle defects and evolving hyperammonemic coma initially exhibit central hyperventilation, which leads to respiratory alkalosis.

1.6  Basic Understanding of Inborn Errors of Metabolism and Metabolic Disorders

17

Important first-line investigations in metabolic encephalopathy: A. Ammonia: • Among the most important laboratory findings associated with inborn errors of metabolism presenting with an acute encephalopathy. • A significant hyperammonemia is observed in a limited number of conditions and urea cycle defects and many of the organic acidemia and fatty acid oxidation are at the top of the list. • Ammonia levels in newborns with these conditions frequently exceed 1000 μmol/L. • Marked Hyperammonemia provides an important clue to diagnosis and indicates the need for urgent treatment to reduce the ammonia level. • The degree of neurologic impairment and developmental delay observed subsequently in affected infants has been shown to be dependent on the duration of the neonatal hyperammonemic coma. • Transient hyperammonemia of the newborn (THAN) is a condition seen in the newborn for no obvious reason and subsides on its own. • High ammonia is also seen in liver disorders but here you should see abnormal liver functions like conjugated bilirubin, transaminases, and prothrombin time. Again in liver diseases, the level of ammonia is not in thousands but in hundreds and generally 2–5 times the normal amount. • The timing of the onset of hyperammonemic symptoms may provide an important clue. • Patients with some of the organic acidemia, such as glutaric acidemia type II or with pyruvate carboxylase (PC) deficiency, may exhibit symptomatic hyperammonemia during the first 24 h. Symptoms in the first 24 h also are characteristic of Transient Hyperammonemia of the Newborn, THAN, a condition that is poorly understood but apparently not genetically determined. The typical patient is a large, premature infant who has symptomatic pulmonary disease, often from birth, and severe hyperammonemia. The condition can occur in full-term infants, however, including those without respiratory symptoms. Survivors do not have recurrent episodes of hyperammonemia and may or may not exhibit neurologic sequelae, depending on the extent of the neonatal insult. Infants who develop severe hyperammonemia after 24 h of age usually have a urea cycle defect or an organic acidemia or liver failure; infants with organic acidemia typically exhibit a metabolic acidosis as well. Urine organic acid analysis should always be obtained, regardless of whether acidosis is present. Metabolic acidosis is not a typical feature of the urea cycle defects. Plasma amino acid analysis is helpful in the differentiation of the specific defects in this group. In addition, carbamyl phosphate synthetase deficiency and ornithine transcarbamylase (OTC) deficiency may be differentiated by measuring urine orotic acid, which is low in the former and elevated in the latter. Although the family history is often negative, a positive history of early male deaths or females with episodic

18

1  Neonatal and Pediatric Liver Diseases

illness in the family of a male infant with hyperammonemia suggests ornithine transcarbamylase deficiency, the only one of the urea cycle defects with a sex-linked mode of inheritance. HCO3 + NH4 + 2 ATP CPSI

N-acetylglutamate

Carbamyl Phosphate

Citrulline

Aspartate

OTC ASS1 Ornithine

Urea Cycle

Argininosuccinate

ASL Urea

ARG

Arginine

Fumarate

ASA argininosuccinic acid, CPS carbamyl phosphate synthetase, OTC Ornithine Trans Carbamoylase

• Less significant elevations of plasma ammonia than those associated with inborn errors of metabolism and THAN can be observed in a variety of other conditions associated with liver dysfunction, including sepsis, generalized herpes simplex infection, and perinatal asphyxia. Liver function studies should be obtained in evaluating the significance of moderate elevations of plasma ammonia. However, even in cases of severe hepatic necrosis, it is rare for ammonia levels to exceed 500 μmol/L. Mild transient hyperammonemia with ammonia levels as high as twice the normal is relatively common in the newborn, especially in the premature infant, and is usually asymptomatic. It appears to be of no clinical significance, and there are no long-­ term neurologic sequelae.

1.6  Basic Understanding of Inborn Errors of Metabolism and Metabolic Disorders

19

Ammonia Liver disease

O micromol/l

FAOD Organic acidemia

200

500

Urea cycle disorders

1000

Another way of practically narrowing down the differential diagnoses of hyperammonemia is as follows: • Very high: >10 ULN: Consider Urea cycle disorders, organic acidemia, and fatty acid oxidation disorders. • Mild to moderate with respiratory alkalosis: Consider urea cycle disorders. • Mild hyperammonemia with significant hepatocellular damage: Consider liver diseases. B. Metabolic Acidosis/alkalosis: The second important laboratory feature of many of the inborn errors of metabolism during acute episodes of illness is metabolic acidosis with an increased anion gap. Organic acidemias, including methylmalonic acidemia, propionic acidemia, and isovaleric acidemia are some of the very common inborn errors associated with overwhelming metabolic acidosis in infancy. • Apart from specific organic acid intermediates, plasma lactate often is elevated in organic acidemias. Neutropenia and thrombocytopenia are commonly observed and therefore could be easily confused with neonatal sepsis. Hyperammonemia, of varying degrees could also be seen. • Defects in pyruvate metabolism or in the respiratory chain/mitochondrial disorders may lead to primary lactic acidosis presenting as severe metabolic acidosis in infancy. Unlike most of the other conditions presenting acutely in the newborn, clinical features of these disorders are unrelated to protein intake. Measuring plasma pyruvate and calculating the lactate/pyruvate ratio helps in the differential diagnosis. A normal ratio (25) suggests PC deficiency, a respiratory chain defect, or a mitochondrial myopathy. Other tests may also be required if the suspicion of IEM is strong. Among them, the most common are amino acids and organic acids, analysis of which can be obtained in any part of the country through reference laboratories.

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1  Neonatal and Pediatric Liver Diseases

Emergency Treatment of the Infant with an Acute Metabolic Encephalopathy: • The immediate treatment of infants with disorders in this group has two primary goals. • The first is the removal of accumulating metabolites such as organic acid intermediates or ammonia. • At the first suspicion of a disorder associated with protein intolerance, protein intake should be discontinued immediately. • In critically ill infants with severe hyperammonemia, say  >  500  μmol/L, requires urgent hemodialysis. • In suspected urea cycle defect, an infusion of 6  mL/kg of 10% arginine HCL (0.6  g/kg) can be given intravenously over 90  min results in dramatic fall in ammonia levels in citrullinemia and argininosuccinic aciduria. • IV Sodium Benzoate and IV Sod Phenyl Butyrate are also extremely useful and are given at 250/kg/day as continuous infusion. Where IV preparation is not available, oral sodium benzoate at same dose may be tried. If an organic acidemia is suspected, vitamin B12 (1 mg) should be given hope that it could be a case of a B12-responsive form of methylmalonic acidemia. Biotin (10 mg) should be given orally or by Ryle’s tube because some patients with multiple carboxylase deficiencies are biotin responsive. • If acidosis exists, intravenous bicarbonate should be administered liberally. The acid–base status should be monitored frequently, with therapy adjusted accordingly. Dialysis should be considered for severely acidotic neonates with organic acidemias, regardless of whether hyperammonemia is present. • After removing toxic metabolites, the second major goal of therapy in infants with inborn errors of metabolism should be to prevent catabolism. • Intravenous glucose should be administered liberally to provide as many calories as possible. • Intravenous lipids can be given to infants with urea cycle defects and other disorders in which dietary fat plays no role. • Protein is started as soon as clinical improvement is observed even in absence of final diagnosis. Amino acid intake should be started after a maximum of 2 to 3 days of complete protein restriction. Essential amino acids or total protein can be provided orally or intravenously at an initial dose of 0.5 g protein/kg/24 h. This should be increased incrementally to 1.0 g/kg/24 h and held at that level until the diagnostic evaluation is complete and plans can be made for definitive long-term therapy.

1.6  Basic Understanding of Inborn Errors of Metabolism and Metabolic Disorders

21

2. Vomiting: • Vomiting is a striking feature of many of the inborn errors of metabolism associated with protein intolerance, although considerably less common in the newborn than in the older infant. • If persistent vomiting occurs in the neonatal period, it usually signals significant underlying disease. Inborn errors of metabolism should always be considered in the differential diagnosis. 3. Acid–Base disturbances: • Apart from metabolic encephalopathy, acid–base disturbance could be a feature of many metabolic diseases, like organic acidemia and urea cycle disorders. 4. Hypoglycemia: • Hypoglycemia and its associated symptoms are seen more commonly in disorders of carbohydrate metabolism or fatty acid oxidation. • Among the best known inborn errors of metabolism associated with hypoglycemia are the hepatic glycogen storage diseases (GSD) except type 2, Pompe disease. The hypoglycemia in these disorders is related to the inability of the liver to release glucose from glycogen, and it is most profound during periods of fasting. Hypoglycemia, hepatomegaly, and lactic acidosis are prominent features of these disorders. • Hypoglycemia is not a feature of GSD type II (Pompe disease). Clinical manifestations of this disorder include macroglossia, hypotonia, cardiomegaly with congestive heart failure, and hepatomegaly. Cardiomegaly is the most striking feature and may be apparent in the neonatal period. Congestive heart failure is the cause of death in most cases. • Hypoglycemia may be a prominent feature of both Galactosemia and hereditary fructose intolerance, although symptoms of the latter disorder occur only after fructose (sucrose) has been introduced in the diet. Fatty acid oxidation disorders are important cause of hypoglycemia. They are frequent but easily missed because of the variability of the initial presentation. Here there is an impaired capacity to use stored fat for fuel during periods of fasting once they have depleted glycogen stores. Despite the development of hypoglycemia, acetyl CoA production is diminished because of fatty acid oxidation defects, and impaired ketone production. The hypoglycemia occurring in these conditions is typically characterized as hypo/nonketotic. Hypoglycemia may occur as an isolated finding or may be accompanied by many of the other biochemical derangements typically associated with Reye syndrome, such as hyperammonemia, metabolic acidosis, and elevated transaminases. Hepatomegaly may or may not be present. Any infant presenting with findings suggesting Reye syndrome should be evaluated for fatty acid oxidation defects.

22

1  Neonatal and Pediatric Liver Diseases

• The most common of the fatty acid oxidation defects is medium-chain acyl CoA dehydrogenase, MCAD, deficiency. In addition to presenting as nonketotic hypoglycemia or a Reye’s-like syndrome, it may present as sudden death or an acute life-threatening event. Fat accumulation in the liver or muscle of any infant dying unexpectedly should suggest strongly the possibility of this or a related disorder of fatty acid oxidation. Very long-chain fatty acyl CoA dehydrogenase deficiency is associated with similar clinical findings, although there also may be evidence of cardiomyopathy. Infants with this and several other fatty acid oxidation defects may present with cardiac arrhythmias or unexplained cardiac arrest. The accumulation of fatty acyl CoA in patients with fatty acid oxidation defects leads to a secondary carnitine deficiency. Urine organic acid analysis, measurement of serum carnitine, and analysis of the plasma acylcarnitine profile are the most helpful laboratory studies in the initial screening for defects in fatty acid oxidation. Enzymatic assays may be necessary for the definitive diagnosis. As is true for the defects in carbohydrate metabolism leading to hypoglycemia, treatment of the fatty acid oxidation defects involves avoidance of fasting and provision of adequate glucose. Restriction of dietary fat intake and supplemental L-carnitine therapy is recommended.

Fatty acids Cell wall

FACS

CPT 1 Fatty acyl CoA

Acyl carnitine

FACS-Fatty Acyl CoA synthase CPT: Carnitine palmotyl transferase

CAT

Carnitine CTL

Acyl carnitine CPT 2

Cat=Carnitine acyl transferase

Fatty acyl CoA

CTL=Carnitine translocase

Acetyl CoA

Carnitine Mitochandria

Beta Oxidation

Understanding fatty acid metabolism is not at all difficult!! F or fatty acid to take part in energy production, it has to get converted in Acetyl CoA. it first gets converted in to fatty acyl CoA. Camitine takes it inside mitochondrion, that’s all. Once inside the mitochondrion, fatty acyl CoA gets converted, by beta oxidation in to Acetyl CoA, ready to participate in Krebs/TCA cycle.

1.6  Basic Understanding of Inborn Errors of Metabolism and Metabolic Disorders

23

Hypoglycemia - Some common metabolic conditions With Hepatomegaly Huge GSD Hypoglycemia could be severe;

Without significant hepatomegaly

mild to moderate FAOD Hypoglycemia with out or low ketonemia is the hallmark;

Doll like face;

With jaundice Galactosemia (classic)

Fructose intolerance (HFI)

Developes within few days Starts only after Fructose from birth introduction;

Lactic acidosis;

Jaundice and liver failure;

Early decompensation

Severe aversion to fruits;

Renal

Reye’s like syndrome;

Recurrent sepsis

Hyperuricemia

involvement (Type 1) Low carnitine; Abonormal acyl carnitine profile

Without structural or functional liver involvement

cataract

Persistent hyperinsulinemic

Insulinoma older age;

Hypoglycemia of infancy (PHHI).

Profound hypoglycemia

Profound hypoglycemia; Insulin levels high

Reducing substance in urine; Gal 1 T is absent

5. Jaundice and liver dysfunction: • Jaundice or other evidences of liver dysfunction may be presented in infancy. This could be due to a number of inherited metabolic disorders. Mostly the elevated serum bilirubin is of the direct-reacting type. Galactosemia is the best-known metabolic disease associated with jaundice. Jaundice and liver dysfunction in this disorder are progressive and usually appear at the end of the first or during the second week of life with vomiting, diarrhea, poor weight gain, and eventually cataract formation. Hypoglycemia may be observed. The disease may present initially with indirect hyperbilirubinemia resulting from hemolysis secondary to high levels of galactose-1-phosphate in erythrocytes. Alternatively, the effects of acute Galactose toxicity on the brain may rarely cause the CNS symptoms to predominate. Hereditary tyrosinemia is another common disorder. The biochemical hallmarks of this disorder include marked elevations of tyrosine precursors and generalized aminoaciduria with a disproportionate increase in the excretion of tyrosine. However, these findings are relatively nonspecific and may be observed as a secondary phenomenon in other forms of liver disease. Determination of succinylacetone in the urine is a gold standard diagnostic test for the disorder. • Neonatal hemochromatosis, an alloimmune disorder may be the most common cause of congenital cirrhosis. The definitive diagnosis is established by liver or

24

1  Neonatal and Pediatric Liver Diseases

lip biopsy or autopsy. Most infants affected succumb to the disorder during the early weeks of life unless the diagnosis is positively looked for and IV IgG is given. Iv IgG given during the later part of pregnancy prevents this disorder in the newborn. • Less common metabolic causes of neonatal liver dysfunction include: Niemann-Pick disease type C and GSD type IV. Infants with Niemann-Pick disease type C exhibit cholestatic jaundice that typically resolves by several months of age. They are then clinically normal for a period of months to years before developing findings of a degenerative neurologic disorder. Infants with GSD type IV accumulate an abnormal form of glycogen in the liver as a result of a deficiency of the glycogen branching enzyme. This leads to progressive cirrhosis and generalized hepatic dysfunction. Hypoglycemia is not a prominent feature as it is in some other forms of GSD. Zellweger syndrome, another cause of neonatal jaundice and hepatic dysfunction, is usually recognizable clinically because of the associated hypotonia and dysmorphic features. It is the prototype of the peroxisome assembly disorders and is associated with generalized peroxisomal dysfunction. Another disorder that may be associated with neonatal jaundice is 1-antitrypsin deficiency. Although Alpha-1- antitrypsin deficiency is very common in western countries, practitioners in India see it rarely and for practical purpose; this diagnosis must be kept last in the list. • In contrast to disorders in which there is an elevation of the direct-reacting bilirubin, a persistent elevation of indirect bilirubin beyond the limits of physiologic jaundice, without evidence of hemolysis, suggests the diagnosis of Crigler-Najjar syndrome. 6. Hepatosplenomegaly. • Many of the well-known lipid storage diseases do not typically present in early infancy. Among those that occasionally may be associated with hepatosplenomegaly in the first few months of life are GM1-gangliosidosis type I, Gaucher disease, Niemann-Pick disease, and Wolman disease. • The GSDs may be associated with hepatomegaly in the newborn period. Infants with the most common mucopolysaccharidoses, such as the Hurler and Hunter syndromes, uncommonly exhibit clinical abnormalities in the first few months of life. • Newborns with the typical features of these syndromes, such as coarse facial features, hepatosplenomegaly, skeletal abnormalities, and hernias, are more likely to have GM1-gangliosidosis or a mucolipidosis, such as I-cell disease. • If one of these disorders is suspected, urine screening tests for mucopolysaccharides and oligosaccharides should be performed. These can be helpful diagnosti-

1.6  Basic Understanding of Inborn Errors of Metabolism and Metabolic Disorders

25

cally, but negative results do not rule out the possibility of a storage disorder. In addition, false-positive mucopolysaccharide test results are commonly observed in neonates. The definitive diagnosis of most lysosomal storage disorders is made by appropriate biochemical studies on leukocytes or cultured skin fibroblasts. 7. Respiratory distress and apnea. • Could reflect underlying acid–base abnormality. 8. Abnormal Odor: • Abnormal body or urinary odor is an important but often overlooked clue to the diagnosis of several of the inborn errors of metabolism and may be the most specific clinical finding in these patients. • In the acutely ill infant with an abnormal odor, isovaleric acidemia, glutaric acidemia type II, and maple syrup urine disease are the most likely entities to be encountered. • In maple syrup urine disease, the urine has a distinctive sweet odor, reminiscent of maple syrup or burnt sugar. • The odor associated with isovaleric acidemia and glutaric acidemia type II is pungent and unpleasant and similar to that of sweaty feet. 9. Dysmorphic Features: • Inherited metabolic disorders may be associated with consistent patterns of birth defects, suggesting that metabolic derangements in utero may disrupt the normal process of fetal development. • Isolated malformations maybe even more commonly associated with inherited metabolic disorders than are specific malformation patterns. • Patients with nonketotic hyperglycinemia frequently have agenesis of the corpus callosum and may have gyral malformations related to defects in neuronal migration. • Agenesis of the corpus callosum also is seen in PDH deficiency. 10. Abnormal eye findings: Typically are associated with many of the inborn errors of metabolism, although they are not always found at the time of initial presentation. Cataracts may be observed in Galactosemia, Zellweger syndrome, Lowe syndrome, and a number of other conditions. Dislocated lenses, seen in homocystinuria, molybdenum cofactor deficiency, and sulfite oxidase deficiency, may be found as early as the first month of life and are an important clue to the diagnosis. Retinal degenerative changes are typical of the peroxisomal disorders and are observed in several other conditions as well. Other abnormalities that may be associated with inborn errors of metabolism include corneal clouding and congenital glaucoma. A careful eye examination by an ophthalmologist should be performed whenever an inherited metabolic disorder is suspected.

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1  Neonatal and Pediatric Liver Diseases

Samples Collection in Suspected Inborn Errors of Metabolism The following samples may be collected and stored: • Urine, frozen. • Plasma. • In specific cases, small snip of skin obtained using sterile technique and stored at room temperature or 37  °C in tissue culture medium, if available, or sterile saline. • With widespread availability of TMS and urine GC-MS by filter paper method, they should be obtained also. • Where relevant and possible liver biopsy frozen at 20 °C for subsequent biochemical studies and for routine histopathology and electron microscopy. • With advent of Next Generation Sequencing (NGS), it is now required to collect samples on filter paper for molecular work-up also. Increasing number of cholestatic and Hepatocellular disorders of liver are due to genetic disorders and NGS is expected to play an increasingly robust role in work up of all neonatal and pediatric jaundice of any variety. Summary of when to Suspect Metabolic Disorders in Pediatric Office Practice, and What to Do Once Detected? 1. Suspicion An important key to diagnosing an IEM is thinking about the possibility in the first place! The symptoms and signs of IEM are common and nonspecific: • Acute illness following a period of normalcy. (E.g., amino acidopathy, organic acidopathy, urea cycle disorders, Galactosemia, and hereditary fructose intolerance). • Severe metabolic acidosis. • Hyperammonemia. • Rapidly progressive encephalopathy of obscure origin. • Lethargy and coma. • Hypotonia, seizures (especially if hard to control), and intractable hiccups. • Apnea or respiratory distress. • Sepsis, particularly with Escherichia Coli. • Unusual odor. • Jaundice. • Dysmorphic features. • Organomegaly. • Positive family history or parental consanguinity.

1.6  Basic Understanding of Inborn Errors of Metabolism and Metabolic Disorders

27

Evaluation 1. History: The history largely focuses around the features that made you suspicious for an IEM. The neonate will often be well for 24 hours or more then decompensate. The slightly older infant may have had episodic problems associated with minor illnesses or might just have failure to thrive and developmental delay. The family history is very important but often not taken. Most IEM are autosomal recessive, so there may have been siblings with similar illnesses or deaths from “sepsis” or “SIDS.” The parents may be consanguineous or come from a genetic isolate such as a small village in a given geography. There are also X-linked, and mitochondrial inherited IEM, so a family history must include information about the mother’s siblings, their children, etc. A pedigree only containing nuclear family members is inadequate. 2. Physical Examination: The physical examination of patients with IEM is usually normal except for nonspecific findings such as lethargy, coma, apnea or hyperpnoea, seizures, and hypotonia. Physical findings that are important and will help to narrow the differential diagnosis include: • • • • • • •

Facial dysmorphism. Cataracts, retinopathy. Structural brain anomalies. Hypertrophic or dilated cardiomyopathy. Hepatomegaly. Multicystic dysplastic kidneys. Myopathy.

• Odor: An unusual odor can be particularly helpful in several disorders: • • • •

Musty = Phenylketonuria. Cabbage = Tyrosinemia. Burnt sugar/MAPLE SYRUP = Maple syrup urine disease. Cat urine  =  3-Methyl crotonyl CoA carboxylase or multiple carboxylase deficiencies.

Do you suspect metabolic disease? These are the initial screening tests you should be carrying out:

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1  Neonatal and Pediatric Liver Diseases

The initial evaluation of an acutely ill infant for an IEM should include: • CBC—Neutropenia is frequent in some organic acidemias. • Electrolytes, ABG—To evaluate for acidosis, respiratory alkalosis, and anion gap. • Glucose—Hypoglycemia is a feature of many IEM. • Ammonia*—Hyperammonemia is present in urea cycle abnormalities and some organic acidemias. • Uric acid—If neurologic abnormalities are present, low uric acid is suggestive for molybdenum cofactor deficiency. • Galactosemia screening tests. • Lactate, pyruvate*. • Plasma amino acids—1–2 ml of blood in heparin or EDTA tube, on ice, or by Mass spectroscopy–Mass spectroscopy (MS-MS/Tandem mass spectroscopyTMS). It is important to draw this while the patient is ill, not after treatment. If TMS is used it has the advantage that it requires only a drop of blood on the filter paper and it is useful in diagnosing organic acids, and fatty acid disorders also. • Urinalysis—The presence of ketones is unusual even in sick neonates and suggests an organic acidemia. Test for reducing substances should be performed, but should be interpreted carefully because of a high false-positive rate. –– Other useful tests include ferric chloride for ketoacids, positive in Phenylketonuria, Tyrosinemia, maple syrup urine disease, histidinemia, alkaptonuria, and in the presence of other substances such as acetoacetic acid, salicylates, phenothiazines, antipyrin, isoniazide, and acetaminophen, and a cyanide nitroprusside test for disulfides, positive in cystinuria and homocystinuria. –– Urine organic acids by Gas chromatography-Mass spectroscopy (GC-MS). 10–20  cc of urine, frozen. It is important to obtain this sample when the patient is ill. This is now done on filter paper also. This, if passes through the test of time, will make do without immediately freezing urine. –– Numerous other specialized tests are performed depending on the clinical context. Examples include carnitine, acylcarnitines, very long chain fatty acids, and lysosomal enzymes. Definitive Diagnostic Tests • A definitive diagnosis may sometimes be made from screening tests but often specific enzymatic analysis or DNA testing is required. • It may be necessary to biopsy tissues such as liver or muscle. • These tests, if done at all, are usually done in research laboratories and it may take several weeks for results. After you have sent the initial screening tests, you need to sort out the type of IEM you may be dealing with. The categories of IEM that may be present in the neonatal period include:

1.6  Basic Understanding of Inborn Errors of Metabolism and Metabolic Disorders

• • • • • • • • • • • • •

29

Organic acidemias. Amino acidurias. Urea cycle disorders. Glycogen storage. Lysosomal storage. Peroxisomal disorders. Fatty acid oxidation disorders (FAOD). Mitochondrial defects in energy generation. Galactosemia. Nonketotic hyperglycinemia. Molybdenum cofactor deficiency. Menke’s disease. Lowe’s syndrome.

Do all these intimidate you?? Not to worry!! For general pediatricians, this difficult looking list can be simplified to disorders presenting with: • Hypoglycemia: Consider GSD, Fatty Acid Oxidation Disorders (FAOD), Hereditary Fructose Intolerance (HFI), Galactosemia. • Increased anion gap metabolic acidosis: Consider organic acidopathy, lactic acidosis, and ketoacidosis. • Prominent jaundice with or without evidence of decompensation. Consider galactosemia, FAOD, Tyrosinemia. • Hyperammonemia without acidosis or with respiratory alkalosis: Consider urea cycle disorder. And with acidosis consider organic acidemia and FAOD. • Prominent neurologic features. Consider Menke’s Lowe’s and Molybdenum cofactor deficiency. • Dysmorphic features: Consider lysosomal storage disorders. Beyond these, they may be referred to expert metabolic unit. It is important to realize that all medical algorithms are imperfect and vary somewhat depending on individual expertise and available resources both from laboratory point of view and financially from patient’s point of view. But the disease does not recognize whether you are a general pediatrician or a metabolic specialist! So you must have a working knowledge of primary treatment, which could allow the patient to be transferred to an appropriate center. Treatment at General Pediatrician Level The basic principles for treatment of the acute inborn errors are: • Prevent catabolism—The dietary intake of offending substances is usually a small fraction of the amount contained within the body. Since cellular proteins turnover about every 24 h, an increase in catabolism due to stress from infection, surgery, birth, etc. can rapidly overwhelm the compensatory mechanisms and result in clinical decompensation. Administration of calories is used in the treat-

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ment of acute episodes to try to slow down catabolism. A poor intake of calories can contribute to poor metabolic control just as much as an excessive intake of the offending substance. We use IV dextrose as it does no harm whatever the underlying pathology and helps most of the patients. • Limit the intake of the offending substance—If possible, through manipulation of the diet. Limit protein in urea cycle disorders, fatty food in FAOD. • Increase excretion of toxic metabolites—By using alternative pathways. For example, carnitine is useful in the elimination of organic acids in the form of carnitine esters. Sodium benzoate and phenylacetate are useful in treating hyperammonemia. • Increase the residual enzyme activity (if possible)—This is usually accomplished by administration of pharmacologic doses of the vitamin cofactor for the defective enzyme. Specific Treatment The specific treatment provided depends a lot on the particular disorder. It may be left to the specialist who has the core competence to treat such cases. Genetic Counseling Since IEMs are hereditary in nature, the family should have formal genetic counseling including prognosis of the patient, recurrence risk, possibility of prenatal diagnosis, and screening of other family members (if appropriate). Female carriers of X-linked recessive disorders may be at risk for milder forms of the same disease afflicting their sons. Let us solve some real-life cases that will make you start thinking and linking these disorders!!

1.7

 ext Generation Sequencing in Neonatal, Infantile N and Pediatric Liver, and Metabolic Diseases

A large number of cases of neonatal and infantile liver disorders of both hepatocellular and cholestatic varieties result from Monogenic Disorders. Recent advances in molecular genetics; particularly Next Generation Sequencing (NGS) has revolutionized diagnosis of Monogenic Disorders (MD) bringing clarity in management of these disorders. We find early use of Next Generation Sequencing to be very useful in diagnostic algorithm of these disorders for its diagnostic accuracy and cost and time effectiveness. Neonatal jaundice could of hepatocellular variety or of cholestatic variety. Hepatocellular type of Neonatal liver disease is defined as “transient or progressive hepatocellular injury of any etiology”; and Neonatal liver failure can be defined as “failure of the synthetic function of liver within 4 weeks of birth.” Neonatal cholestatic disorders are defined as “Impairment of bile flow, without any significant hepatocellular injury.”

1.7  Next Generation Sequencing in Neonatal, Infantile and Pediatric Liver…

31

We describe utility of NGS in hepatocellular and cholestatic types of liver disorders at our institute. NGS in Hepatocellular Liver Injury in Neonatal Period In neonatal age group traditional infective etiology like Hepatitis A to E type viral hepatitis, is distinctly uncommon. In our own center providing secondary and tertiary care for this condition, we rarely see them. Cytomegalovirus (CMV) hepatitis is seen infrequently and Herpes Simplex Viral (HSV) hepatitis rarely. In this context, we focus on metabolic disorders and their corresponding MD aggressively. Improved understanding and treatment of metabolic diseases and improving liver transplantation facility with state support, demands an early and definitive diagnosis of these conditions to allow effective and timely intervention preventing irreversible damage and where required timely liver transplantation. We use a two track protocol to proceed in such cases where possibility of using Next Generation Sequencing (NGS) is taken in to account right at the beginning. What Is Next Generation Sequencing (NGS)? NGS is an advance technology to identify a large number of MDs; it is very practical, reliable, fast, and cost effective. It is increasingly used in early diagnosis of monogenic liver diseases in neonatal and pediatric age group. This assumes importance for the fact that nearly half of the children with chronic liver disorders have a genetic cause and approximately 20% of pediatric liver transplantations are performed in children with MDs. Here NGS offers the opportunity to significantly improve the diagnostic yield. As further refinement of the NGS, geographically defined targeted gene panels have been devised and this helps to rapidly and reliably confirm a clinical suspicion. Targeted NGS is thus a game changer in discriminating various neonatal/infantile cholestatic disorders, unravel genetic causes of acute liver failure, and diagnose the subtype of inborn errors of metabolism presenting with a similar phenotype, e.g., glycogen storage disorders. If targeted gene panels are devised for a given geography, the whole exome sequencing (WES) is then used only in unclear clinical scenarios. WES detects a large number of variants of unknown significance, which at times is confusing. In summary, NGS used optimally, helps to unravel the underlying MD causing neonatal hepatic injury or cholestasis; reliably and quickly. Protocol for Hepatocellular Injury Hepatocellular type of neonatal liver diseases are classified according to the time of onset, severity at presentation, and rapidity of progress and associated physical and laboratory features. Scenario 1: Some etiologies, metabolic or otherwise are so gross that it may affect the fetus and this may manifest in the form of intra uterine growth retardation (IUGR). Common examples are mitochondrial disorders and neonatal

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1  Neonatal and Pediatric Liver Diseases

hemochromatosis (NH), the latter being not a genetic but an alloimmune disorder. Neonates with these etiologies become very ill with liver disease very soon after birth. Similarly, HSV hepatitis also progresses very fast and if HSV hepatitis or NH or any other non-metabolic disorder is suspected, investigations are carried out accordingly. Metabolic work up is not started then. If it is not the case metabolic work up is started with biochemical tests describe below and suitably modified Targeted Gene panel. Scenario 2: In some metabolic disorders like Galactosemia, Tyrosinemia, or fatty acid oxidation disorders (FAOD) neither there is any intrauterine event nor liver disease is present at birth, because the fetus and the newborn are protected by the mother, so they appear comparatively late in neonatal or infantile period and the progression is not catastrophic like previously described, but nevertheless fairly acute. Keeping these both patterns in mind we use an algorithm which is fast, accurate, and cost effective. First step in our approach is history of consanguinity and family history of similar liver disease in siblings, and any antenatal danger signals like IUGR. This acts as an alert for subsequent testing and selecting targeted gene panel. Onset of jaundice, its progression and severity and associated abnormalities are ascertained. Next step includes laboratory tests, which generally accompany metabolic liver diseases. These are basic tests (Table 1.1) and some specialized tests (Table 1.2). They are included based on prevalence of various metabolic disorders in our geography. Results of the tests mentioned in Table 1.1 are available within 12 h, providing vital clue to the underlying problem and treatment could start at this point. Simultaneously we also do the tests mentioned in Table 1.2. Results of the tests mentioned in Table  1.2 are available between 48 and 72  h. If succinyl acetone is positive, we start process to procure its treatment. If Galactosemia is confirmed, lactose-free formula is started. Similarly Acyl Carnitine profile and TMS may hint at the possibility of FAOD and Mitochondrial disorders. Table 1.1  Common biochemical tests Test Low blood sugar

Relevant metabolic disorder Galactosemia, mitochondrial disorders, fatty acid oxidation [email protected] (FAOD), hereditary fructose intolerance*(HFI)

Moderate to severe hyperammonemia

Urea cycle disorders (UCD) or organic acidemia

Metabolic acidosis with anion gap Prolonged Prothrombin time/ INR LDH

Mitochondrial disorders, organic acidemia, FAOD Any liver disease

High in mitochondrial disorders

Comments @urine tested simultaneously shows no or very low ketones, Reye’s like phenomenon *only if fructose is introduced in diet Liver functions are not critically deranged, respiratory alkalosis in UCD Multisystem involvement in mitochondrial disorders In tyrosinemia, it is difficult to correct even with plasma Multisystem involvement

1.7  Next Generation Sequencing in Neonatal, Infantile and Pediatric Liver…

33

Table 1.2  Special tests Tests Tandem mass spectroscopy with acyl carnitine profile Galactose-1-transferase Urinary organic acids with gas chromatography-mass spectroscopy (GC-MS)

Relevant metabolic disorder Tyrosinemia, urea cycle disorders, and FAOD Classic Galactosemia Tyrosinemia and organic acidemia

Comments Gives good idea about FAOD and also points toward UCD and Tyrosinemia Reduced or absent Urinary succinyl acetone is diagnostic of Tyrosinemia

Table 1.3  Next Generation Sequencing at a glance Next generation sequencing (NGS)

A very large number of MDs detected. Some may be of doubtful significance

Apart from giving specific cause for jaundice, it is useful in preimplantation embryonic.

Liver diseases diagnosed: Galactosemia, Tyrosinemia, FAOD, UCD, GSD, HFI, mitochondrial disorders, Alagille syndrome, Niemann-­ pick C, bile acid disorders, MPS, and others

Etiologies mentioned in Tables 1.1 and 1.2 are the most commonly found metabolic liver disorders causing neonatal hepatocellular insult, at least in our geography. Increasing usage of TMS and GC-MS has led to both cost and turnover time for the test coming down dramatically some times as low as 48 h. These tests allow treatment to be started immediately and with reasonable confidence. This particularly relevant in Galactosemia, Tyrosinemia, UCD, and FAOD where very effective treatment exists. If and when, turn over time of NGS comes down significantly, both TMS and GC-MS will find very limited usage or may be taken out of algorithm altogether. Step three: While results of the tests in Table II are awaited, processing (i.e., collecting the sample and transporting it to the concerned laboratory and saved there, but not processed) for Next Generation Sequencing (NGS) is started because sample for NGS takes 48 to72 h to reach central laboratory (Table 1.3). Apart from Galactosemia and Tyrosinemia, all other tests mentioned in Tables 1.1 and 1.2 are suggestive but not diagnostic. Their confirmation needs molecular diagnosis. Over and above this, there are a large number of cases where tests mentioned in Tables 1.1 and 1.2 are non-contributory and further tests are required. Here NGS may provide a clear answer. NGS may throw up some mutations that are difficult to correlate with the clinical condition; still there is a large group of undiagnosed cases where a definitive diagnosis could be made. One particular condition of utmost importance is mitochondrial disorders. Since it contraindicates liver transplant as per present understanding, a definitive diagnosis may prevent a catastrophe if erroneously listed for liver transplant.

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1  Neonatal and Pediatric Liver Diseases

In summary, for hepatocellular injury/liver failure in neonatal period, an accurate diagnosis is increasingly found in a majority of cases, in the range of 70% in our center, by 4 weeks.

A front line pediatrician’s guide to Neonatal jaundice

Sick child Conjugated hyperbilirubinemia Sick child= Liver failure, Metabolic abnormalities Blood sugar and urinary ketones, pH, Ammonia, Lactate, Full LFT and INR

Hyperacute presentation? Immediately on or soon after birth +/-IUGR Yes HSV: Urgent specific treatment NNH: Urgent specific treatment Mitochondrial

NO

TORCH, HBsAg, HCV, CBC, Urine all negative

Recent change in diet? Multisystem involvement? Reye’s like ? Huge liver? TMS and acyl carnitine profile, Gal-1-T, Urinary GC-MS -

NGS: Galactosemia, Tyrosinemia, HFI, FAOD, UCD, Mitochondrial, Organic acidemia

Cholestatic Disorders Cholestatic disorders form another chunk of neonatal and infantile liver disorders. Extra Hepatic Biliary Atresia (EHBA) is a major cause of neonatal cholestasis accounting for up to 10 to 25% of cases in different geographies. If this single entity is left aside, then there are a large number of cases that are monogenic in origin. Here again NGS can play a significant part. In protocol for cholestatic disorders, once biliary atresia is ruled out by appropriate tests; we use NGS early in the work up. It helps confirming various MDs like Alagille syndrome, Progressive Familial Intrahepatic Cholestasis (PFIC) group of disorders, Niemann-Pick type C (NP-C), Mucopolysaccharidosis (MPS), and Bile acid disorders to name a few. There still remain some cases where no definite conclusion could be arrived at.

1.7  Next Generation Sequencing in Neonatal, Infantile and Pediatric Liver…

35

A front line pediatrician’s guide to Neonatal jaundice:

Hypocholic stool and chld not sick

Hypocholic stool? USG: Upper abdomen

TORCH, HBsAg, HCV, CBC, Urine all negative

GB and CBD not clearly seen?? Options:

Possibility of BA

Liver biopsy

1: MRCP

Surgery

Choledochal cyst, Carolir’s, spontaneous perforation, triangular coard sign

Y

2:Lap cholangio and biopsy BA??

NO?

NGC:

Fiber-ductular proliferation, bile duct paucity Gaint cell hepatitis

PFIC, Allagille Gaucher, NP-C, MPS, Bite acid disorders, TALDO, ARC

A front line pediatrician’s guide to Neonatal jaundice:

Normocholic stool and child not sick Normal stool No liver failure and no metabolic abnormalities USG: No biliary tree abnormality

TORCH, HBsAg, HCV, CBC, Urine All negative

NGS: PFIC. Alagille, NP-C, Bile acid disorders, Gaucher’s, MPS, TALDO, ARC

36

1  Neonatal and Pediatric Liver Diseases

Cost Versus Benefit Analysis of NGS We have described the contracted time span for arriving at a correct diagnosis using NGS. Now we discuss cost effectiveness. The cost of NGS has come down significantly although still high compared to routine laboratory tests; however, compared to cost of hospital stay, it comes to not more than two hospital days stay or sometimes even less (based on hospital stay cost in hospitals we admit). Even in a government setup where the test may be free, the cost of days off work for caretakers and cost of staying away from home with its financial, physical, and psychological costs will all need to be counted in. This almost always overtakes the free NGS testing. Often not taken in to account but nevertheless the most important factor is patients’ point of view and the “human cost”; knowing the exact cause means end of anxiety, clearer roadmap, and prognostication and decreased hospital stay. Unnecessary, expensive and potentially harmful treatment is avoided. Most importantly delay which eats up precious time for care takers to mobilize their resource is avoided. The unavoidable turn over time of NGS, which is about 4 weeks at present, is long enough as it is for health to deteriorate and therefore removal of any “slack” in the diagnostic algorithm is welcome.

1.8

Conclusion

Monogenic disorders form a large chunk of neonatal and infantile liver diseases, some of which are optimally treatable if diagnosed accurately in time. NGS offers a speedy, reliable and cost effective way of achieving this goal.

2

Case 1: A 20-Month-Old Child Who Returned to the Clinic After a Lapse of 12 Months and a 20-Month-Old Child with Recurrent Convulsions

A 20-month-old child returned to the clinic after about a year of lost follow-up for abdominal distention. She first came to the clinic nearly a year ago for abdominal distention. This was noted soon after the birth and got progressively more apparent. She had no other complaints. She was the first child of a non-consanguineous marriage, born at full term. Pregnancy was uneventful. Antenatal history was unremarkable. There was no family history of recurrent abortions, sudden infant deaths, or neurological deficits. Vaccination chart was adequate. Milestones appeared normal for the age. There were no convulsions or attacks of unconsciousness. Vision and hearing appeared normal on routine check. She had not learnt to crawl. Only history that the parents gave was that she could not wait for feeding. On examination she had “doll like face,” with very prominent cheeks. Abdomen was hugely distended and liver was grossly enlarged. It was firm and non-tender and had a smooth surface and edges appeared rounded. Spleen was just palpable. Heart sounds were normal and lungs appeared normal. Genitals were of a female. Musculoskeletal system revealed normal tone and deep tendon reflexes, and power appeared good. Planters were flexors. CBC, LFT, RFT, and random blood sugar were normal. Sonography of abdomen showed very large liver with a smooth surface and margin and spleen was mildly enlarged. Both kidneys appeared normal. Urine for metabolic screening and reducing substances was negative. A liver biopsy was suggested but the patient was lost to follow-up. She returned to the clinic about a year later when she had almost similar complaints but now it was apparent that she was not walking and could stand only with

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2  Case 1: A 20-Month-Old Child Who Returned to the Clinic…

the support. Abdomen was grossly distended due to huge liver and moderate splenomegaly. Neurologically, there was no focal weakness, but power in the limb muscles appeared grade 4. Deep tendon reflexes were present and planters were flexures. CBC, LFT, RFT, urine were normal. Fasting blood sugar was 85 mg. A 20-day-old child from a 2-degree consanguineous marriage was seen for recurrent hypoglycemia and convulsions. He was the first child, born vaginally at full term. At birth, he weighed 2.5 kg and examination was normal. On the fourth day, he developed convulsions and was taken to a pediatrician who found him to have very low sugar of 12 mg%. Neurological examination was normal and the child recovered with dextrose infusion. Routine lab investigations were normal. He kept having recurrent convulsions and each time his blood sugar was in the range of 10–20 mg%. He would require a large amount of IV dextrose to recover. Detailed neurological examination including EEG, CT scan and MRI were normal. Electrolytes, renal function tests, and liver function tests were all normal. In between the attacks, he would be feeling all right and there was no failure to thrive. His milestones were all normal. The child was referred to us for workup. The above-mentioned history was corroborated and physical examination was confirmed to be normal. Liver and spleen were not palpable and muscles appeared normal for tone, power, and deep tendon reflexes. The child was admitted, a large bore, i.e., line was inserted and 10% dextrose was kept ready for immediate infusion. The child was fasted and blood sugar was monitored ½ hourly till it dropped to below 30  mg%. At this point, blood was obtained for sugar, insulin, C peptide, growth hormone, and cortisol. Urine was obtained for sugar and ketones.

2.1

 hat Are Your Working Diagnoses? What Would You Do W Next in Each of These Two Cases?

Do you connect in these two cases? Here we can see two different presentations of disturbed glucose homeostasis. Now how do we proceed in such cases?

2.1.1 Analyzing a Case of Hypoglycemia Homeostasis of glucose  Glucose is kept in a narrow range by gluconeogenic factors that include oral glucose, fructose, sucrose, lactose, and hormones including Glucagon, Growth hormone, adrenaline, and cortisol; and by glycogenolysis. Glucose is decreased by Insulin.

2.1  What Are Your Working Diagnoses? What Would You Do Next in Each of These…

39

Glucose Glucogen synthesis

Glucose 6 phosphate Pyruvate

When an individual is not requiring energy glucose is converted to glycogen in liver and stored there

Lactate To Kreb’s cycle in mitochondria Glucose is broken down to participate in energy generating Kreb’s cycle if an individual requires energy.

Now let us take each factor and see in which scenario they act. If the child is not eating, he will have failure to thrive and weight loss and even then the sugar levels will never go as low as in second child because the fat will burn and provide energy. So for any child to have severe hypoglycemia, he has to starve for several days; which was not the case in either of these two children. What about Galactosemia? Here again, the degree of hypoglycemia should be mild to moderate, and it takes several days before the signs and symptoms become obvious, which could be in the form of liver dysfunction or cataract. In Hereditary Fructose Intolerance, the effect starts only when the fructose is introduced in the diet. So if the diet does not include fructose, the patient cannot have symptoms from fructosemia. If the liver is enlarged, then there is liver dysfunction also. Fat is an important source of energy in form of ketones. In fatty acid oxidation disorders, generally there is a failure to thrive, recurrent unexplained vomiting following trivial illness, and the disease manifests after the age of two and there is absence of ketones in the urine even during hypoglycemia. Patients have aversion to fatty food. Here this seems unlikely. For GH deficiency or cortisol deficiency, there should be growth failure or hypotension or abnormal electrolytes. Now let us think about Glycogen Storage Disorders. Since glycogen is stored in liver and muscles; and since skeletal muscles and heart uses lots of energy provided by glycogen; in GSDs there must be hepatomegaly, muscle weakness, fatigue, or cardiac problems. The first child fitted this bill and hence she has to be investigated along those lines (Discussed later). Now let us consider excessive insulin as the cause of hypoglycemia. Excessive secretion of insulin is due to either autonomous secretion as in Insulinoma, or abnormal signaling or secretion due to mutation of the concerned receptors. Since Insulinomas are rare in very young, abnormal signaling or release of insulin could be the responsible factor for excessive insulin secretion. Glucose enters into B cells of pancreas by GLUT2 receptors. Once inside the B cell. It increases the level of ATP through the Krebs cycle, thus altering the ratio of ATP-to-ADP. This activates inwardly rectified potassium channels (Kir-6). This

40

2  Case 1: A 20-Month-Old Child Who Returned to the Clinic…

leads to the loss of potassium from the cell and depolarization of the cell membrane. This depolarization then activates Voltage-Dependent Calcium Channels (VDCC). This then leads to shift of calcium into intracellular compartment. Increase in intracellular calcium then releases pro-insulin in a biphasic way. If there is abnormal functioning of any of these, i.e., GLUT2 receptor, Kir-6 or VDCC then there is abnormal secretion of the insulin in spite of hypoglycemia. This is seen in Persistent Hyperinsulinemic Hypoglycemia of Infancy (PHII). Considering all the factors, the second child seems to fall into this category. The first child had a very large liver and very little in the way of biochemical liver function abnormality, which is very typical of storage disorders, and associated splenomegaly would favor developing portal hypertension or storage disorder. It has to be either glycogen storage disorder (GSD) or mucopolysaccharidosis (MPS). Typical face, portal hypertension with absence of azure blue reaction on metabolic screening of urine favored GSD, but it must be noted that urine metabolic screening has a high false-positive rate. Her history of going violent when hungry sugggested possible hypoglycemia, but this was not proven biochemically on fasting sample. Glucose tolerance test with lactate samples and liver biopsy and red cell glycogen were the next investigations. GTT was normal. Basal lactate was high. It went higher during GTT. Liver biopsy showed glycogen storage and evidence of cirrhosis. Thus, it appeared that this was a case of GSD type IV. Further enzyme studies were not possible locally. Liver transplant was suggested. On her way to liver transplant center, she had a massive hematemesis and died. The second child had high insulin and C peptide levels in spite of low blood sugar levels; normal growth hormone and cortisol levels and mild ketones in urine. During his stay, his glucose never went above 62 mg%. He was treated with K channel blocker hydrochlorothiazide and calcium channel blocker nifedipine. Over next month his home sugar measurement was very favorable with lowest level being 58 and average level around 110 mg%. This is simplified in the figure below. If you follow the diagnostic algorithm, evaluating hypoglycemia is not at all difficult. Hypoglycemia - Some common metabolic conditions With Hepatomegaly

Huge GSD Hypoglycemia could be severe;

Renal involvement (Type 1)

Without structural or functional liver involvement

mild to moderate

FAOD

Hypoglycemia with out or low ketonemia is the hallmark;

Doll like face; Lactic acidosis;

Without significant hepatomegaly

With jaundice Galactosemia (classic)

Fructose intolerance (HFI)

Developes within few days Starts only after Fructose from birth introduction;

Jaundice and liver failure;

Early decompensation

Severe aversion to fruits;

Reye’s like syndrome;

Recurrent sepsis

Hyperuricemia

Low carnitine;

cataract

Abonormal acyl carnitine profile

Reducing substance in urine; Gal 1 T is absent

Persistent hyperinsulinemic

Insulinoma older age;

Hypoglycemia of infancy (PHHI).

Profound hypoglycemia

Profound hypogly cemia; Insulin levels high

2.1  What Are Your Working Diagnoses? What Would You Do Next in Each of These…

41

Glycogen storage diseases: • Glycogen storage diseases (GSD) are a group of disorders, which are inherited as an autosomal recessive condition. • Since the synthesis of glycogen and its breakdown requires a series of steps involving various enzymes, and since it is stored in various organs, we see more than one type of abnormality and hence various sub-types of GSD. • Organs which consume lots of energy and which store glycogen are therefore the main target organs in GSD. • Since glucose is the “immediate” source of energy, fat has to be mobilized but when GSD prevents glycolysis the result may be an increased concentration of fatty acids in the blood and ketonemia. • Since glycogen keeps accumulating, there is organomegaly, which may impair their functions. • Type I, III, and IV are most common. • Type I involves “final common pathway,” i.e., glucose-6-phosphatase, which is the final enzyme that converts glucose-6-phosphate into glucose. Both glycogenolysis and gluconeogenesis go through this step hence this is the most severe variety of GSD with profound hypoglycemia. These patients require constant supply of glucose. • Type III is almost asymptomatic and type IV produces fibrosis and cirrhosis. • A genetic defect in the isoform of the Glycogen synthase enzyme expressed in the liver causes GSD type 0. There is no synthesis of glycogen for emergency and short-term use. The body depends entirely on ingested glucose and fat to provide energy. Clinical presentation, in addition to excess glycogen storage, which produces organomegaly: • When a genetic defect affects mainly an isoform of an enzyme expressed in the liver, a common symptom is hypoglycemia, relating to impaired mobilization of glucose for release to the blood during fasting. • When the defect is in muscle tissue, weakness, and difficulty with exercise results from inability to increase glucose entry into glycolysis during exercise. • Additional symptoms depend on the particular enzyme that is deficient. –– The patient may have a “doll like” face. –– Abdomen may be very large and this may impair mobility of the patient. Many times it is the distended abdomen that the patient brings to the pediatrician’s notice first. –– There may be delayed milestones, inability to walk, and short stature. Complications: • Hepatic adenoma is common in patients with GSD.  Muscle involvement is prominent in some types and muscle biopsy may also be useful. • Hypoglycemia requires very frequent feeding and nocturnal tube feeding and feeding with corn starch.

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2  Case 1: A 20-Month-Old Child Who Returned to the Clinic…

Investigations: • Blood sugar, urinary and blood ketone levels, lipid profile, plasma lactate, on fasting and after glucose ingestion, and RBC glycogen are basic investigations. • Liver biopsy may show glycogen deposition and in some types, evidence of fibrosis, and cirrhosis. • Enzyme assays in the fresh liver tissue are diagnostic for a particular type of GSD. • Sonography may show enlarged liver with or without enlarged spleen and kidneys. There may be evidence of portal hypertension. • Where available, Next Generation Sequencing (NGS) will detect molecular defect and the exact type of GSD. CH2OH O

H

H OH

H

H OPO32–

OH

H OH glucose-1-phosphate

This is the structure of glucose-1-phosphate. Just look at it and compare it with the next picture, that of a glycogen molecule. Do you see any similarity? When several molecules of glucose-1-phosphate join together glycogen is formed. You can compare it with a tree. When a tree grows, its stem forms first and then its branches; but all have the same structure, as you can see in both figures. Debrancher enzymes will cut branches when fuel in the form of glucose is required. CH2OH H

CH2OH O

H OH

H

H OH

CH2OH H

O

H OH

O

OH H

H

H

H

OH

CH2OH O

H OH

H

H

OH

OH

H

H O

O

H OH

H

H

OH

H

H O4

glycogen

H 1 O 6 CH2 5 H OH 3 H

CH2OH O H 1 2 OH

H

H O

H 4 OH H

CH2OH O H OH

H

H O

O

H OH

H

H

OH

H OH

Counseling: It is possible to screen for the affected fetus and this must be discussed with the parents.

2.2  Understand Various Types of GSDs Affecting the Liver in a Significant Way

2.2

Understand Various Types of GSDs Affecting the Liver in a Significant Way

2.2.1 GSD Type-I • • • • • • • • •

Autosomal recessive Often diagnosed between ages 3 and 4 months Early diagnosis and treatment prevent many complications Bleeding diathesis Delayed puberty Short stature “Doll-like” faces Xanthoma Eyes may show lipemia retinalis

Abdomen: • Protuberant abdomen • Hepatomegaly, liver adenomas, and hepatocellular carcinoma • Pancreatitis • Intermittent diarrhea Cardiovascular: • Hypertension. Renal: • Reduced creatinine clearance • Focal segmental glomerulosclerosis • Renal stones • Renal enlargement Musculoskeletal: • Decreased muscle mass • Osteoporosis • Gouty arthritis • Short stature Laboratory abnormalities: • Hypoglycemia • Hyperlipidemia • Hyperuricemia • Lactic acidosis • Proteinuria • Liver transaminases normal to slightly increased

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2  Case 1: A 20-Month-Old Child Who Returned to the Clinic…

2.2.2 GSD Type-III • Autosomal recessive • Caused by mutations in the amylo-1, 6-glucosidase, glucoanotransferase genes • Type IIIa has both liver and muscle involvement • Type IIIb liver involvement only (15% of all cases) • Liver symptoms improve with age and disappear after puberty • Muscle weakness increases with age

4-alpha-­

Abdomen: • Hepatomegaly • Hepatic fibrosis Muscle: • Muscle weakness, which increases with age • Distal muscle wasting • Myopathy Growth: • Short stature • Growth retardation Head and neck: • Face: Dysmorphic face Cardiovascular: • Cardiomyopathy • Ventricular hypertrophy on ECG Laboratory abnormalities: • Hypoglycemia • Hyperlipidemia • *Normal blood lactate • *Normal uric acid • *Elevated transaminases • *Increased serum creatine kinase –– *Differentiate it from type I GSD

2.2.3 GSD Type-IV • Autosomal recessive • Brancher enzyme deficiency (Amylo1,4-1,6 transglucosidase) is caused by mutations in the glycogen branching enzyme gene (GBE1)

2.2  Understand Various Types of GSDs Affecting the Liver in a Significant Way

45

• Extreme clinical heterogeneity • Classic hepatic form begins in the first months of life with hepatic failure and death by 5 years of age • Non-progressive hepatic form is less frequent • Neuromuscular forms can present as perinate, infant, child, or adult • Failure to thrive Abdomen: • Hepatosplenomegaly • Liver cirrhosis • Portal hypertension • Ascites Liver biopsy shows diffuse interstitial fibrosis. Enlarged hepatocytes with periodic acid-Schiff-positive, diastase-resistant inclusions. Electron microscopy shows fibrillar aggregations typical of amylopectin. Musculoskeletal: • Arthrogryposis multiplex (in perinatal or congenital neuromuscular forms) • Muscle weakness • Muscle atrophy • Hypotonia • Decreased to absent deep tendon reflexes Prenatal manifestations (in perinatal or congenital neuromuscular forms): • Decreased fetal movement • Polyhydramnios • Fetal hydrops Laboratory abnormalities: • Broad tissue deposition of amylopectin-like material. • Normal serum creatine kinase

3

Case 2: A 9-Year-Old Boy Presenting with Hepatitis, Epistaxis, and Bleeding from Gums

A 9-year-old boy was referred from dental OPD for opinion with a year’s history of recurrent bleeding gums and epistaxis and liver function tests suggestive of hepatitis. There were no other complaints. There was no history of fever, abdominal pain, diarrhea, rashes, or weight loss. Family history was unremarkable except for the fact that his maternal aunt (maasi) had recurrent “skin rashes.” On physical examination, the patient appeared comfortable though little anxious. He was alert and oriented. There was obvious bleeding from gums. The abdomen was soft, non-tender, with hepatomegaly ++ with the liver edge palpable 5-cm below the right costal margin and had a total span of 10 cm. There was no splenomegaly. His neurologic examination was normal. Investigation: • Hemoglobin 10.3 g/dL • WCC 9.2 with normal differential; and platelets 312,000 • Total bilirubin was 1.4 and conjugated bilirubin 0.2 • SGPT (ALT) 1295 IU • SGOT (AST) 836 IU • Gamma glutamyl transferase (GGT) 116 IU • Alkaline phosphatase (ALP) was normal at 184 IU • Prothrombin time 16 s, INR was high at 1.27. S • Albumin level was 3.6 g/dL and globulin was 6.3 Recurrent nature of his complaints suggested some chronic health problems. With abnormal LFT’s and presence of coagulopathy, chronic hepatitis was on the top of the list. Since he was not under any medications, either viral hepatitis or metabolic disorder or uncommonly autoimmune hepatitis was the most likely cause in our differential diagnosis.

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3  Case 2: A 9-Year-Old Boy Presenting with Hepatitis, Epistaxis, and Bleeding…

Investigating chronic liver disease is based on local disease profile and genetic background of the patient. In certain areas of the world like India HBV infection is around 4.5% of the total population and HCV infection is around 1.5%, and hence in India investigating for these viruses is going to be rewarding but if the child is from the Western world, then you may consider other causes as priority, especially alpha-1-antitrypsin deficiency if the child is very young, which again is very uncommon in India. The fact that his maternal aunt had recurrent “skin rashes,” which we learned were due to idiopathic thrombocytopenic purpura, was in favor of autoimmune hepatitis and so were significantly raised globulin levels. Of course, other rare causes could also be present. Since we see Wilson’s disease commonly, that is always included in evaluation of any case of chronic liver disease. Hematological malignancy was also kept in mind. Epistaxis with a prolonged APTT, and a normal blood and platelet counts, could be consistent with Von Willebrand disease. Further investigations include: • An abdominal ultrasound, which revealed an enlarged liver with a coarsened echo texture. GB was normal and no stones were seen. CBD and IHBR were normal. Portal vein was 11 mm and spleen was mildly enlarged. • Serology for hepatitis A, B, C, and E viruses was negative. • 24-h urinary copper excretion, serum Ceruloplasmin, and alpha-1 antitrypsin level were all normal. • Antiplatelet antibodies were negative. • Antinuclear antibodies (ANA) were negative; serum anti-smooth muscle antibody (SMA) was positive at titers of 1:2560, and anti-F-actin was present at a level of 154 units. Anti-liver-kidney microsomal antibody was negative and perinuclear antineutrophil cytoplasmic antibody (p-ANCA) was detected at titers of 1:80. This very much suggested autoimmune hepatitis type I.

3.1

Would a Liver Biopsy Help?

As far as helping is concerned, it will help in confirming the diagnosis, and in future, to monitor disease activity. Whether we should be doing it? This is perhaps debatable. The diagnosis is almost certainly auto immune hepatitis (AIH), and if there is a resistance from the patient or the guardians, we would start treatment for AIH. However, with age so young and possibility of prolonged treatment, it is desirable that all possible evidences are collected. Thus, it was decided to proceed with liver biopsy after necessary correction of coagulation profile. Liver biopsy showed nodule formation, with fibrous expansion and bridging of portal tracts. “Interface hepatitis,” characterized by a mononuclear inflammatory

3.1  Would a Liver Biopsy Help?

49

infiltrate at the edge of a portal tract infiltrating into adjacent lobules was also present. Treatment and progress: The patient was started on oral corticosteroids and Azathioprine. His liver enzyme levels decreased steadily over the following several months. Repeat liver biopsy revealed persistent mild inflammation. We tried to reduce his steroid and were successful to bring it down to prednisone 5 mg/per day and Azathioprine 50 mg/day. AIH: • AIH is a process of inflammation and progressive destruction of the liver parenchyma. • Characteristic features of AIH on biopsy are interface hepatitis and plasma cell infiltrate in the portal areas. • Laboratory markers include circulating autoantibodies and hypergammaglobulinemia. • Etiology could be multifactorial, involving environmental factors interacting with a genetically predisposed population. Exposure to triggers, results in an immunoregulatory response and the generation of autoantibodies. • AIH affects all ethnic groups but has a female predominance and could occur at any age. • The most common presentation is that of acute hepatitis with nonspecific symptoms. • Anorexia, nausea and vomiting, intermittent fatigue, weight loss, pruritus, and arthralgia of the small joints are common symptoms. • Advanced cases present with gastrointestinal bleeding from portal hypertension or ascites, which developed after progression to liver cirrhosis. • In some cases, it is detected during the workup for incidental finding of elevated aminotransferases. • AIH is classified into two types on the basis of antibody profile. • Type 1 has anti-SMA, ANA titer, and the presence of anti-F-actin antibody. It can also be associated with positive p-ANCA, anti-DNA antibody, and serum anti-­ asialoglycoprotein receptor (ASGPR) antibodies. It is strongly associated with human leukocyte antigens HLA-A1 DR3 and DR4. Associated extrahepatic autoimmune diseases include ulcerative colitis (with or without primary sclerosing cholangitis), arthritis, vasculitis, and autoimmune thrombocytopenia. • Type 2 AIH has anti-liver-kidney microsomal (LKM-1) antibody and is frequently associated with anti-LC-1 (liver cytosol-1), and anti-ASGPR antibody. It can be accompanied by polyendocrinopathy, vitiligo, diabetes, and thyroiditis. It is associated with HLA-B14 and DRB1*07. • Cell-mediated and antibody-dependent cell-mediated cytotoxicity is believed to be the main pathological phenomena.

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3  Case 2: A 9-Year-Old Boy Presenting with Hepatitis, Epistaxis, and Bleeding…

Treatment • Centers largely on immunosuppression. • Corticosteroids and Azathioprine have been used as first-line therapies. • Corticosteroid therapy is commonly initiated at 1–2 mg/kg/day, with or without concurrent Azathioprine, to allow faster reduction of the corticosteroid dose. 75–90% of the patients achieve normalized serum aminotransferases within 6–9 months. If successful, the corticosteroids may be tapered and discontinued with close monitoring. • Alternative treatment options, especially for patients who do not respond to first-­ line therapy, include cyclosporine, tacrolimus, and mycophenolate mofetil. • Successful treatment is directly related to the liver histology. If there is a complete disappearance of inflammation on liver biopsy there are excellent chances that the patient will not relapse.

4

Case 3: Lightning Strikes at One Place Thrice!

An 8-year-old boy was seen by a family physician for malaise, anorexia, and vomiting. Hepatitis was diagnosed and he was given supportive treatment. His jaundice increased, so he was referred to a specialist center. He was the second of the three brothers. There was no family history of consanguinity. His development till date was normal. He never had any illness, accident, operation, or blood transfusion in the past. He was not taking any drugs prior to this illness. On examination he appeared very unwell and pale. There were ascites and pedal edema. Liver was enlarged +++ and spleen was palpable too. Visible veins were present on anterior abdominal wall. Central nervous system was normal. CVS and RS were normal too. Investigations were as follows: • Hb: 3.5, MCV 102, MCH 27, retics12%, WCC: 11,200. • Bilirubin 24.2 (conjugated 11, Unconjugated 13.2) • SGPT: 675, SGOT 781, ALP: 200. • PT: 37/14 s • Albumin 2.0, globulin 3.1. • HBsAg and HCV were negative. • Urea 64, creatinine 2.8, Na was 128, and potassium 5.2. • LDH was 1603. • SAAG was 2 and ascitic fluid cell count was 78 with main polys. • Urine analysis showed trace of protein and multiple amino acids were present. Reducing substances were negative in urine. • USG showed coarse echo structure of the liver and mild splenomegaly and ascites. Portal vein was marginally dilated.

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4.1

4  Case 3: Lightning Strikes at One Place Thrice!

 hat Is Your Differential Diagnosis? What Additional W Tests Would You Do?

Obviously this child has, what looks like, chronic liver disease with acute exacerbation and hemolysis. Practically this does not fit into any single disease except Wilson’s disease (WD) with acute hemolytic crisis. One could consider chronic liver disease and acute hemolysis due to a different cause like falciparum malaria or drug toxicity, but this appears too farfetched. Auto-­ immune hepatitis with immune-mediated hemolysis was another possibility, but we have not seen such a gross hemolysis in AIH. So, we went for Wilson’s with hemolytic crisis. In fact, I have seen a large number of cases of Wilson’s disease (and suspected in even larger numbers) but hemolytic crisis was never seen by me before and in fact I was waiting to see it, so it was not difficult to diagnose it the moment we had all the reports at hand. Ceruloplasmin, 24-h urinary copper, and K.F. ring were examined and they all favored Wilson’s disease. We also did ANF and anti-SMA just to make sure but they were negative. Treatment and progress  The child appeared very sick on admission and was immediately shifted to ICU where he was started with a high dose of d-­penicillamine and transfused with blood, clotting factors, and other supportive treatment, although in our experience this is the terminal stage and no treatment is effective except liver transplant. He soon developed type I HRS and went into hepatic coma and died. Soon after this, his two brothers were also brought with hepatomegaly and jaundice and one of them had ascites and ankle edema too. Both were confirmed to have Wilson’s disease by elaborate testing. Both are on treatment and so far doing well. Wilson’s disease: • Wilson’s disease is a systemic disorder, resulting from copper overload. Main organs involved are brain, liver, and hematological system. Kidneys are also affected. • There is a genetically determined defect in copper transport, due to mutant gene, viz., ATP7B, resulting in the accumulation of the copper. • ATP7B encodes for copper-transporting P-type ATPases, which facilitates copper transport. Genetic study for ATP7B could be carried out in asymptomatic siblings of an index case to allow early diagnosis and treatment. One word of caution here; many students confuse defective ATP7B gene as the genetic defect itself. The fact is that this genetic defect could result from several mutations that are generally specific to the population studied. To elaborate further I will give an example. If your car does not start in the morning, then it could be that your battery is down, or that there is no petrol, or there may be some other defect. These various types of defects could

4.2  Clinical Features

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be compared to different mutations. The end result, the car not starting could be compared to the defective gene. So if you look for specific mutations, you will succeed in coming to a molecular diagnosis in a specified population only. Different populations could have different mutations and testing for only a few mutations may miss the relevant mutation in a given person. In India, we do not know the common or uncommon mutations leading to defective ATP7B gene and we have a problem relying on mutational analysis. Epidemiology: • The disease occurs in all races and geographic population. • Worldwide prevalence of about 1:30,000 and a heterozygous carrier frequency of about 1:90. Pathology and Pathogenesis: • Excess dietary copper is excreted by the liver. In WD, there is hepatic retention. And when this capacity to store copper is exceeded, copper is released into blood and taken up into extrahepatic tissues like the brain and other organs also. • Fatty infiltration of the hepatic parenchyma and nuclear glycogen deposits are the earliest findings by light microscopy. • Mitochondria are targeted and characteristic mitochondrial abnormalities appear to be specific for Wilson’s disease. • Later, necrosis, inflammation, fibrosis, bile duct proliferation, and cirrhosis ensue.

4.2

Clinical Features

Liver disease could manifest as follows: • Acute hepatitis, indistinguishable from other viral hepatitis. This may resolve completely or progress subclinically to develop chronic active hepatitis and cirrhosis. • Chronic hepatitis. • Cirrhosis of liver. • Acute fulminant hepatitis where there is a rapid deterioration in liver functions and even death. There may be accompanying hemolytic anemia due to toxic effect of copper on RBC membrane. WD should be considered in any patient younger than 40 years with: • Unexplained acute hepatitis, chronic active hepatitis, unexplained persistent elevations of serum aminotransferase, and cirrhosis. • Hemolytic anemia in the presence of hepatitis. • In any patient who has a relative with Wilson’s disease.

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4  Case 3: Lightning Strikes at One Place Thrice!

Investigations and Diagnosis: The diagnosis is confirmed by the demonstration of either • Ceruloplasmin level 250 μg/g dry weight with low Ceruloplasmin. • 24-h urinary copper >100 μg. • Mutation in ATP7B gene by NGS. Treatment: • D-Penicillamine given orally 15–20 mg/kg, daily in single or divided doses at least 30 min before and 2 h after food, given with supplement of 25 mg/day of pyridoxine, is the main treatment. Fever and skin rashes, two of the earliest side effects, must be checked daily. WCC and platelet count and urinalysis should be performed weekly during the first month of treatment. • Trientine, 1 g/day on an empty stomach, is used, if side effects are detected or if neurologic worsening accompanies the institution of d-penicillamine and persists for a week or more. It is as effective as penicillamine with a favorable side effect profile. • Free serum copper (total serum copper minus Ceruloplasmin-bound copper) should be measured to bring the level to less than 10 μg/dL. • Once this is achieved, the maintenance dose of d-penicillamine is 0.75  g/day taken 45 min before breakfast. • Zinc acetate or gluconate given separately from penicillamine or trientine, are effective as maintenance therapy, at doses 150  mg/day of elemental zinc, for patients who are asymptomatic or have improved maximally on penicillamine or trientine. • Treatment is lifelong. Inadequate treatment or interruption of therapy can be fatal or cause irreversible relapse. • Prophylactic therapy with penicillamine or trientine can maintain the asymptomatic state indefinitely. • Liver transplant is required when all else fails. • Normal pregnancy is possible with regular treatment.

Hemolysis and hepatitis Autoimmune Wilson’s Rarely Falciparum infection

5

Case 4: A Worried Couple with a Child Having Jaundice

A 3-day-old child was brought to us with jaundice. It was the couple’s first child and they were worried. History of consanguinity: Present. Two abortions at 6 weeks and 14 weeks. Mother’s brother (who was married to father’s sister), had a child who died at the age of 4 years because of “jaundice.” Physical examination: No dysmorphism. Abdomen: NAD, CVS and RS: NAD. Bilirubin 12 mg, conjugated 0.2 mg, unconjugated 11.8 mg SGPT: 12 ALP: 84 Hb: 11.2, WCC: 9400, Plt: 184,000, Retics: 1% Peripheral smear: Nil significant. G-6-PD: No deficiency detected Total Galactose 312 mg (up to 300) Urine examination was normal on microscopy and no reducing substances were found. • C-reactive protein was within normal limits. • Neonatal TSH was normal. • • • • • • • •

So this child has unconjugated hyperbilirubinemia without any gross evidence of hemolysis. Physiological jaundice, breast milk jaundice, galactosemia, sepsis, neonatal hypothyroidism, all can give this type of picture of unconjugated hyperbilirubinemia at this point in life. But at the back of our mind was Crigler–Najjar syndrome. Physiological jaundice should not last beyond a week. Breast milk jaundice is another possibility. Here the child is otherwise absolutely okay and in such cases wait and watch approach is appropriate if there is no family history, like in this case.

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5  Case 4: A Worried Couple with a Child Having Jaundice

Galactosemia generally produces some evidence of liver failure like prolonged PT, low albumin, hepatomegaly, or evidence of ascites. Neonatal hypothyroidism was ruled out, so was the hemolysis and sepsis by appropriate tests. Relatives were warned. There was a rapid rise in unconjugated bilirubin, in spite of withdrawing all forms of milk, giving blind antibiotics, and supplementing with IV dextrose. The child required intensive double surface phototherapy and phenobarbitone, which could just manage to keep bilirubin in the range of 14–16  mg. Repeat liver enzymes, CBC were normal and there was no evidence of hemolysis. Physical examination was unremarkable.

5.1

 o You Agree with Our Suspicion? What Other D Investigations Would You Do?

Crigler–Najjar Syndrome (CN syndrome) was our working diagnosis. We had reasonably ruled out all other causes including lesser known but widely prevalent causes like galactosemia. This is our usual practice because of two reasons, the first being we do not want to miss any treatable cause, however, unlikely it may seem and the second being once a diagnosis is made, people have a tendency to treat the diagnosis and not the patient and if unfortunately a wrong diagnosis is made in the first place it sticks for the rest of the life. History of consanguinity and family history both would also favor one of the autosomal recessive diseases. The child had extended phototherapy for more than 6 weeks, but unconjugated bilirubin remained in the range of 18–20 mg with normal transaminases. There was failure to thrive. After a few follow-ups, the patient was lost to follow-up.

5.1.1 Crigler–Najjar Syndrome (CN Syndrome) Pathology and pathophysiology  Unconjugated bilirubin is conjugated with glucuronic acid in the hepatocyte to form water-soluble bilirubin glucuronides, which is then excreted by the kidneys. UGT 1A1 of Uridinediphosphoglucuronate glucuronosyltransferase (UDPGT/UGT) group of enzymes catalyzes this process. They are concentrated in the endoplasmic reticulum of hepatocytes, intestinal cells, kidneys, and other tissues. Deficiency of this isoform causes unconjugated hyperbilirubinemia. Liver biopsy is essentially normal. Bilirubin metabolism

old RBCs

Criggler Najjar syndrome

Spleen: unconjugated bilirubin is produced

Liver: Conjugation takes place and bilirubin made water soluble and excreted in urine

5.1  Do You Agree with Our Suspicion? What Other Investigations Would You Do?

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Genetics  One or more mutations in the gene, located on chromosome 2, coding for UGT 1A1 can cause CN syndrome. Depending on the severity, CN syndrome type­I, a complete absence of enzymatic activity, or CN syndrome type-II, with UGT level 15% of the total bilirubin) so we do not need to look for any causes of unconjugated hyperbilirubinemia. • Since they have developed jaundice at the age of 5 months and have a normal biliary tree on sonography, biliary atresia, and other developmental abnormalities were unlikely because they would have presented much earlier or say almost from birth. Second important learning point from this case is discordance between ALP and GGT. GGT generally goes parallel with ALP in biliary obstruction. If you have noted here ALP is markedly raised but GGT is not. There is no mechanical cause of obstruction where only ALP is raised and not GGT. This suggests selective enzymatic or functional block. • Metabolic diseases were unlikely without elevation of SGPT and SGOT.  Furthermore, they would have started much earlier and by 11 months they would have decompensated. So they cannot be the cause of severe cholestasis. • Infections like Cytomegalovirus or Herpes virus do not generally develop so late, produce milder jaundice and the pattern is that of hepatocellular damage or mixed hepatocellular and cholestasis rather than severe cholestasis alone and importantly multisystemic involvement in the form of CVS, CNS, or eye is generally present. • Idiopathic neonatal hepatitis generally presents near birth as the name suggests; have raised SGPT and SGOT, and if they were to improve they would have done so by now or they would have decompensated. • Some sort of cholestasis was certain. Could these children have progressive intrahepatic familial cholestasis (PFIC)? Could they have abnormal bile causing cholestasis? Could they have something like autoimmune cholangitis? • Liver biopsy was done next. This showed marked intrahepatic cholestasis with amorphous bile suggestive of type-2, progressive intrahepatic cholestasis.

10.2 What Next? These were difficult patients. If they really had PFIC, then medical treatment was only supportive and transplant was the choice, which seemed a farfetched thing in these cases at that point. Devoid of any choice we put them on a high dose of Ursodeoxycholic acid, 25  mg/kg in divided doses after meals and sent the patients home. A few weeks later we got a phone call from the father that the children were doing well and should they continue the treatment? The answer was yes but we thought the father was exaggerating or having a wishful thinking. The boys were seen again in the clinic at 3 months.

10.3  Progressive Familial Intrahepatic Cholestasis

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The examination was nothing sort of dramatic. We were told, from day 1 the boys stopped crying with dramatic drop in all liver tests. In fact, the parents told us that the children never cried after leaving hospital!! The response was so dramatic it made us question the diagnosis of PFIC-2. It is more likely in retrospect that these boys had toxic/abnormal bile, structurally different from the normal bile and replacing this with Ursodeoxycholic acid may have provided dramatic results. This hypothesis could not be tested, as we have no easily accessible facility to study the chemical composition of bile. Nearly 15 years on, these boys are living a normal life with normal LFTs on Ursodeoxycholic acid!!

10.3 Progressive Familial Intrahepatic Cholestasis Progressive Familial Intrahepatic Cholestasis (PFIC) is a group of chronic cholestasis disorders, which appear in infancy and usually progresses to cirrhosis within the first decade of life. There is a varying degree of severity but average age at onset is 3 months, although some patients do not develop apparent cholestasis until later, even as late as adolescence. In severe forms, progress is rapid and causes cirrhosis during infancy, but milder forms may progress relatively slowly with minimal scarring well into adolescence. Epidemiology  Previously it was thought that it is a disease of Jewish race but these disorders are known to occur in all races and both sexes. In India, we see it in all racial groups. Classification: • PFIC is classified as 1–4, depending upon the underlying genetic and pathophysiological defects. • Types 1 and 2 have low GGT and type 3 has high GGT. • Type 4 is where phenotype is same but has no identifiable defect yet. Genetics: • PFIC is an autosomal recessive disorder. • The gene for PFIC-1 has been mapped to 18q21-22. The FIC-1 gene regulates the transport of phospholipids and/or bile salts. • The gene FIC-2, located at band 2q24, regulates the bile salt export pump (BSEP). Mutation of this gene results in PFIC-2. • PFIC-3 is due to the mutation of the MDR3 gene and has been mapped to band 7q21. Pathophysiology  In types 1 and 2, there is a defect in canalicular bile acid t­ ransport with primary retention of hydrophobic bile salts, particularly of c­ henodeoxycholic acid conjugates, as the mechanism of disease. These findings suggest a defect in biliary excretion.

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Patients with PFIC-1 have associated watery diarrhea, which reflect an important role for FIC-1 in the intestine. In fact, we have seen patients who, at birth present with severe diarrhea and only later on develop liver abnormality. Light microscopy and electron microscopy demonstrate that liver tissue from patients with PFIC-1 has coarse granular bile and bland canalicular cholestasis, whereas patients with PFIC-2 have amorphous or finely filamentous bile. MDR-3 is a primary active export pump and is expressed in the canalicular membrane of the hepatocyte. It helps translocation of phosphatidylcholine across the canalicular membrane. The stability of mixed micelles is determined by a 3-phase system in which a proper proportion of bile salts and phospholipids are necessary to maintain solubility of cholesterol. The absence of phospholipid could destabilize micelles and promote lithogenic bile with crystallized cholesterol, which could produce small-bile duct obstruction. Canalicular membrane of hepatocyte Amlnophospholipids • Phosphatidylserine • Phosphatidylethinolamine FIC 1

Bile acids

BSFP

Phosphatidylchaline

MDR 3

Hepatocyte

FIC 1

Bile acids

Phosphatidylchaline

Canalicular lumen

PFIC 1

BSFP

MDR 3

PFIC 2

PFIC 3

Hepatocyte

Clinical findings: • The most common feature is pruritus, which could be out of proportion to the level of jaundice, which often is low grade, and can wax and wane. The pruritus is very disabling. In patients that we have seen, pruritus appears around 5 months of age and not before. • Growth failure. More than 95% of patients have a short stature. • Jaundice is apparent but could wax and wane. • Perennial asthma-like disease and recurrent epistaxis in the absence of thrombocytopenia or coagulopathy are common problems. • Fat-soluble vitamin deficiencies. • About one-third have cholelithiasis. • Hepatomegaly with splenomegaly due to cirrhosis and portal hypertension. • There are steatorrhea and malabsorption.

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Investigations: • Bilirubin is elevated which is predominantly conjugated. • Alkaline phosphatase is elevated. • GGT level is normal in types 1 and 2 and elevated in type 3. • Total serum bile salt concentration is elevated. • Qualitative serum and urine bile acids by mass spectroscopy are used to exclude genetically determined errors in bile acid synthesis. • Liver biopsy: In patients with types 1 and 2 PFIC, hepatocellular and canalicular cholestasis with pseudoacinar transformation are the most common histological findings. Giant cell formation and ballooned hepatocytes are seen. Bile duct damage leads to their progressive loss and ductal paucity. In advanced cases, there is progressive fibrosis and cirrhosis. Electron microscopy from patients with PFIC-1 shows the retention of coarsely granular bile in canalicular spaces while in type 2 the retained bile is mainly amorphous. Liver biopsies from patients with high-GGT PFIC reveal expanded portal areas with proliferation of interlobular bile ducts plugged with bile. • USG does not show any dilatation of the biliary tree, which rules out most of the obstructive causes. Management: • Low-GGT PFIC may respond to Ursodeoxycholic acid, 20–30 mg/kg/day. • Fat-soluble vitamins are required. • Vitamin E is given as Alpha-tocopherol: RDA dose: 3–10 mg/day. • Therapeutic dose: 1–100 mg/kg/day. • Vitamin D 400–1000 U orally. Calcium supplements. Vitamin K is given 1 mg IM. • A diet containing medium-chain triglycerides may improve fat absorption and nutrition. Surgery: • Surgical therapy that diverts bile salts from the enterohepatic recirculation arrests the progression of the disease and relieves pruritus in most patients with low-­ GGT PFIC. • The most common procedure, partial cutaneous biliary diversion, diverts gallbladder bile to a cutaneous ostomy. • A variation on this procedure is the limited ileal diversion, in which the distal 20–25% of the ileum is removed from the intestinal mainstream and made into a self-emptying blind loop. This diverts the bile salts pool similarly to a partial biliary diversion. Ileal diversion usually is reserved for patients who have had a cholecystectomy but has been used with some success in lieu of biliary diversion. After diversion, the bile salt pool converts to predominantly cholic acid conjugates, which can be transported normally, and the liver disease resolves in most patients. • Liver transplantation is indicated in patients with decompensated cirrhosis or with a failed diversion with debilitating pruritus. Survival rates after transplantation are excellent. Liver transplantation is the only effective treatment of high-GGT PFIC.

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Prognosis Remains guarded. Supportive treatment, Ursodeoxycholic acid, and surgical intervention do help some patients but very few patients remain symptom free beyond third decade. Inborn Errors of Bile Acid (BA) Metabolism: • These are inherited and believed to be autosomal recessive. • They are synthesized from cholesterol through a complex series of reactions involving at least 14 enzymatic steps. • A failure to perform any of these reactions will result in failure to produce “normal bile acids” and instead, the accumulation of unusual bile acids and intermediary metabolites causing liver disease. • Some are associated with jaundice and significantly impaired hepatic synthetic function while in others there may be mild elevations of liver enzymes with poor bile flow and associated malabsorption of fat and fat-soluble vitamins. • In some conditions, there is a liver disease associated with neurologic dysfunction. • Patients with peroxisomal diseases, including Zellweger and Neonatal Adrenoleukodystrophy, have abnormalities in bile acid production because part of the synthesis of bile acids requires reactions that take place within the peroxisome. Clinical Features: • Symptoms include jaundice, poor growth, liver or spleen enlargement, bleeding, rickets, or liver disease of an unknown cause. • Liver disease may be transient, delayed in the onset and mild. • Liver disease may be variable in severity and is accompanied by neurologic disease, which may include mental retardation, seizures, deafness, blindness, and muscular weakness. • Progression of liver disease is most rapid when the defect results in the accumulation of toxic monohydroxy and unsaturated oxo- bile acids. Diagnosis: • Diagnosis requires a high index of suspicion. • In the presence of obstructive jaundice, the elevated serum bile acid levels usually exclude the diagnosis. • If the levels of bile acids in the blood are low or normal, urine must be sent for measurement of urinary bile acids by fast atom bombardment-mass spectrometry (FAB-MS). • Pathological findings may include intralobular cholestasis with giant cell transformation, necrotic hepatocytes, and hepatitic injury confined to the portal limiting plate where the smallest bile ductules may be injured, resulting in neocholangiolar proliferation, and where fibrosis typically develop. Interlobular bile ducts are usually spared.

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• Giant cell transformation is present in all symptomatic infants with BAD and seems to have a more consistent association with BAD than with the many other liver diseases in infants when it occurs. Treatment: • For all inborn errors of bile acid metabolism except conjugation defects, bile acid therapy with cholic acid or Ursodeoxycholic acid may be used. • For conjugation defects, glycocholic acid is available as an investigational drug. • Other nutritional and fat-soluble vitamins as required. Prognosis: Patients treated with bile acids usually fare well. Improvement occurs over a period of several weeks to several months after starting the therapy. Occasionally, the liver disease worsens in patients despite treatment, with the development of cirrhosis of the liver.

MRP3/4 Blood bile salts

Blood

OSTα/β

NTCP BSEP

P–gp

OATPs MATE 1 OAT2 OCT1

MRP2

BCRP

In situ bile salts Bile salt exporter pump-BSEP

Hepatocytes

Case 10: A Child with Recurrent Diarrhea That Made the Family Measurable

11

A 2-year-old female child was referred for recurrent dehydration with low sodium and chloride during these episodes. She was the third child of a non-consanguineous marriage. The other two siblings were doing well. She was delivered by cesarean section. She remained well for about a couple of months after birth and then developed chest infection and breathlessness for which she was first admitted. This was treated with antibiotics. At that time she was found to have low sodium and chloride, which was corrected with intravenous saline, and she improved immediately. Subsequently, she had several admissions. Each time she would develop distention of abdomen and profuse diarrhea so much so that her abdomen would be almost concave, with deep sunken eyes and loss of tissue turgor and decreased urine output with hypotension and feeble pulse. Her typical finding would be low sodium, low chloride, and at times low potassium and at one time when arterial blood gases were done she had metabolic alkalosis. • CBC would show normal picture with some elevation of Hematocrete consistent with severe dehydration. • Stool examination on several occasions showed no pus cells or RBCs and no organisms were isolated on culture. • Serum cortisol and thyroid profile were normal. With intravenous saline and electrolytes and an assortment of antibiotics and anti-amebic, she would get better. She was referred for a second opinion. History was corroborated and we further found that the reason for CS was because she had developed “intra uterine diarrhea.” On examination, she appeared well after IV saline. Her growth appeared normal and milestones were on target. Her sclera had a distinct blue tinge. Her abdomen was flat and there were loud borborygmi heard. CVS and RS were unremarkable. Investigations showed © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2021 M. K. Ghoda, Neonatal and Pediatric Liver and Metabolic Diseases, https://doi.org/10.1007/978-981-15-9231-7_11

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• Na 120, K 2.1, chloride 77. • pH 7.49 and bicarbs were 33. • Stool examination revealed no ova, parasite, and no RBCs or WBCs. There were no fat droplets by Sudan III staining. • Urine showed low Na at 5 and K was 12  mmol/dL.  No amino acids were detected. Let us analyze this case… When this child came, the history was so beautifully given by the mother and it was apparent that this child had some sort of metabolic reason for her diarrhea. • With repeated low Na and Cl, one considers adrenal insufficiency, drug-induced Na wasting with salt restriction, syndrome of inappropriate ADH secretion (SIADH), cystic fibrosis with NaCl wasting, and dilutional hyponatremia in advanced cirrhosis with hepatorenal syndrome or excessive infusion with dextrose solution or congenital chloride diarrhea. • Normal genitalia, normal cortisol study, and very prominent history of diarrhea, were all suggestive of intestinal Na and Cl loss. • Patient was not taking any drugs nor was on salt restriction and these could not be causal factors. • Intermittent nature of illness was against SIADH. • The child had no liver disease so HRS was not in question. • Negative Sudan III staining for fat and no failure to thrive and no respiratory infections were not favoring cystic fibrosis. Moreover, electrolyte abnormalities and severe dehydration would not fit. • Infection was never detected to account for recurrent diarrhea. • So all in all, clinically only congenital chloride diarrhea fitted the bill. • Next step was to do stool electrolytes. This was possible after some ingenious methodology and lots of persuasions. Stool Na + K were less than stool Cl, favoring chloride diarrhea. Congenital chloride diarrhea: • Congenital chloride diarrhea is caused by a mutation in the DRA gene. Gene map locus 7q22-q 31.1. DRA gene is expressed in the gut and encodes a protein, which regulates anion transporters. • The children are often premature. • Hydramnios, presumably due to intrauterine diarrhea, may complicate pregnancy and is probably an invariant feature. • Both sexes have been affected and two sibs appear to have been affected in several families. • All children generally have a shortened gestational period, abdominal distention, and chronic diarrhea. • The serum electrolytes show hyponatremia, hypokalemia, hypochloremia, and metabolic alkalosis. • Diagnosis is confirmed by a stool chloride content that exceeded the sum of fecal sodium and potassium.

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In chloride diarrhea, juxtaglomerular hyperplasia, hyperreninemia and hyperaldosteronism, leading to hyperkaluria and hypokalemia, simulate the Barter syndrome. In the intestinal brush border, there is a Na/H and a Cl/HCO3 exchange mechanism. A defect in either, can impede NaCl absorption and lead to secretory diarrhea. The latter exchange mechanism is defective in chloride diarrhea; the former is deranged in sodium diarrhea. Most of the patients reported have normal growth and mental development. Two patients with cystic fibrosis and one patient with osteogenesis imperfecta have been reported. In patients with congenital chloridorrhea, the oral intake of chloride, sodium, and potassium must exceed fecal output so that obligatory losses in sweat can be replaced. Potassium chloride is the main therapy. A positive balance can best be insured by a high intake of chloride, even though it exacerbates diarrhea. Suppression of gastric chloride secretion by a proton-pump inhibitor, Omeprazole, reduces fecal electrolyte losses in patients with this disorder and thus promotes a positive gastrointestinal balance. However, this treatment does not reduce the need for careful monitoring of dietary intake, serum electrolyte concentrations, and urinary chloride excretion.

Case 11: A 3-Month-Old Child with Recurrent Fever, Diarrhea, Failure to Thrive, and Electrolyte Disturbances

12

A 3-month-old child of a two-degree consanguineous marriage was referred for failure to thrive and tachypnea. This child was a FTNVD and weighed 2.7 kg. At about 1 month, he weighed 4 kg. Then he developed recurrent fever and chest infections and diarrhea. His weight progressively decreased to 2.6  kg over the next 2 months. During these 2 months, he had a few admissions and during those admissions he was found to have low Na, K, and chloride for which supplementation was given. He had recurrence of chest infection and fever and hence he was referred to us. He was the eighth child. Two of his sibs had died at the age of 1 and 3 months, without any investigations done but they, reportedly, had recurrent fever and chest infections. One sib had died at 7 months of pregnancy, but no further information was available. His four sisters were all right. There was no other family history of note. On examination, the child was malnourished and dehydrated, weighing 2.5 kg, tachypneic and tachycardic. He had fever of 102 F. Chest showed bilateral scattered crackles but nil else. Heart sounds were normal. Abdomen was soft and no organomegaly was present. CNS showed mild hypotonia but deep tendon reflexes were present and no sensory or motor deficit was noted. Head circumference was within normal range and bony skeleton appeared normal. Genitals were normal. His investigations revealed, • Hb: 11.2 with normochromic normocytic picture, WCC: 11,200 with normal differentials. • Na: 122, K: 2.3, Cl: 75, HCO3: 44. • pH: 7.45, PO2: 67 mmHg. PCO2: 57 mmHg. • Urea, creatinine, and liver function tests were all normal. • Urine showed occasional pus cell and no RBCs. Urine electrolytes were Na: 20, K: 10.

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• Stool showed fat droplets ++. • Chest X-ray was normal. • Ultrasound showed altered corticomedullary differentiation suggestive of medical renal disease.

12.1 H  ow Will You Explain These Abnormalities in His Blood Gas Picture? 12.1.1 What Is Your Diagnosis? Three sibs of this patient had died with what looks like similar illness; therefore, there was every reason to suspect that this was some kind of a genetic disorder we were faced with. Severe respiratory compromise without respiratory acidosis could only be explained by accompanying metabolic alkalosis, these two together pushing up serum bicarbonate levels. Hypoelctrolytemia could be due to loss of electrolytes from kidney as suggested by higher than expected electrolytes levels in urine in spite of severe deficiency in serum. There may be some leak in the stool as well but we could not get the stool electrolytes done. Failure to thrive, respiratory problems, and family history of death following respiratory problems had to be linked. Now for the diagnosis, we thought cystic fibrosis was the only plausible diagnosis, with repeated respiratory involvement, diarrhea with fat droplets ++, and failure to thrive. Death of three sibs could be because of the same genetic defect. Delta F 508 mutation was confirmed. How could we explain electrolyte abnormalities? Kennedy and colleagues reported five cases of cystic fibrosis with hypoelectrolytemia. Their patients had almost identical presentation. They proposed that chloride loss through sweat results in hypochloremia. This results in lack of absorption of chloride in proximal renal tubule. This in turn leads to Na loss accompanying the chloride loss. Proximal tubular sodium leak results in the exchange of both potassium and hydrogen in the loop of Henle resulting in hyperkaluria and metabolic alkalosis. They also suggested that there is increased leak of potassium through sweat as well. Thus the picture resembles Barter’s syndrome without the accompanying abnormalities and hence the term “Pseudo Barter’s Syndrome” (PBS). Persistent electrolyte abnormalities lead to renal changes like interstitial nephritis and glomerulonephritis. In fact, at autopsy about 34% of CF patients show nephrocalcinosis. Changes detected in our patients on sonography could be explained on these bases. Suggested treatment of hypoelectrolytemia is increased intake of sodium, potassium, and chloride. Of course, treatment of cystic fibrosis is independent of this treatment. Progress  This child was treated with saline with potassium and I.V. Piperacillin+ Tazobactum, nebulized bronchodilators, mucolytic agents, and pancreatic enzyme

12.1  How Will You Explain These Abnormalities in His Blood Gas Picture?

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supplements and medium-chain triglycerides, multivitamins, calcium, and supplemental oxygen. There was a prompt improvement in his chest. His electrolytes returned to normal by the fifth day and metabolic alkalosis was corrected. There was a weight gain of about 110 g, in 5 days. He is kept on an oral potassium chloride solution.

Case 12: A 13-Year-Old Girl with Chronic Abdominal Pain and Vomiting

13

A 13-year-old girl presented with the chief complaints of abdominal pain, nausea, and vomiting for 2 weeks. The vomiting was not associated with eating and occurred once to twice daily. Her abdominal pain was mid-epigastric and was described as “deep” in nature. She has had no diarrhea, weight loss, or fever. There were no other symptoms present. The patient’s medical history suggested recurrent abdominal pain of similar nature requiring a few admissions. On examination, she was alert, pleasant, well developed, and nourished, and in no acute distress. Her weight and height were both within 90 percentiles for her age. The abdomen was soft, flat but was mildly tender to deep palpation just superior to the umbilicus. No organomegaly or masses were appreciated. The remainder of the physical examination was normal. • Complete blood count with differential, liver function tests, and renal function tests were normal except for mild elevation of serum amylase at 247 IU and lipase at 311 IU. • Abdominal ultrasound and a CT scan revealed an 8-cm cystic lesion near the head of pancreas.

13.1 W  hat Is Your Diagnosis, What Sort of Clinical Course You Predict, and What Is Your Expected Outcome for This Patient? We thought that this girl had acute recurrent pancreatitis. Cystic lesion was almost certainly pancreatic pseudocyst. From her old notes, we found that during the previous episode of abdominal pain, serum amylase and lipase levels were elevated to 294 IU and 233 IU, respectively, and sonography had revealed bulky pancreatic head. Since she © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2021 M. K. Ghoda, Neonatal and Pediatric Liver and Metabolic Diseases, https://doi.org/10.1007/978-981-15-9231-7_13

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• Was Afebrile. • Had a normal pulse and respiratory rate. • Had soft and flat abdomen with normal peristalses, and since she looked well, we predicted that the course of illness must be smooth and that she should recover without any problem. Various criteria that include a host of parameters are devised and three most popular are Ranson’s criteria, APACHE criteria, and Imrie’s criteria. They all work but in our experience the above-mentioned clinical criteria rarely mislead you. These scoring systems are for research study only. Clinical features suggestive of being outcome in acute pancreatitis: • Comfortable afebrile patient • No significant tachycardia • No tachypnea • Normal SpO2 • Tolerating oral fluids • Passing flatus or stool • Abdomen soft and non-distended The patient responded well to intravenous fluids, antacid therapy (usually of no use), and painkillers and was discharged home in 3 days after tolerating a low-fat diet. Fasting calcium and triglycerides were normal. Autoimmune profile to rule out autoimmune pancreatitis was normal and MRCP did not reveal any pancreas divisum and annular pancreas. Results of genetic testing for CFTR, PRSS-1, and SPINK1 revealed that the patient was positive for the SPINK1 mutation and he was subsequently diagnosed with hereditary pancreatitis. Hereditary pancreatitis: Hereditary pancreatitis is a rare congenital disorder. Patients develop repeated episodes of acute pancreatitis that are indistinguishable from pancreatitis due to any other cause. Recurrent acute bouts lead to the subsequent development of chronic pancreatic damage with morphologic, functional, and clinical findings similar to those of the classic forms of chronic pancreatitis. Several mutations of the SPINK1 gene, located on chromosome 5q32, have been described. Mutations affect the function of, pancreatic secretory trypsin inhibitor (PSTI), which normally inactivates up to 20% of trypsin activity. The end result is likely chronic elevation of active trypsin within the pancreas. Mutations have been associated with fibrocalculous pancreatic diabetes, tropical calcific pancreatitis, and idiopathic chronic pancreatitis. In some families, a clear autosomal dominant inheritance pattern has been observed. No specific or proven therapy is available for hereditary pancreatitis as yet. During acute, recurrent pancreatitis episodes, the treatment remains the same as that

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used for other forms of acute pancreatitis. Patient was not allowed anything orally, given intravenous fluids, analgesics, and proton-pump inhibitor therapy. In between the episodes, pancreatic enzyme preparations may decrease the chance of pancreatitis episodes. In patients with dilated pancreatic duct (>7 mm), a Roux-en-Y side-to-­ side pancreaticojejunostomy (Puestow procedure) can be performed in order to improve drainage of the pancreas. Pseudocysts develop in the body and tail of the pancreas, and the natural history may include spontaneous resolution or progressive increase in size. In the event of worsening symptoms, endoscopic drainage or surgical resection may be required. Acute Pancreatitis (AP): It is an acute inflammation of the pancreas. It could be very mild at one end, easily missed, and at the other end it could be life threatening. Pathology and pathogenesis: • It appears that more than one mechanism leads to pancreatic acinar damage and leakage of pancreatic secretion into interstitial tissue. • Pancreatic duct hypertension, most commonly during passage of stone from ampulla of Vater. • There may be abnormal pancreatic enzyme handling in certain conditions like hypertriglyceridemia and hypercalcemia. • There is a definite role of genetic mutation, which prevents normal activation, or destruction of active pancreatic enzymes. Etiology: • Genetic mutations like CFTR gene, PRSS gene, SPINK-1 gene mutations are increasingly implicated in many, if not all cases. • Pancreas divisum and annular pancreas, which are genetically determined. • Hyper triglyceridemia. • Viral. • Hypercalcemia. • Drug induced. Steroids, salazopyrine, Azathioprine are a few of them. • Gallstones, this is probably the commonest cause in adults but not at all common in pediatric population. • Alcohol. • Post ERCP. Clinical features: Sudden onset of pain is the most common presenting feature. This may be after a heavy meal or heavy alcohol intake. • • • •

It is epigastric or supraumbilical. May radiate to back. Severity varies but at worst it could be extremely severe. Nausea or vomiting may accompany.

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• • • • •

Dyspnea. Occasionally hematemesis and malena. There may be associated jaundice in gallstone pancreatitis. Low-grade fever, tachycardia, and peripheral vasodilatation. Epigastric tenderness, guarding, or rigidity may be present. There may be paralytic ileus. • At a later stage bruising around umbilicus, Cullen’s sign, or in flanks. • Grey-Turner’s sign develops. • Ascites, pleural effusion may develop. Diagnosis: Diagnostic procedures are twofolds: • To confirm the diagnosis • To find the etiology of pancreatitis • S. Amylase >3 times normal and S. Lipase >2 times normal are cornerstone for the diagnosis, but pancreatitis could exist without significant elevation of these enzymes and there are other intra-abdominal conditions like perforation, which could give rise to false elevation of these enzymes. –– Higher the value more reliable the diagnosis. Amylase rises within a few hours and may start falling by 16  h or so, and hence it may give false-negative results if done later than 24 h. –– Lipase rises later on and may remain elevated for up to 72 h, and hence useful if the patient has presented late. –– These enzymes have only diagnostic value but no prognostic value. –– Amylase may be falsely high in parotid gland diseases. –– In severe pancreatitis, amylase and lipase may be within normal range, the false-negative result. –– They may be raised in other body fluids like pancreatic ascites, pleural effusion associated with pancreatitis, and fluid of the pseudocyst. • Sonography may show: –– Hypoechoic, bulky pancreas, and peri-pancreatic fluid collection. –– Annular pancreas, gallstones, or CBD stones can be detected. –– Pancreatic ascites and pseudocyst may be seen. –– In chronic pancreatitis, pancreatic calcification, stones, and dilated duct may be seen suggesting a diagnosis of acute on chronic pancreatitis. –– Left-sided pleural effusion may also be seen. • CT scan may show: –– Hypoechoic bulky pancreas with the involvement of peripancreatic tissue. –– With contrast, it may suggest degree of necrosis or hypoperfusion. –– Ideal timing to do a CT scan is around 4–5 days but very few require it. –– CT scan can also be used to gauge the severity of pancreatitis, the popularly known as Balthazar’s CT severity index but there are good bedside criteria already available for this. –– Pancreatic pseudocyst, pancreatic abscess, and changes of chronic pancreatitis may be seen.

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–– Putative causes of pancreatitis like gall stones; annular pancreas may also be seen. To prevent exacerbation of necrosis and renal failure, it is important to hydrate the patient properly before contrast injection. • MRI with Gadolinium is said to be useful with a very high sensitivity and specificity, more than 90%, but this is not routinely available. Differential Diagnosis: Many acute abdominal conditions could be confused with pancreatitis. • Biliary colic. • Perforation may have more diffuse and more dramatic onset of pain and amylase may be falsely elevated. • Mesenteric ischemia. Intestinal obstruction causes predominantly vomiting and, initially at least, the pain is spasmodic rather than crescendo pain of pancreatitis. Abdominal X-ray helps to rule out intestinal perforation and obstruction. Assessment of severity: In our experience: • • • • •

Toxic look. Persistent tachycardia. Persistent fever. Tachypnea, are useful features, which suggests moderate-to-severe pancreatitis. Normal rate of pulse, normal respiratory rate, normal temperature, and a soft abdomen is suggestive of mild attack of pancreatitis for all practical purposes.

Ranson’s criteria  This takes into account the following parameters: • • • • • • • • •

Hematocrete. White cell count. Blood sugar. Urea. pH of blood. paO2. SGOT. LDH. S. Calcium.

These are monitored over 48 h, and deterioration in three or more parameters suggest severe disease.

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APACHE-II (Acute Physiological and Chronic Health Evaluation) criteria, a detailed list of variables, are increasingly used which gives accurate assessment within 24 h, and could also be used for monitoring. The following may be independent risk factors: • Age above 65 years • Body mass index (weight/height 2) more than 30 • Pleural effusion • “C” reactive protein >120 mg/L Management: • Supportive: –– Analgesia: Analgesics depending upon severity of pain. The fear of sphincter of Oddi spasm with opioids is not authenticated and these agents may be used, if required. –– Patient is kept nil by mouth for as little time as possible. –– IV fluids, colloids, and crystalloid, to maintain peripheral perfusion and urine output. –– For the first few days, several liters of fluid and colloids may be required as there is a large amount of sequestration in the third space. –– Antibiotics may not be required in mild or moderate cases and a wait and watch strategy is followed. In severe cases or patients with concurrent cholangitis, third-generation cephalosporins, e.g., cefotaxime and metronidazole may be required. Carbapenum group antibiotics like imipanum and meropanum have high penetration into the pancreatic tissue and are very useful when there is pancreatic necrosis. Other antibiotics like Cefuroxime, Ceftazidime, and combination of Piperacillin and Tazobactum are all useful. –– Calcium may be required for hypocalcemia. –– Insulin for hyperglycemia. It is preferably given as a continuous infusion. –– Oxygen to counter hypoxemia. –– Enteral nutrition started early is reported to help recovery. This is achieved by putting a nasojejunal tube. At the first sign of intestinal activity, small amount of fluid is started and increased if tolerated well. –– Over and above being cheap, it is practically without any side effects. –– In an appropriate case, even oral fluids could be started. –– An impacted stone at papillary orifice needs to be removed by ERCP in emergency and associated cholangitis may also require emergency drainage by sphincterotomy or stenting. –– If infected necrosis is suspected, a fine needle aspiration is done to identify the organisms. In practice though, this is rarely done. –– Patients with severe narcotizing pancreatitis require necrosectomy. Current concept though is to delay the surgery as long as possible. –– Pancreatic abscess may need draining either internally or externally or an open surgical intervention may be required.

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–– Pancreatic pseudocyst may need draining only if it is causing pressure symptoms. This could be done under sonography guidance or by internal drainage by placing a nasopancreatic drain or pancreatic stent at EUS/ERCP through the pancreatic duct and into the cyst, or by endoscopic cysto-gastrostomy or cysto-­duodenostomy, when the cyst is projecting prominently into the respective organ or by surgery. –– In future antioxidants and TNF alpha-receptor antagonists, recombinant human interleukin-10, which downregulates inflammatory response, may play a crucial role. Prognosis: • Excellent in mild and moderate pancreatitis. • Severe pancreatitis has high morbidity, and mortality, may approach 30% in infected necrosis. • Old age, creatinine level >2 mg/dL, pleural effusion, or a pulmonary infiltrate within 24 h of admission, coma, and comorbid condition, are all predictors of increased mortality. • Alcoholic and gallstone pancreatitis have low mortality rates, around 5%, whereas mortality is high in idiopathic and postoperative pancreatitis.

Case 13: A 6-Month-Old Child with Neonatal Cholestasis and Generalized Edema

14

A 6-month-old child was referred for neonatal cholestasis and generalized edema. He was born in seventh month because of oligohydramniose. There was no parental consanguinity. His elder sister died of “sepsis” when she was a week old. That pregnancy was also affected by oligohydramniose. No further information was available on her death. This child had unconjugated hyperbilirubinemia at birth requiring phototherapy. Subsequently, he was breastfed and seemed to be doing well. At about 10 weeks, he was noted to have anemia and was admitted and transfused. • Liver functions done at that time showed conjugated bilirubinemia of 3 mg. and SGPT/ALT of 248 IU, and alkaline phosphatase of 800 IU. • He was negative for HBsAg, VDRL, and TORCH complex. • Neonatal TSH was normal. • Sonography showed normal looking liver, gall bladder, and biliary tree. Spleen was normal. • No further information was available on anemia. At about 24 weeks, the child was taken to the pediatrician for a routine check and was found to have puffiness of the eyes, and generalized edema with bilateral hydrocele. Liver functions showed mild conjugated hyperbilirubinemia with markedly raised alkaline phosphatase. SGPT/ALT was mildly raised. Patient was then referred for further opinion. On examination, the child looked cheerful and alert. He had a puffy face and pronounced hydrocele. Liver and spleen were not palpable. There was obvious jaundice. There was gross pedal edema, which was pitting in nature. CVS showed normal heart sound. Lungs were normal. CNS showed normal tone and power and normal sensorium.

© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2021 M. K. Ghoda, Neonatal and Pediatric Liver and Metabolic Diseases, https://doi.org/10.1007/978-981-15-9231-7_14

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• His Hb was 10.8 with normochromic normocytic picture. • G6PD levels, hemoglobin electrophoresis, serum iron, B-12, and folate were all normal. Peripheral smear was unremarkable. • TSH, renal functions, and electrolytes were normal. • Bilirubin was 2.2 with 70% conjugated variety. SGPT was 238, GGT was 650 and alkaline phosphatase was 810. Albumin was 3.4 g/L and globulin was 2.1 g/L. Prothrombin time was 14/12 s. • Urine was normal with only a trace of albumin and urine for metabolic screening was normal. • Stool was also reported to be normal. • USG of abdomen and CT scan revealed normal liver, spleen, and biliary tree and fluid collection in the tunica vaginalis on both sides. • Doppler study revealed normal flow in all major vessels of abdomen. Echo study of heart showed normal valves and normal ejection fraction.

14.1 What Is Your Line of Thinking? What Is Your Diagnosis? This was difficult. • Mild cholestasis was undeniable but there was no serious decompensation to account for the amount of lower limb edema and hydrocele. • There was no evidence of nephrotic syndrome as judged by urinary protein loss and total serum albumin. • Renal functions were normal. • Anemia was insignificant to account for the level of edema. • CVS and RS both were in good shape to give rise to edema. • Hydrocele was aspirated at the suggestion of a pediatric surgeon in case it was tense and pressing on internal iliac vessels and causing lower limb edema (although it seemed very farfetched). This did not result in any reduction of the lower limb edema. At this point, we really searched hard and we think this child could have Aageneas syndrome. Aageneas syndrome: • Aageneas syndrome is characterized by neonatal cholestasis and lower limb edema. • The salient features are neonatal hepatitis syndrome which later goes on to develop into a chronic cholestatic condition. • There may be an abnormal development of lymphatics leading to lymphatic abnormalities. • The lymphatic abnormalities could take various forms like localized lower limb edema, or sometimes a more subtle generalized edema in absence of hypoalbuminemia. • There may be hemangiomas or lymphangiomas.

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• Lymphatic abnormality may appear simultaneously or after jaundice has developed. • Lymphedema may pose a major problem as the child grows. • Chronic liver disease or portal hypertension has not been reported. • The abnormality is now detected to be on chromosome 15q, but the exact genetic mutation is not found out. Progress  The child is now put on fat-soluble vitamins and calcium and weekly vitamin K. He is also given high-calorie diet.

Case 14: A 6-Week-Old Child Who Had Progressive Jaundice and Creamy White Stools

15

A 6-week-old child was seen because of progressive jaundice. He was the firstborn, FTND, from non-consanguineous marriage. Pregnancy was uneventful. Soon after birth, he was noticed to have jaundice. Parents were reassured that this will settle down. After about 7 days, jaundice became more prominent and the parents noted very light-colored stool. • Liver functions done at that time showed mild conjugated hyperbilirubinemia with raised SGPT/ALT at 300 IU. This was thought to be breast milk jaundice and the child was put on top feed. At about 3 weeks, there was no improvement and stool now was nearly white. • Bilirubin was 9 mg with 60% conjugated variety. SGPT/ALT was 237 IU. At this point, the child was referred to us. The child was playful and had normal growth and milestones. There was a deep jaundice. Liver was enlarged ++, firm and non-tender, and spleen was just palpable. There were no ascites, ankle edema, or visible veins on abdomen. There was partial ptosis with dilatation of the pupil in the left eye but there were no focal motor signs. Deep tendon reflexes were present and planters were flexures. There was no neck rigidity. Just as the examination finished, the child had a generalized convulsion.

15.1 What Is Your Working Diagnosis for Convulsions? Neurological findings, which had appeared on the very morning, were suggestive of third nerve palsy. In a chronically jaundice patient, this is taken to be an intracranial bleed secondary to vitamin K responsive coagulopathy. We were planning an urgent CT scan of the brain when the child had convulsions. The child was stabilized and © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2021 M. K. Ghoda, Neonatal and Pediatric Liver and Metabolic Diseases, https://doi.org/10.1007/978-981-15-9231-7_15

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a CT scan done later that afternoon showed an intracranial bleed in the middle cerebral territory. PT was grossly prolonged at more than 2 min. This was corrected with plasma and vitamin K was given intravenously. • Liver functions showed bilirubin of 10 mg ALT/SGPT of 215 IU, alkaline phosphatase was at 1159 IU, GGT was 758 IU, and serum albumin was 3.8 g/dL. • Urine metabolic screen was normal. • No reducing substances were seen in urine and total Galactose was within normal range. • CBC showed normal pattern and electrolytes, sugar and creatinine were all normal. • HBsAg and HCV antibodies were negative and so was the TORCH screening. • Sonography showed a collapsed gall bladder and CBD was not seen. • Liver was moderately enlarged, spleen was mildly enlarged, and portal vein and splenic veins were of normal diameter. No varices were detected.

15.2 What Further Tests Would You Like to Do? That this child had chronic severe cholestasis was evident. • The commonest cause is Extra Hepatic Biliary Atresia (EHBA) but other causes need ruling out as well. • In our practice, we see galactosemia very frequently so we always rule it out by appropriate screening tests and a trial of Galactose-free diet while the tests are being carried out. • We in India see very little of alpha-1 antitrypsin deficiency so we do not look for it now on a priority bases. • TORCH group and other metabolic diseases may also need looking for but they rarely involve liver only and severe cholestasis is uncommon. At the beginning of this book, we have shown an algorithm to deal with neonatal jaundice. To us, it seems a perfect algorithm for practicing pediatricians in small or mid-sized towns. Generally, in a non-sick child, we start with a good sonography in a well-­prepared patient, if required with IV support for proper fasting. If the USG shows collapsed gall bladder and CBD is not outlined, then in a case of persistent clay-colored stool, EHBA is a very strong possibility and we proceed for laparoscopic cholangiogram and liver biopsy. This will clearly diagnose EHBA, which if not present, biopsy taken simultaneously may be useful. If, on the other hand, GB or CBD is normal with or without creamy stool, EHBA is very unlikely. We also look for infections in an appropriate setting, look for common metabolic causes, and then proceed for liver biopsy. Since HIDA scan cannot distinguish between severe cholestasis and EHBA, in our practice it is used prior to surgery. This is discussed later on. In this case, the liver biopsy was in keeping with the clinical diagnosis of EHBA and all other common causes were absent. Surgery was offered and declined as it

15.3  Extra Hepatic Biliary Atresia

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happens so often. The child developed portal hypertension and died nearly a year after the initial consultation.

15.3 Extra Hepatic Biliary Atresia Extra Hepatic Biliary atresia (EHBA) is characterized by obliteration or discontinuity of the extrahepatic biliary system, resulting in obstruction to bile flow. It is the most common surgically treatable cause of cholestasis encountered during the newborn period. If not surgically corrected, secondary biliary cirrhosis invariably results. Epidemiology • Incidence of biliary atresia is highest in Asian populations. • It occurs more commonly in females than in males. • It is unique to the neonatal period. • The fetal/perinatal form is evident within the first 2 weeks of life; the postnatal type presents in infants aged 2–8 weeks. Anatomy and classification: Patients with biliary atresia can be subdivided into two distinct groups: Those with isolated biliary atresia (postnatal form), which accounts for 65–90% of cases. Those with associated situs inversus or polysplenia/asplenia with or without other congenital anomalies (fetal/embryonic form), comprising 10–35% of cases. EHBA could also be classified based on the predominant site of atresia: • Type I: Obliteration of the common duct; the proximal ducts are patent. • Type II: Atresia of the hepatic duct, with cystic structures found in the porta hepatis. • Type III: Atresia of the right and left hepatic ducts to the level of the porta hepatis. It is the commonest with about 90% of the patients falling in to this group. Etiology: • The disorder is rarely seen in infants who are stillborn or in premature infants, which supports a late gestational etiology. • It is not clear what is causing EHBA but infectious agents are the most likely culprits. • No single agent has been identified as causative for biliary atresia, but reovirus 3 and cytomegalovirus are thought to have some role in the etiology. • Genetic factors may also play some part but the exact role is not defined yet. Clinical presentation: • Variable degrees of jaundice, dark urine, and creamy white stools. • In most cases, acholic stools are not noted at birth but develop over the first few weeks of life.

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• Appetite, growth, and weight gain may be normal, although a higher incidence of low birth weight may be observed. • Hepatomegaly may be present early, and the liver is often firm or hard to palpation. • Splenomegaly is common, and an enlarging spleen suggests progressive cirrhosis with portal hypertension. • In the more common postnatal form, physiologic jaundice frequently merges into conjugated hyperbilirubinemia. • In patients with the fetal/neonatal form (polysplenia/asplenia syndrome), a midline liver may be palpated in the hypogastrium. • Associated cardiac anomalies may be detected. Differential diagnosis: It could be confused with several other causes of neonatal hepatitis and especially distinction from severe neonatal cholestasis could be very difficult. Two broad categories could be developmental defects and non-obstructive cholestasis due to infective or metabolic causes. Developmental defects: • Alagille Syndrome • Caroli Disease • Nonsyndromic intrahepatic bile duct hypoplasia • Non-obstructive cholestasis: This includes all causes of neonatal hepatitis. Investigations: • Conjugated hyperbilirubinemia, which is commonly 6–12 mg/dL, with the conjugated fraction comprising 50–60% of total. • Significantly elevated alkaline phosphatase and gamma-GT. • ALT/SGPT and AST/SGOT are raised but generally less than three times normal. A markedly elevated ALT/AST >800 IU/L, indicates significant hepatocellular injury and is more consistent with the neonatal hepatitis syndromes. • Ultrasonography: It may demonstrate absence of the gallbladder and no dilatation of the biliary tree. Unfortunately, the sensitivity and specificity of these findings do not exceed 80%. It is more important in ruling out biliary atresia than confirming it. If in a properly prepared patient a well-distended gall bladder is seen with normal IHBR and normal CBD, EHBA is most unlikely. It can also exclude specific anomalies of the extrahepatic biliary system, particularly Choledochal cysts. • Intraoperative cholangiography: It definitively demonstrates anatomy and patency of the extrahepatic biliary tract. It must be done before attempting an anastomosis. • Hepatobiliary scintiscanning is useful in evaluating infants with suspected biliary atresia. Unequivocal evidence of intestinal excretion of radiolabel rules out EHBA. Although failure of this does not confirm EHBA. We generally use this test prior to surgery to remove the remote possibility of unnecessary surgery, otherwise use other modalities in combination to come to the correct diagnosis. • Liver biopsy: It is the most valuable study for evaluating neonatal cholestasis. In experienced hand, which is a rarity, an adequate biopsy specimen can differenti-

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ate between obstructive and hepatocellular causes of cholestasis, with 90% sensitivity and specificity for biliary atresia. Biopsies are not usually diagnostic in those younger than 2 weeks, and serial samples, usually at 2-week intervals, may be required to reach a definitive diagnosis. Treatment and complications: • Once biliary atresia is suspected, surgical intervention, Kasai portoenterostomy, is the only mechanism available for therapy. • Results of surgery are best in high volume centers with dedicated surgeons. These types of patients must not be referred to an occasional pediatric surgeon. Complications following portoenterostomy include both acute and chronic problems. • Later in the course, complications related to progressive liver disease and portal hypertension occur in more than 60% of infants who achieved initial surgical success. • Cholangitis develops in 50% of patients following portoenterostomy. • Hepatocellular carcinoma may be a risk for those patients with cirrhosis and no clinical evidence of portal hypertension. Prognosis: • The most critical determinant of the outcome remains age at the time of operation and center where the surgery is done. Patients are significantly less likely to require early liver transplantation if the portoenterostomy is performed when they are younger than 10 weeks. • The rate of decline in serum bilirubin levels directly correlates with a positive prognosis. • Overall, 66% of infants undergoing the Kasai procedure ultimately required a liver transplant.

Case 15: Milk by Any Other Name Could Also Be Milk

16

A 3-month-old child was referred for jaundice. He was FTND, from a non-­ consanguineous marriage. He had one sib who was 2 years old and doing well. Antenatal history was unremarkable. He had a “physiological jaundice,” which continued well beyond 3 weeks and hence it was thought to be breast milk jaundice and the child was given top feed with a proprietary brand. Even after this “switch,” the child did not improve, started having vomiting and intermittent creamy white stool. There was failure to thrive and excessive irritability. On examination, the child was malnourished, had deep jaundice and appeared irritable. Liver was moderately enlarged and firm and non-tender. Spleen was not palpable. There were no visible veins and there were no ascites. Central nervous system examination did not reveal any focal localizing signs, deep tendon reflexes were present and planters were flexors. Examination of the eye showed no cataracts and fundus was normal. Heart and lungs were normal. • Bilirubin was 9.3 mg, with 60% conjugated variety, SGPT/ALT was 593 IU, ALP was 240 IU, PT was 24.15 s, albumin was 3.0 g/dL. • Blood glucose was 51 mg. • Urea and electrolytes were normal. • USG showed enlarged liver but spleen and portal veins were normal. • Gall bladder was distended and CBD was traced up to the papilla of Vater. There were no ascites. • Urine showed nonreducing substance while the child was on top feed. Total galactose was 1880 mg (up to 300 mg). Urine did not show any other metabolic abnormalities. • HBsAg, HCV were negative. • Cytomegalo IgG was raised. • X-ray chest was normal.

© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2021 M. K. Ghoda, Neonatal and Pediatric Liver and Metabolic Diseases, https://doi.org/10.1007/978-981-15-9231-7_16

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Let us analyze… This child is most likely to have galactosemia. Raised IgG against Cytomegalovirus is a very common finding and not of any consequence. We need to do confirmatory enzyme assays, which have been described below. As soon as the initial screening tests are done, it is our practice to stop galactose till we are reasonably certain that we are not dealing with Galactosemia. Progress  Enzyme study confirmed classical galactosemia. The child was put on soy formula and we monitored a good recovery in liver functions and clinical features. Now he has become a very playful child and thrived very well. About a year later the child was again brought with jaundice. He was irritable and had mild hepatomegaly. Both mother and father denied any lapse in the dietary advice.

16.1 How Will You Proceed Now? It was puzzling. Most of the time there is always a lapse in dietary restriction. Or he could have incidental jaundice. What could this be? We did not have to struggle too much. On the same evening, the child’s “mama” came surreptitiously. The child with his mother had gone to his mama’s. There they ran out of soy formula, so they gave him cow’s milk. Soon the child became irritable and started vomiting and having yellow urine. Scared, they went to the town’s only chemist looking for the “powder.” The “chemist” reassured them that he had the “same” powder. This powder was ordinary lactose-­containing variety. Since the child did not improve they panicked and brought him back. To avoid in-laws’ wrath, the mother and mama concocted the story that there had been no dietary digression. He pleaded not to disclose this fact or his sister would be in trouble. A sad reflection on society!!! The child was put back on the soy formula. There was a prompt resolution of his jaundice. About 3 years later he came again, this time with convulsions. There was no focal localizing sign, no neck rigidity, and MRI of brain was normal. There was no hypoglycemia and CBC, LFTs, electrolytes, and urea was normal.

16.2 What Could This Be? No cause was found. Since normal metabolism could produce a small amount of galactose, neurological features may progress slowly and we thought this could be the cause in this child. Galactosemia: Galactosemia is the inability of the body to metabolize the simple sugar galactose, causing the accumulation of galactose-1-phosphate in the body. This causes damage to the liver, central nervous system, and other body systems.

16.2  What Could This Be?

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Etiology and epidemiology: • Galactosemia is transmitted as an autosomal recessive trait. • It occurs in approximately 1 out of every 60,000 births among Caucasians, while the rate is different for other groups. In India, it appears to be fairly common. Biochemistry of Galactosemia: Galactose makes up half of lactose, a disaccharide. If an infant with galactosemia is given milk, derivatives of galactose build up in the infant’s system, causing damage to the liver, brain, kidneys, and eyes. Individuals with galactosemia cannot tolerate any form of milk, human or animal, and must carefully watch intake of other galactose-­containing foods. There are three forms of the disease: • Galactose-1-phosphate uridyl transferase (GALT) Galactosemia, the most common and most severe form • Deficiency of galactose kinase (GALK) • Deficiency of galactose-6-phosphate epimerase (GALE)

Galactose

deficiency,

classic

Galactitol

Galactokinase

X

Galactose-1-P Gal-1-T (GALT)

UDP gal Galactose epimerase (GALE)

UDP glucose Gluconeogenesis or Glycolysis Galactose is metabolized to glucose (1-phopsphate) with the help of three enzymes shown. Galactose tranferase is the commonest enzyme missing resulting in class galactosemia. This results in decreased product of glucose which may lead to hypoglycemia and increased production of Galactitol which is toxic to various cells including those of liver and results in liver failure and cataract amongst many other things.

Clinical presentation: • Jaundice: This could be initially unconjugated also and only after some time that it becomes hepatocellular type and this may put the pediatrician off his guard. If this is not treated in time the child may develop decompensated the liver disease with ascites, ankle edema, and visible veins on abdominal wall. In such cases, the liver may be enlarged significantly. • Vomiting.

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• • • • • • • •

16  Case 15: Milk by Any Other Name Could Also Be Milk

Poor feeding. Failure to thrive. Lethargy. Irritability Convulsions. Mental retardation. Cataract formation, although in our practice we have not seen many such cases. Recurrent septicaemia, especially with Escherichia coli.

Investigations: Since galactosemia is fairly common in India, it is our practice to suspect galactosemia in every case of neonatal jaundice and to look for it. We also withdraw milk till the test results are pending. The presence of non-glucose “reducing substances” in the infant’s urine with normal or low blood sugar while the infant is being fed breast milk or a formula containing lactose. This will disappear if the child is off galactose while being tested. • Total galactose in the blood is raised if the child is still on galactose. • Measurement of enzyme GAL 1 T activity in the red blood cells could give a definite diagnosis. • Hypoglycemia. • Aminoaciduria. • There may be evidence of septicemia with high WCC and CRP. • Sonography may reveal evidence of portal hypertension and hepatomegaly. Ascites may also be seen. • Prenatal diagnosis by direct measurement of the enzyme galactose-1-phosphate uridyl transferase is possible now. • Molecular diagnosis by NGS is an important advance in diagnostics. Treatment: • Strictly avoid all milk, milk-containing products, and other foods that contain galactose. The infant can be fed with soy formula or other lactose-free formula. • The condition is lifelong and requires abstinence from milk, milk products, and galactose-containing foods for life. • Calcium supplements are given. • Complications in poorly treated patients are Cataracts and Cirrhosis. • Severe infection with bacteria, particularly with E. coli. • Delayed speech development. • Severe mental retardation. • Irregular menstrual cycles, decreased function of ovaries, leading to ovarian failure. • Tremors and uncontrollable motor functions. • Death.

16.2  What Could This Be?

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Prognosis: If diagnosis is made early and milk products are strictly avoided, the prognosis is reasonably good. Despite strict avoidance of galactose, mild intellectual impairment may still develop. This is because normal human metabolism is producing a small amount of galactose. Prevention and genetic counseling: If there is a family history of galactosemia, genetic counseling will help prospective parents make decisions about pregnancy and prenatal testing. Once the diagnosis of galactosemia is made, genetic counseling is recommended for other members of the family.

Case 16: An 8-Year-Old Son of a Lady Executive Who Was a Keen “Net” Searcher

17

Dr. Google has played havoc in the medical field. These days you see all sorts of confusion regarding health because patients consult Dr. Google first. Here is one example. A lady executive at the local hospital, of north Indian origin, asked for urgent appointment as she found out that her son had “abnormal liver function tests” done at a routine health check-up. She had kept ready with her a pile of investigations and “printouts” by first trying herself to evaluate the case from “Internet.” Since she was an executive at the local hospital, few doctors, “cronies” may be a more appropriate word, were also accompanying her and had already mentioned to her about cirrhosis and the rest of it. She suggested that the child should be admitted and if necessary she could take her to a nearby metro city for further evaluation. The whole “circus” was a bit amusing to say the least. But with spread of corporate culture in health industry, these scenarios are going to be routine, so be mentally prepared! There was no history of jaundice, abdominal pain, weight loss, diarrhea, fever, fatigue, failure to thrive, psychiatric, or neurologic symptoms. There was no past history of accidents, operations, or blood transfusions. There was no family history of any sort. On examination, the child appeared well-nourished, weighing 44 kg, and measuring 142  cm, in height. He had no complaints. Vital signs were within normal limits for her age. The abdomen was soft, flat, and non-tender with normal bowel sounds. Liver and spleen were not palpable. There was no ascites or visible veins. Neurological examination was normal. There were no stigmata of chronic liver disease. Investigations showed: • Hb of 12.2 g/dL, WCC of 7400 with normal differential, MCV of 77fl. and MCH of 25, platelet count of 253,000.

© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2021 M. K. Ghoda, Neonatal and Pediatric Liver and Metabolic Diseases, https://doi.org/10.1007/978-981-15-9231-7_17

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• Bilirubin was 1.2 g, with 70% conjugated. SGPT/ALT level was 67 IU and SGOT/AST was 59  IU.  Alkaline phosphatase was 123  IU.  Albumin was 3.8 g/dL, globulin was 2.1 g/dL. • HBV, HCV, HAV, HEV were all negative. Serology for dengue, malaria, leptospira, infectious mononucleosis, and HIV were negative too. • Serum copper and Ceruloplasmin were within the normal range. • ANA was positive, anti-smooth muscle, anti-F-actin, and anti-liver/kidney microsomal antibodies were all negative. The ANA titer was 1:320, with a homogeneous pattern. Rheumatoid factor, anti-double-stranded DNA, and complement three levels were normal. • Fasting sugar and lipid profile were entirely within the normal range. Electrolytes and urea and creatinine were normal too. • Sonography showed a normal liver, spleen, portal vein, and biliary tree. Doppler study was showing normal blood flow in the portal venous system.

17.1 What Should I Do Now? Almost all investigations were done by the time I saw the child. I had to think fast. The whole case was being “discussed” with the consultant in the nearby metro city. All I had to think was: • Is it a case of autoimmune hepatitis? Then why the globulin was not raised at all?! Was it a case of nonalcoholic steatohepatitis? Sonography was not showing any fatty liver, but it still could exist! Fasting glucose and lipid profiles were normal too. Still it could be NASH, but the child was not obese at all! Still NASH could exist. But why then abnormal autoimmune profile? That is not a feature of NASH. • Could it be a case of drug-induced hepatitis? With his mom being very busy, was the child mixing with the wrong company? I may have to go for liver biopsy, but will she agree? Or should I be doing it in the first place? At this point, I remembered the genetic background of the child. He was of a north Indian lineage. My previous work has established that celiac disease is not uncommon in this geographical region. Could this be then immune-mediated enteropathy? I suggested that serologic testing for celiac disease should be performed because this disease has been increasingly recognized as a potential cause of hepatitis. Failing this we go for liver biopsy. We did tissue transglutamase antibodies (TTGA) and anti-endomysial antibodies (anti-EMA) and both were strongly positive. In our experience, they are excellent markers for celiac disease.

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This was then confirmed by distal duodenal biopsy, which showed villous atrophy, crypt hyperplasia, intraepithelial lymphocytic infiltrate, and expansion of the lamina propria by plasma cells, consistent with a diagnosis of celiac disease. Progress  The child was offered gluten-free diet. Fortunately for us, the parents had already looked upon the “net” about celiac disease by then and were more than willing to go for it. We generally suggest that the whole family goes on the diet to assure successful outcome. The patient was maintained on a gluten-free diet. His growth and development continued to be adequate for age. On follow-up laboratory studies, his TTGA, EMA, ALT, and ANA levels normalized. His bone density scan revealed reduced mineral density requiring calcium supplementation. Celiac Disease: Celiac Disease (CD) is an immune-mediated chronic enteropathy with a wide range of presenting manifestations of variable severity. It is triggered by the ingestion of the gliadin fraction of wheat gluten and similar proteins of barley and rye in genetically susceptible individuals with subsequent immune reaction, leading to small bowel inflammation. Epidemiology: • Celiac disease is seen in all races and all geographies, but some populations have higher incidences. • The distribution of celiac disease is bimodal, with a first peak at 6–24 months of age and a second peak in the fourth and fifth decades of life. Pathogenesis: • Gluten is the environmental factor that triggers CD; it is the gliadin fraction of wheat gluten and similar proteins in other grains, collectively known as prolamins, which is associated with the development of intestinal damage. • Alpha-gliadin epitopes are important only after eating wheat, whereas DQ2-­ omega-­I is important after eating wheat, rye, or barley. • Although the pathogenesis of the disease is not fully understood, gluten is thought to induce mucosal damage, both by a direct toxic effect and by initiating a cascade of immunologic responses. Pathology: • There is a variable degree of inflammatory cells infiltrate and there is a variable degree of villous atrophy. • There is an increase in the intraepithelial lymphocytes. • These changes are totally reversible with gluten withdrawal. • Mucosal injury does not necessarily correlate with the severity of the symptoms.

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Genetics: • HLA genotypes DQ2 and DQ8 play a major predisposing role in the development of CD, being found in almost 100% of patients. • Despite their key role in the pathogenesis of celiac disease, HLA genes account for only 40% of the genetic component of this disease. • Genes other than HLA may also be playing an important role. • The gene expressing myosin IXB (MYO 9B), a molecule involved in the regulation of intestinal permeability, is strongly associated with complications of CD, such as refractory celiac disease type II and enteropathy-associated T-cell lymphoma. Clinical features: • It may present at any age, from infancy to adulthood. • There are essentially three different presentations of celiac disease: –– Classic or early onset –– Atypical or late onset –– Asymptomatic • CD can manifest with a range of clinical presentations, including the typical malabsorption syndrome, chronic diarrhea, weight loss, abdominal distension, as well as a spectrum of symptoms potentially involving any organ system. • Patients with classic or early-onset celiac disease usually present before 2 years of age with gastrointestinal symptoms and complications, such as failure to thrive, diarrhea, constipation, vomiting, decreased appetite, and abdominal distention. • Asymptomatic patients are classified as either silent or latent celiac disease. Patients who present with no symptoms but with abnormal biopsies and serologic markers are classified as “silent-type.” • Patients with abnormal serological markers and normal biopsy are called “latent” celiac cases. • Stunting of growth could be remarkable and in our experience present in both classic and silent types of celiac disease. • There may be recurrent mouth ulcers. • There may be iron deficiency anemia refractory to oral iron therapy. • Megaloblastic anemia and mixed type of anemia is also commonly seen. • Dermatitis herpatiformis is also seen. • The clinical presentation of CD in the elderly (≥65 years of age) can be different from the clinical presentation in the young patient (patients diagnosed at 18–30 years of age). • Lesser known extraintestinal manifestations are: –– Neurologic: Ataxia, depression, seizures, autistic-like behavior, headaches, and peripheral neuropathy. –– Rheumatologic: Arthritis or arthralgia is sometimes associated with systemic lupus erythematosus or rheumatoid arthritis.

17.1  What Should I Do Now?

–– –– –– –– ––

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Chronic autoimmune hepatitis and liver failure requiring liver transplant. Cardiac: Pericarditis. Dental/oral: Dental enamel hypoplasia, aphthous lesions. Endocrine: Short stature, delayed puberty. Infertility and miscarriage. Bone: Decrease in bone density.

Liver involvement in celiac disease: • The pathogenesis of liver disease in celiac disease is unclear. • Hypertransaminasemia is the most common hepatic presentation of celiac disease; it has been described in up to 54% of children with a classic presentation at the time of celiac disease diagnosis. • Other abnormalities encountered are; primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis. • The abnormal transaminases frequently improve on a gluten-free diet in 75–95% of patients. • False-positive celiac serology in the setting of liver disease has been described, so intestinal biopsy for confirmation of celiac disease is uniformly recommended. Investigations: • A small intestinal biopsy showing the typical celiac enteropathy is the gold standard for proper diagnosis of celiac disease. • The combination of serologic markers offering most sensitivity and specificity for the diagnosis of celiac disease is the anti-endomysial. • IgA and TTG IgA antibodies. • Since IgA deficiency is often seen in patients with celiac disease, patients should have a total IgA level measured at the same time that the antibody testing is done. In IgA deficiency, IgG levels may be of help. • Both serologic markers may be falsely negative in children younger than 2 years of age. • HLA haplotyping is required only in a very select subgroup of patients, where the diagnosis is indeterminate based on inconclusive biopsy and serology results, HLA testing may help in classifying the patient as being at high or low risk for having celiac disease. The DQ2 and/or DQ8 markers are present in 97% of celiac disease patients. Therefore, patients negative for these two markers are very unlikely to have celiac disease. • Tissue trans-glutamase antibodies (TTGA) testing is a very robust serological test and could be used for mass screening as well. It is highly sensitive and specific and may be preferred by patients and their relatives, in an appropriate case, over jejunal biopsy. • Guanosine diphosphate (GDP) is another reliable enzyme used as a marker for CD.

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Treatment: Suspect Celiac Disease in India if * Diarrhea with severe bloating after weaning * Diarrhea with severe microcytic hypochromic anemia * Failure to thrive with aphthous ulcers and microcytic hypochromic anemia. * Juvenile diabetes of hypothyroidism with or without microcytic hypochromic anemia * Recurrent jaundice or chronic liver disease with microcytic hypochromic anemia

• Lifelong gluten withdrawal is the gold standard treatment. Vitamin and iron supplements may be required. • Involving the entire family in the diet change yields far higher success than involving only the patient. • An experienced physician or dietician familiar with local milling pattern could be of immense help. • In addition to diet restrictions, patients may require supplementation with folic acid, calcium, vitamin D, zinc, and iron. Complications: • Small bowel lymphoma is the most dreaded complication and needs regular monitoring. Prognosis: • Prognosis is good for those who can follow a strict diet. • Monitoring a celiac patient: –– Six monthly anthropological measurements, growth velocity, CBC, iron, folate, vitamin D3, and B12 levels. –– Check serum calcium and bone density. Monitor thyroid functions and fasting blood sugar, LFTs, and thyroid functions. –– Lookout for any GI symptoms like abdominal pain and weight loss, which may suggest development of lymphoma. Screening for family members  Siblings of the index case may be offered screening by means of TTGA, which may detect latent cases.

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In summary, this case emphasizes the importance of maintaining a high index of suspicion for celiac disease, in appropriate population, given the wide array of signs, symptoms, and laboratory abnormalities with which a patient may present.

Celiac histology

NORMAL

CELIAC Duodenal folds show scalloping which is easy to understand when compared with medieval fort

Case 17: Neo Rich Parents Who Wanted the Best for Their Child!

18

A full-term male neonate presented at age 12 weeks with vomiting, pale loose stools, and failure to thrive. His liver was slightly enlarged and he had cholestasis with a total and conjugated plasma bilirubin of 3.4 mg and 2.6 mg, respectively. As stool consistency and vomiting worsened, an acute enteric infection was assumed and the child was given intravenous fluid and antibiotics. While on this regime, vomiting subsided and the child was discharged with advice to be breastfed only. About a week later, the child was readmitted with vomiting and constant crying for almost 24 h and the child was referred to us. This was a first child from a non-consanguineous marriage born at full term. There was no significant family history. Though not related, the parents came from a small community. Both worked in IT industry and lived an affluent lifestyle, which was not the family norm. They had a nuclear family and parents from neither side were staying with them. A nursemaid looked after the child. Both parents were well versed with various modern-day nuances of parenting and wanted “the best” for their child as they had a “pretty ordinary” childhood. The child was top-fed from birth for reasons we did not go into. On physical examination, the child appeared malnourished (3700  g, 53  cm). Both liver and spleen were enlarged. CVS, RS, and CNS were normal on examination. • Bilirubin was 4.2  mg with 70% conjugated variety. SGOT/AST 95  IU, SGPT/ALT 107 IU, total proteins were decreased at 4.4 g% with albumin of 2.2 g%. • Blood glucose levels were slightly decreased at 57 mg% and prothrombin time was in the low normal range. • Urine metabolic screening showed positive reducing substance but total galactose and screening for galactosemia were normal. • Histology of the liver disclosed mild periportal fibrosis, macrovesicular steatosis, and mild portal infiltrate of mixed variety. Bile plugs were present. © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2021 M. K. Ghoda, Neonatal and Pediatric Liver and Metabolic Diseases, https://doi.org/10.1007/978-981-15-9231-7_18

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The number of bile ducts per portal tract was adequate. PAS, orcein, and staining for iron were within normal parameters. The child was given intravenous glucose and electrolyte-containing fluids and observed and appeared to be doing well. The mother reluctantly agreed to try breast-­ feeding but there was no milk flow. The parents expressed their desire to go to a “higher center” for further evaluation and hence the child was discharged. About 6 h later, the child was admitted in emergency. The child, after leaving the hospital was given “orange juice” of a bottled variety, which is fortified with sucrose and developed convulsions and then went into coma while the plane he was to travel to a “higher center” was about to take off. On the mother’s insistence, the child was given “glucose drip” as she told the paramedics that the child “gets better” every time he was given a “glucose drip” in the hospital. Blood sugar done in emergency department was 30  mg%, which was double checked with two different methods, and hence 25% glucose was administered in emergency department. By the time we reached the department, the child was still sweating but appeared to be regaining consciousness. The usual hostility apart, when a patient who has left your services to consult another specialist is readmitted in emergency, we were wondering what could have caused this?

18.1 What Is Your Thinking? From the patient’s history, laboratory results, and liver histology, an additional diagnosis, HFI, was suspected. In fact, we were ready for this. As the child took discharge, we were wondering what could be the cause of this child’s illness. If you have noted, he had borderline low glucose the first time around and reducing substances in the urine, during his last admission, but this was negative for galactosemia, the condition that we often see. Important clues came from two or rather three observations. One of our residents said that while talking to the nursemaid, she came to know that every Sunday the parents would buy tons of fruit juices, proprietary food, and lots of toys for the child. That the present admission appeared to be precipitated by drinking sucrose fortified orange juice and the mother’s observation that the child gets better when admitted and given “glucose drip.” Could this be fructosemia if not galactosemia? We informed the parents if they wished us to pursue further tests and confirm this when the child settled down, or that they would still want to go to a “higher center”? The parents, having seen the child nearly die, agreed promptly. The child was given IV glucose and a totally fructose-free diet and seemed to do very well. Now we sent blood for molecular diagnosis and the child was positive for mutation for HFI. Thus, this appeared to be a case of Hereditary Fructose Intolerance, HFI. The child was discharged on strict zero fructose diet and at 4, 8, and 12 weeks appeared to be thriving very well.

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Hereditary Fructose Intolerance: • Hereditary fructose intolerance (HFI) is a rare autosomal recessive disorder of fructose metabolism due to a deficiency of fructose-1-phosphate aldolase activity that results in the accumulation of fructose-1-phosphate in the liver, kidneys, and small intestine. • The symptoms include vomiting, hypoglycemia, failure to thrive, cachexia, hepatomegaly, jaundice, coagulopathy, severe metabolic acidosis, coma, and renal Fanconi syndrome. • In infants and young children, the disorder manifests with intolerance to fruits and vegetables, Reye’s like syndrome and hepatic failure. • In older children and adults, it can present as an aversion to fruits, vegetables, sweet-tasting foods, cirrhosis of liver, or intolerance to fructose infusion. • Current diagnostic methods for HFI include the fructose tolerance test that measures clinical symptoms upon intravenous fructose challenge and direct assay of aldolase activity in liver biopsy samples. These tests are relatively invasive and not routinely available. They must only be done at those centers that have the experience in this. • A molecular diagnosis by NGS looking for common mutation is increasingly available and especially useful in a sibling of an index case. Epidemiology: • It is equally distributed between the sexes. • The prevalence has been estimated to be as high as 1 per 20,000 individuals. • Very few cases have been reported from India so far. Genetics: • The gene has been mapped to one locus, band 9q22.3. • More than 21 mutations had been reported at this locus, most of them single-base substitutions. • Both structural and controller mutations may exist. Pathophysiology: Three isoenzymes of aldolase (A, B, and C) exist, of which aldolase B is expressed exclusively in the liver, kidney, and intestine. • Aldolase B mediates three separate reactions, viz. –– Cleavage of fructose 1-phosphate [F-1-P]. –– Cleavage of fructose 1,6-diphosphate. –– Condensation of the triose phosphates, glyceraldehyde phosphate, and dihydroxyacetone phosphate to form fructose 1,6-diphosphate). • In normal cellular conditions, the primary enzymatic activity of aldolase B is to cleave fructose diphosphate (FDP) to Triose phosphate compounds, which then takes part in the glycolytic pathway.

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• Because the same reaction is reversible, aldolase B is an essential enzyme in the process of gluconeogenesis. The absence of the latter function results in clinical hypoglycemia in with HFI. • Reduced cleavage of F-1-P leads to its cellular accumulation and fructokinase inhibition, causing free fructose accumulation in the blood. This results in a change in the adenosine triphosphate (ATP)–adenosine monophosphate (AMP) cellular ratio, with a resultant acceleration in the production of uric acid. This accounts for the hyperuricemia observed during an acute episode. • Competition between urate and lactate for renal tubule excretion accounts for the lactic acidemia. • Depletion of ATP in tissues leads to depletion also of magnesium concentration. • Severe hepatic dysfunction may be a manifestation of focal cytoplasmic degeneration and cellular fructose toxicity. • The renal tubular dysfunction primarily presents with a proximal tubular acidosis complicated by aminoaciduria, glucosuria, and phosphaturia. • Hypoglycemia and acidosis may act together to cause organ shock or coma. • Ongoing hepatocellular insult may result in cirrhosis and eventual hepatic failure. • Failure to thrive progressing to cachexia is the rule. • Mortality may result from any or all of the above conditions. Clinical presentation: • A clinically well patient demonstrates no abnormal physical findings. • There is a marked aversion to sweets and fruit. • Most patients, if not all, with fructose intolerance have neonatal hypoglycemia, lactic acidosis. • Cholestasis may be very marked. • Growth retardation, which is reversible, may occur. • Intractable vomiting. • Acutely ill children are often tachypneic because of acidosis. • They have enlarged liver and are slightly-to-moderately icteric. Accompanying hypoglycemia may cause tremors or seizures, as well as sweating. • Hyperuricemia and hypomagnesaemia may be present. • Renal tubular acidosis. • An adult form of fructose intolerance does exist. Upon inadvertent exposure to fructose, these patients may develop acute jaundice, gastrointestinal bleeding, hypoglycemia, proximal tubular acidosis, and disseminated intravascular coagulation. • The Fanconi syndrome characterized by glycosuria, aminoaciduria, phosphaturia, and bicarbonaturia with high urinary pH despite metabolic acidosis may also be precipitated. • Cirrhosis of liver and cataract are other uncommon presentations.

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Investigations and diagnosis: • There is presence of a non-glucose-reducing sugar in the urine. Thin layer chromatographic separation should be used for confirmation. • Molecular diagnosis by NGS is the preferred modality. Glyceraldehyde

Fructose

Cleaving by ALDOLASE B

Fructose–1–phosphate

is accumulated

Hypoglycaemia inhibition of glycolysis and gluconeogenesis

Dihydroxyacetone phosphate

Toxic effect on liver, kidney, small intestine

• Urine metabolic screening results may also provide evidence of glucosuria, proteinuria, and aminoaciduria, all of which are part of renal Fanconi syndrome. • Liver function tests may show hepatocellular disease. • Since aldolase B is normally present in kidney and intestinal mucosa as well as in liver, enzyme levels may be measured in intestinal biopsy. This facility is not routinely available. • The combination of therapeutic response to fructose elimination and a positive response to the fructose tolerance test is sufficient to exclude obtaining a biopsy sample. However, molecular analysis in leucocytes of the gene on chromosome 9 may provide definitive evidence of a mutation at the q22.3 band. Management: Definitive treatment simply consists of eliminating fructose from the diet. Eliminating fructose early in the disease course totally restores the affected child’s health within days. However, hepatomegaly may require a number of months to resolve. Prolonged delay in diagnosis may result in cirrhotic changes with subsequent degeneration of function. Diet: Appropriate treatment consists of the elimination of fructose, Sorbitol, and sucrose sources, such as fruits and table sugar. Unsuspected sources of these sugars abound. For example, potatoes that are prepared in a certain way provide a significant amount of fructose. For this reason, a highly trained nutritionist’s input is mandatory to properly maintain the health of individuals with this disorder.

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Complications: • Hypoglycemia, if sufficiently severe, may result in diminished intellectual capacity. • Hepatocellular damage and fibrosis may result in cirrhosis. • Severe metabolic acidosis may result in hypoperfusion and serious organ damage. Prognosis: • The prognosis is excellent for infants who receive rapid diagnosis and treatment. • In the absence of substantial hepatic damage, life expectancy is normal. Counseling: • Parents must receive genetic counseling as part of their education in the care of the child. • Stress on the importance of input from a nutritionist and the essential nature of a cooperative relationship in the long-term care of the child.

Hereditary Fructose Intolerance Incidence: 1:20,000 Gene: 9q22.3; 21 mutations known Pathogenesis: Accumulation of Fructose- 1Phosphate which is very toxic. Depletion of intracellular ATP

Case 18: A Case of “Crigler–Najjar Syndrome”

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Full-term breast-fed baby who was noted to be jaundiced on fourth day. Mother and the child both had B+ blood group. • Initial bilirubin at that time was 10 mg, with 9.5 indirect and 0.5 direct. • ALT and ALP were both within the normal range. • Hb 13.2 g, WCC of 10,000, and reticulocyte count 3%. Baby had lost 250 g from birth weight. Pediatrician reassured the parents that the baby had “normal” (physiological) jaundice and no treatment was needed. At about 15 days bilirubin was 20 mg with 19.7 indirect and 0.3 direct. ALT and ALP were in normal range. • CBC showed Hb of 11 g and WCC of 7400. Reticulocyte count was 1.8%. The baby was nursing well and had gained 80 g a day. The child was administered double bank, blue light phototherapy in a private nursing home, continued on breast–feeding, and told that the child had “Crigler–Najjar” syndrome. The child was started on phenobarbitone and multivitamin drops. Subsequently, the child did very well and had no further tests as none were required. The parents felt that yellowness had disappeared by about 6 weeks or so. At about 4 months, the parents were discussing the child with their medical relatives who were alarmed at the diagnosis and its prognosis and referred the patient to us. There was no parental consanguinity. The child appeared very playful and had absolutely white sclera. Weight and height were at 95th centile for her age. Abdomen was soft and no liver or spleen was palpable. Neurological examination was normal. CVS and RS were both normal. She was still on phenobarbitone and multivitamin syrup. CBC and LFT were within the normal range as expected.

© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2021 M. K. Ghoda, Neonatal and Pediatric Liver and Metabolic Diseases, https://doi.org/10.1007/978-981-15-9231-7_19

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19.1 W  hat Do You Think Is Happening? What Precautions You Would Take Before Labelling Any Child with “Crigler–Najjar Syndrome”? All things considered, this was never a case of “Crigler–Najjar” syndrome, as the child had no jaundice by about 6 weeks. Since there was no evidence of hemolysis or blood group incompatibility or history of any drugs or failure to thrive, we thought that this was one of the “benign” varieties of neonatal unconjugated hyperbilirubinemia. We thought that this child might have had breast milk jaundice. Since the parents never knew the seriousness of the “original” diagnosis they did not need much reassurance. The infant was taken off phenobarbitone and is doing just as well as before. • In case of unconjugated hyperbilirubinemia, one can wait and watch if the child is thriving and does not have any problem. • If there is any doubt or there is a parenteral pressure to “do the tests,” one may need to rule out hemolysis, sepsis, galactosemia, neonatal hypothyroidism, and the lot but generally these children are sick and have failure to thrive. • In Crigler–Najjar syndrome, there is a relentless increase in unconjugated hyperbilirubinemia, which fails to come down by stopping breast milk or giving phenobarbitone when other causes of unconjugated hyperbilirubinemia are ruled out. • It is our practice to rule out practically all treatable causes of unconjugated hyperbilirubinemia; however, unlikely they may appear before finally labeling someone as CN syndrome because it has altogether different prognosis. There is a serious risk of developing kernicterus in Crigler–Najjar syndrome. Breast milk jaundice: Breast milk jaundice (BMJ) is persistently high levels of bilirubin in a newborn’s blood caused by certain chemicals found in breast milk. • It is one of the commonest problems in pediatric practice. • It is characterized by indirect hyperbilirubinemia in a breastfed newborn that develops after the first 4–7 days of life, persists longer than physiologic jaundice, and has no other identifiable cause. • Breast milk jaundice peaks at 10–21 days, but may last for 2–3 months. • It should be differentiated from (inadequate) breastfeeding jaundice, which manifests in the first week of life and is caused by insufficient production or intake of breast milk. • Various studies have found breast-fed newborns do have a higher mean serum bilirubin level. • In conclusion, breast-feeding is one common cause of jaundice in normal newborns in the first week of life and beyond.

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Pathogenesis: The etiology of BMJ is not clearly understood. Epidemiology: • It is found in all races and in both sexes with equal incidence. • A strong familial predisposition is also suggested by the recurrence of BMJ in siblings. • It affects approximately 0.5–2.4% of all newborns. Clinical presentation: • BMJ manifests after the first 4–7 days of life. A second peak in bilirubin level is noted by the 14th day of life and can persist for 3–12 weeks. Jaundice that manifests before the first 24 h of life should always be considered pathologic until proven otherwise. • Clinical jaundice is usually first noticed in the sclera and the face. • Then it progresses caudally to reach the abdomen and extremities. • Apart from this, the child may look absolutely normal with normal neurologic examination, including neonatal reflexes, and there is no failure to thrive. • Depending on serum bilirubin concentration, neonates with hyperbilirubinemia may become sleepy and feed poorly. Differential diagnosis: All causes of unconjugated hyperbilirubinemia may have to be considered in selected cases and ruled out accordingly. • • • • • • • • •

Crigler–Najjar syndrome Galactosemia Hemolytic Diseases Hypothyroidism Neonatal jaundice Sepsis Polycythemia Gilbert syndrome Large cephalhematoma

Investigations and diagnosis: • It is a diagnosis of exclusion. Detailed history and physical examination showing that the infant is thriving and that lactation is well established are key elements to diagnosis. • Liver function tests show unconjugated hyperbilirubinemia with normal conjugated bilirubin and normal ALT and AST.

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19  Case 18: A Case of “Crigler–Najjar Syndrome”

Treatment: • Treatment will depend on the baby’s bilirubin level. Often, this level is relatively low, less than 12  mg/dL, and no specific treatment is needed other than close follow-up. The mother should be reassured about the relatively benign nature of BMJ. • For healthy term infants with breast milk or breast-feeding jaundice and with bilirubin levels of 12–17 mg/dL, the following options are acceptable: • Increase breastfeeding to 8–12 times per day and recheck the serum bilirubin level in 12–24 h. • Continue breastfeeding and supplement with formula. • Temporary interruption of breastfeeding is rarely needed and is not recommended unless serum bilirubin levels reach 20 mg/dL. • For infants with serum bilirubin levels from 17 to 25 mg/dL, add phototherapy to any of the previously stated treatment options. Phototherapy can be discontinued when serum bilirubin levels drop to less than 15 mg/dL. • The most rapid way to reduce the bilirubin level is to interrupt breastfeeding for 24 h, and use phototherapy; however, in most infants, interrupting breastfeeding is not necessary or advisable. • Supplementations with dextrose solution are not recommended because it may decrease caloric intake and milk production and consequently delay the drop in serum bilirubin concentration.

Case 19: A Pleasant Child Who Developed Prolonged Jaundice

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In clinical practice, you see very strange cases and sometimes you wonder about “wisdom” of “wise” man and are amazed at the maternal instinct and courage of apparently simple looking womenfolk. A 13-year-old, pleasant-looking boy was brought to me by a woman who was very diminutive and in her twenties. Her attire suggested that she may be from a low-income group but she looked remarkably well organized and as the consultation advanced, a very understanding and determined woman. I asked before starting the consultation whether the father of the child was present or not. She said that he was but he did not want to come in as he saw no point in having my consultation and that he had very reluctantly agreed to accompany her from a nearby village. The child was first detected to have jaundice by his grandmother. He was taken to a local doctor who thought nothing much of it and some vitamins were given. This did not help. Jaundiced continued and after visits to a few more local doctors and hence the referral. The child was born of a non-consanguineous marriage. According to her mother, he always looked a little yellow and had no problem otherwise and he was doing well at school. Clinical examination was normal including normal liver and spleen. Neurological development was normal. Investigations • CBC, including reticulocyte count was normal. • Bilirubin 4.5 mg with 90% conjugated, ALT and AST, and ALP were within normal range. S. Proteins were within normal range. PT was 12/12 sec. • HBsAg and HCV were negative. • USG showed normal liver, spleen, and gall bladder. • RFTs were normal.

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What Is your Diagnosis? What Other Tests you Would Do to Confirm this? Will Liver Biopsy Help? What Is the Likely Prognosis? That the child was not ill was obvious the minute he walked in. He had conjugated hyperbilirubinemia without elevation of any of the liver enzymes and sonography of the liver was normal. • Conjugated hyperbilirubinemia without any elation of ALT, AST or ALP, and normal biliary tree could be seen in cholestatic phase of viral hepatitis. If we take his mother’s word, it did not fit the bill. • Since he had no symptoms, one of the cholestatic syndromes like progressive familial intrahepatic cholestasis (PFIC) was out of contention. • After the initial tests, we were reasonably certain that the child had Dubin– Johnson syndrome. Urinary coproporphyrin levels were obtained (see below) and the pattern was very suggestive. If there is still any doubt liver biopsy could be done. Here it was not done. With increasing use of NGS, one may offer molecular diagnostic tests for confirmation. We explained the good prognosis to her and asked her to come back if she suspects anything wrong with the child. Dubin–Johnson Syndrome First described in 1954, Dubin–Johnson syndrome (DJS) is an autosomal recessive disease characterized by conjugated hyperbilirubinemia and deposition of melanin like pigment in hepatocytes. Pathology and Pathophysiology • The conjugated hyperbilirubinemia observed in DJS results from a defect in the transfer of endogenous and exogenous anionic conjugates from hepatocytes into the bile. • Lysosomal storage of pigment causes the liver to turn black. • A hallmark of DJS is the reversal of the ratio between the byproducts of heme biosynthesis, urinary coproporphyrin I, and coproporphyrin III.  In unaffected individuals, the ratio of coproporphyrin III to coproporphyrin I is approximately 3–4:1. This ratio is inverted in patients with DJS. • Hepatic biopsy shows a coarsely granulated pigment in hepatocytes in the centrilobular regions. The nature of the pigment remains uncharacterized. Genetics The molecular basis for DJS is related to defects in the multispecific anion transporter (cMOAT) gene, which belongs to the ABC transporter superfamily and is mapped to band 10q24.

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Dubin–Johnson syndrome

Normal Hepatocyte

MRP2

Bilirubin– UGTs glucuronide

Bilirubin

MRP3

Bile

MRP3

Bilirubin– glucuronide

MRP3

Blood

UGTs

MRP3

Bilirubin

Bilirubin– glucuronide Pathophysiology of Dubin Johnson Syndrome

Epidemiology • Incidence in India is unknown. • It occurs in both sexes but has a tendency to predominate in males. Clinical Presentation • Onset occurs most often in early adulthood; onset during infancy is rare. • For the most part, patients are asymptomatic and have normal life spans. • Jaundice is the most consistent finding in patients with DJS. Some neonates present with cholestasis. • DJS is rarely detected before puberty, although neonatal cases have been reported. Onset during infancy is rare; onset occurs most often in early adulthood. • Symptoms can include vague abdominal pains and weakness. Patients are usually asymptomatic. • For most patients, examination findings are normal. • Jaundice is the most striking clinical feature. • Hepatosplenomegaly may be present. • Oral contraceptives, pregnancy, and intercurrent illness may exacerbate icterus. Investigations • Molecular diagnosis with Next Generation Sequencing is confirmatory. • The serum bilirubin level usually ranges from 2 to 5 mg/dL but can be as much as 25 mg/dL. • Urinary excretion of coproporphyrin is altered with urinary coproporphyrin III levels measure as much as 80% and are considered diagnostic. The ratio of uri-

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nary coproporphyrin III to coproporphyrin I in patients with DJS is approximately 3–4:1. • • Serum Bromosulfophthalein testing has an increased level at 90 minutes than at 45 minutes. • Cholescintigraphy shows homogenous uptake by the liver but delayed excretion, which suggests altered canalicular transport. The gallbladder is not visualized.

Dubin Johnson syndrome Lifelong conjugated hyperbilirubinemia No clinical symptoms All liver enzymes are normal Diagnosis: clinical + urinary coproporphyrin 3:1 ratio is elevated

Treatment Treatment is generally not required. Prognosis Excellent.

Case 20: Prolonged Neonatal Jaundice and Cardiac Defects

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A 6-month-old male child, first of the couple, was referred for evaluation of prolonged cholestatic jaundice. There was no significant family history. Jaundice was first detected around the age of 3 months and treated locally. Sonography done at that time showed normal liver architecture and a partially distended gall bladder. Pediatrician also noted “murmur” in CVS examination, which he thought was due to ASD.  ASD was confirmed on echocardiogram done locally. There was some question about pulmonary hypertension also. Pregnancy was uneventful. The development was satisfactory till about 4 months of age, after that there was failure to thrive and some bruising. PT at this point was grossly prolonged and hence vitamin K was given I.V. with good response. LFT did not show improvement though, and hence the referral. On examination, the child was deeply jaundiced and still had some bruises. Weight and height, were both bellow 25th percentile. Liver was just palpable and firm and spleen was not palpable. Cardiology consultation suggested ASD and evidence of pulmonary hypertension. They also detected mild left renal artery stenosis. Neurological examination was unremarkable. LFT confirmed cholestatic jaundice. USG showed partially filled gall bladder but CBD was traced up to duodenum. What further Investigations Would you Like to Do? What Is your Differential Diagnosis? In a patient with cholestatic jaundice and cardiac abnormalities, we ought to consider: • • • •

Rubella Toxoplasmosis Sometimes Cytomegalovirus infection Alagille syndrome

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As is our usual practice, we always start with biliary atresia, if it looks like cholestasis and Galactosemia, if it looks like hepatocellular injury, as these are common in our practice. Since CBD was confidently seen up to duodenum, and with cardiac abnormalities present, we, for the time being, put biliary atresia on the back burner. Both toxoplasma and rubella IgM were negative, so most probably they were unlikely. Could this be a case of Alagille syndrome? On closer look and with the diagnosis in mind, we did notice the broad forehead, a pointed chin and deep-set eyes. Ophthalmic examination was the next investigation we did. Slit lamp examination confirmed posterior embryotoxon and Schwalbe’s line and optic nerve Drusen. X-ray of spine did not show any “hemi vertebrae.” The next step then was to do liver biopsy and look for bile duct paucity. A good long piece was obtained by a Trucut biopsy and this indeed showed bile duct paucity, thus suggesting Alagille syndrome. Genetic study was not available so not done. Thus in all probability this was a case of Alagille syndrome. Alagille/Alagille-Watson Syndrome (AGS) • Also referred to as the Alagille-Watson syndrome, syndromic bile duct paucity, and arteriohepatic dysplasia, it is a significant cause of neonatal jaundice and cholestasis in older children. • In the fully expressed syndrome, affected subjects have: –– Intrahepatic bile duct paucity and cholestasis. –– Cardiac malformations, most frequently peripheral pulmonary stenosis, with or without, other structural lesions. Hemodynamically significant lesions include ASD, VSD, Fallot’s tetralogy, PDA, and pulmonary atresia (PA). Various abnormalities of cranial and renal arteries are also seen. –– Ophthalmological abnormalities, typically of the anterior chamber with posterior embryotoxon being the most common, and Schwalbe’s line, and optic nerve drusen are also frequently seen and hastens the diagnosis. –– Skeletal anomalies, most commonly butterfly vertebrae, –– Characteristic facial appearance. Commonly associated facial features are broadened forehead, pointed chin, and elongated nose with bulbous tip. These may not be obvious during infancy but may become more apparent as the child gets older. –– In infancy and childhood, the commonest causes of mortality are liver and heart abnormalities. In adults, however, the commonest cause of mortality is vascular abnormalities. Because the individual manifestations are rare in the general population, the presence of only one feature (the feces being excluded) is sufficient for considering a family member to be affected with Alagille syndrome.

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Epidemiology • Incidence is approximately 1 in every 100,000 live births. • There is an equal M: F ratio. • Most children are evaluated when younger than 6 months for either neonatal jaundice (70%), or cardiac murmurs and cardiac symptoms (17%). Genetics • AGS is an autosomal dominant inheritance with penetrance is 94% and that 15% of cases are sporadic. • The syndrome has been mapped to the 20p12-jagged-1 locus (JAG1). • Mutations in JAG1 are associated with the majority of cases of AGS. • Mutations in NOTCH2 are associated with less than 1% of individuals with AGS.

Allagille syndrome

Paucity of bile ductules,

Autosomal dominant Mutation in Jagged 1 and notch 2 gene

Peripheral pulmonary stenosis

Multisystem involvement

Butterfly vertebrae

Liver Heart Eyes Vertebrae

Posterior embryotoxon

Diagnosis The diagnosis of AGS may be difficult because of the highly variable expressivity of the clinical manifestations. The clinical diagnostic criteria for Alagille syndrome (AGS) include the following: • The histological finding of bile duct paucity. Although considered to be the most important and constant feature, bile duct paucity may not be present in infancy. Overall, bile duct paucity is present in about 90% of individuals. • Three of the following five major clinical features in addition to bile duct paucity: –– Cholestasis. –– Cardiac defect, most commonly stenosis of the peripheral pulmonary artery and its branches. –– Skeletal abnormalities, most commonly butterfly vertebrae identified in AP chest radiographs.

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–– Ophthalmologic abnormalities, most commonly posterior embryotoxon. –– Characteristic facial features. • Again here, genetic study is easy and diagnostic and should be considered where available and affordable. Differential Diagnosis Include all causes of neonatal cholestasis and particularly toxoplasma and c­ ongenital rubella syndrome. Investigations • LFT shows features of cholestasis and prolongation of PT or APTT. In the majority of children, elevation of bilirubin levels resolves after the first year of life. • Liver biopsy: It typically exhibits features suggestive of chronic cholestasis and paucity of interlobular bile ducts with interlobular bile ducts-to-portal areas ratio of less than 0.4 in 10 portal tracts. However, biopsies during the neonatal period may exhibit ballooning and giant cell transformation of hepatocytes. It is not diagnostic. • Simple ophthalmic examination of children with neonatal cholestatic jaundice and their parents should allow early diagnosis of Alagille syndrome, eliminating the need for extensive and invasive investigations. • Abdominal ultrasonography may show renal anomalies as mentioned above and grossly evaluates the hepatobiliary tree and the hepatic parenchyma. • Echocardiography may reveal various cardiac defects mentioned above and may show evidence of pulmonary hypertension. • Butterfly vertebrae and other skeletal abnormalities are seen on X-ray. • Chromosomal analysis for mutations within the JAG1 gene (20p12) confirms diagnosis of AS. Treatment This is mainly supportive and complications are treated as per standard protocol. Genetic Counselling Under the guidance of a Geneticist, the affected family can be counselled. Approximately 30%–50% of individuals have an inherited mutation and about 50%–70% have a de novo mutation. The parents of a child with a de novo mutation have a low but increased risk for recurrence. Prenatal Diagnosis • This could be in several forms depending upon the gestational age and the local facilities. • Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified in an affected family member.

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• Fetal ultrasound examination: Fetal echocardiogram may detect a significant structural defect of the heart; however, a normal fetal echocardiogram does not eliminate the possibility of AGS. Prognosis Estimated 20-year survival rates are 80% for those not requiring liver transplantation and 60% for those requiring transplantation. Cardiac and pulmonary diseases can affect prognosis.

Case 21: Neonatal Jaundice in a Child with Ocular Problem

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A full-term child was sent for evaluation of hepatosplenomegaly and neonatal jaundice. He was born of a non-consanguineous marriage. Pregnancy was marked by a bout of fever and malaise lasting for about 3  weeks when the mother was about 3  months pregnant. The child had low birth weight of 1.6  kg and had failure to thrive. At about a month he was noted to have mild jaundice, hepatosplenomegaly. HBsAg and ultrasonography were normal. On examination, he looked wasted. His weight was below tenth centile and height was below 15th centile. There appeared to be congenital cataract in his left eye, which was confirmed by an eye specialist. Liver and spleen were mildly enlarged and there was cholestatic jaundice. CVS and RS were normal. Soon after the admission, the child developed generalized convulsions. Analysis of the Case With hepatosplenomegaly, cholestatic jaundice, and congenital cataract, either infective or a metabolic cause had to be considered. If a mother’s illness during pregnancy was significant, then it had to be infective. Could this be rubella or toxoplasma? Of course, it is our practice to always do metabolic screening also, which turned out to be negative. • TORCH IgM was ordered which showed strong reactivity against Toxoplasma. • CT of brain showed a few calcific spots otherwise nil. • Liver biopsy was contemplated but we did not see the patient benefiting from this and hence not carried out. • Echocardiogram was normal. • Ophthalmic examination confirmed cataract in both eyes. Retina was not well seen at the time of admission.

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The child was started on spiramycin, vitamin supplements, and high-calorie diet. Cataract was operated. The child continued to have occasional convulsion even on anti-convulsants and there was still failure to thrive. Toxoplasma Infection (Toxoplasmosis) This is a worldwide infection. It is transmitted from cats to human beings. Epidemiology • Toxoplasma gondii is an intracellular parasite, which has emerged as the second commonest opportunistic infection in AIDS patients, with as high as 75% mortality. • In pregnant women, seroprevalence varies from 7–50% and in women with abnormal pregnancies and abortions, the seroprevalence varies from 17% to 52%. • Acute toxoplasmosis occurs in about 2–7/1000 pregnancies. Pathogenesis • Mode of transmission is feco-oral route. Ingestion of oocysts excreted in the feces of infected cats. • Transmission has been known to occur by the transfusion of blood or blood products. • Transplacental transmission is very well known and most important. In immunologically competent subjects it may have a mild course of manifestations and usually persists latently lifelong. Clinical Presentation Pattern of the disease varies with the mode of infection and the immunocompetency of an individual. Accordingly it could be divided into five broad groups. 1 . Those acquired by immunocompetent individuals. 2. Those acquired by reactivation of the disease in immunocompromised individuals. 3. Ocular Toxoplasmosis, usually chorioretinitis from congenital infection. 4. Congenital Toxoplasmosis due to acute symptomatic or asymptomatic infections of the mother during pregnancy and leading to infection of the infant. 5. Organ transplants like Cardiac transplant and Liver transplant. Pregnancy and Toxoplasmosis • In endemic area, a serial serological screening test is advisable for all pregnant women starting by 10 to 12 weeks of pregnancy and should be repeated at 20 to 22 weeks of gestation. • Seronegative women should be advised to avoid infection by preventing exposure to cat feces, undercooked or uncooked food, especially the meat. • If the pregnant woman is infected before conception, there is no risk of transmission of the organism to the fetus. Maternal antibodies acquired from the infection prior to pregnancy prevent fetal infection.

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• Most dangerous period is the second to sixth month of pregnancy. Toxoplasma organisms sometimes gain access to the placenta and the fetus. If treatment of the mother is disregarded the chance of infection in the newborn is 10%–15% and the consequences will be severe in two thirds. • Infections during the third trimester are more common and usually result in subclinical disease. These are initially relatively benign with the infection being latent for at least the first few years of life. Effect on an Infant Various organs may be involved in varying severity. • Liver and Spleen: Liver and spleen are occasionally enlarged in association with congenital toxoplasmosis. Sometimes there is cholestatic jaundice. Liver biopsy may show giant cell hepatitis and a few granulomas. Features are non-specific. • Stillbirths and intrauterine death. • I.U.G.R. • Heart valvular defects. • The CNS can be severely affected in patients with congenital infection. Long-­ term effects may include seizures, mental retardation, cerebral palsy, deafness, and blindness. • Ocular lesions include: –– Acute chorioretinitis with severe inflammations and necrosis. –– Necrotizing retinitis. –– Microphthalmia. –– Congenital cataracts. –– Glaucomatous chorioretinitis. Investigations • The Sabin-Feldman dye test, indirect immunofluorescent antibodies (IFA) test, and ELISA are all serological tests used with different sensitivity in different situations. • P.C.R. is the most specific method. • The demonstration of IgM antibodies in the neonate is diagnostic of congenital Toxoplasma infection. • Microscopy: The parasites may be demonstrated microscopically in body tissues or fluids has been inoculated intraperitoneally into albinomice or placed in tissue culture media. • Radiographs of the skull or sonographic studies of the head may demonstrate intracerebral calcifications. Treatment Treatment consists of: • Six-week regimen of Pyrimethamine, 100  mg loading dose followed by 25–50 mg/d plus sulfadiazine, 2–4 mg/d in divided doses. Folinic acid10–25 mg/d

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is always used with it. Both drugs have been classified as category C with regard to their level of risk for the fetus. • Alternately for acute toxoplasmosis during pregnancy is spiramycin. Spiramycin is relatively a safe drug that concentrates in the placenta and may reduce the risk of maternal–fetal transmission by 60% without having any effect on the fetus. Dose is 500 mg Q.D.S. for 21 days and then 2 weeks gap with repeat cycles till the end of pregnancy may be used.

Case 22: A 3-Year-Old Girl with Unexplained Vomiting and Failure to Thrive

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A 3-year-old child of non-consanguineous marriage was referred for recurrent unexplained vomiting and failure to thrive. She was the first-born, full term, cesarean due to post maturity, and pregnancy was uneventful. Although marriage was non-consanguineous, the parents were coming from a small genetic isolate. All milestones were on target and she was fully vaccinated. For the first 2 years of life she was doing very well. Soon after that she had episodes of lethargy, malaise, and anorexia and vomiting. This would last for 4–5 days and then gradually settle down. This would then repeat, sometimes following trivial infections and at times for no reason. In the process, she had various antibiotics, anti-amebic, and all without any relief. All efforts to link these episodes were futile. Once she was seen by a pediatrician who thought it to be usual childhood problems. During this span, she failed to thrive and became choosey about various foods to the extent that on her last birthday she refused to eat even cake saying that she just cannot stand it! On examination, she appeared pale and her weight was below third centile for her age. Height was at 95th centile. Abdomen, CVS and CNS were normal. • CBC showed mild microcytic hypochromic anemia, WCC of 7400, platelets of 1, 98,000. • Na was 140; K 4.2; urea 24 mg; and creatinine 0.8 mg. • Bilirubin was 1.4, SGPT 31, ALP 185 I.U., Albumin was little low at 3.0 Gms./ L, and blood sugar was 56 mg. • Urine showed absence of ketones. • USG of abdomen and chest X-ray were normal. What is your thinking in this case? What further inquiries you think the pediatrician who saw her a year ago should have made.

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If I can send one clear message to the reader, I would say that never label anything as trivial. Most of the dreaded diseases start as trivial illness. Vomiting, failure to thrive and becoming ill on trivial illness are always significant and should alert for any underlying metabolic illness. Even if these symptoms were not there, a clear instruction for a follow-up will save you and save some of your patients. If it was something like abdominal tuberculosis, there would not be any symptom-free interval. And then there would be low-grade fever and all. All in all, recurrent unexplained vomiting and failure to thrive should always translate into metabolic disorder. Minimum a pediatrician could do is as above, during illness and also when the child is well. Where available, tandem mass spectroscopy, urine analysis for metabolic diseases, and organic aciduria must also be done. These, in our experience, will always throw up some abnormal results, which will lead you to look in to the problem in more detail. Here we have hypoglycemia but no ketones in the urine. Now the question you should be asking is why fat is not burning to provide energy? If you have forgotten, fat burns down and produces ketones, which are then utilized as fuel! If it was glycogen storage disorder, fat metabolism is unaffected and therefore we would have seen ketones due to fat burning and then there would not be any episodes of vomiting. If it was fructosemia, some linkage with fruit or fruit juice would have been apparent and there would not be aversion to fat, as this child showed, but she would be avoiding fruits and the like. And there would be reducing substances in urine. Could there be a fatty acid metabolism disorder? Recurrent vomiting, failure to thrive, aversion to fatty food and hypoketotic hypoglycemia all are in favor of this possibility. Acetyl carnitine profile by tandem mass spectroscopy is the next thing we did. Also, urine organic acids in these patients typically show elevations of dicarboxylic acids, glycine conjugates, and acylcarnitines. Both these investigations confirmed MCAD. The child was given intravenous 10% dextrose and encouraged oral high carbohydrate feed to which she promptly responded. Parents were instructed to give her high carbohydrate feed and avoid fatty feed. Fatty acid oxidation disorders (FAOD): Clinical Features • Features could be imagined by the energy requirement of a particular tissue or organ. Those with high-energy requirements will suffer in the most dramatic way compared to those with low-energy requirements. • Moreover, there will be infiltration of a tissue or organ with metabolites upstream from the enzyme block. • Clinically, individuals with one of the fatty acid oxidation disorders may present with hypoglycemia, liver disease, SIDS or near SIDS, encephalopathy, myopathy, and cardiomyopathy. Symptoms may appear at any age from birth to adult life. • Children with MCAD are typically normal at birth and develop episodes of hypoketotic hypoglycemia, vomiting, lethargy, and seizures associated with fasting. The first episode usually occurs between.

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• Six months and 2 years of age. The plasma acylcarnitine profile is diagnostic and a common gene mutation is found in a majority of the patients. Urine organic acids in these patients typically show elevations of dicarboxylic acids, glycine conjugates, and acylcarnitines. • Individuals with VLCAD and LCAD are very similar clinically; they can present with SIDS, hypoglycemia, hepatomegaly, myopathy, Reye syndrome, and cardiomyopathy. The plasma acylcarnitine profile in these patients reveals elevated long-chain acyl-carnitine esters. Urine organic acids in these patients typically show elevations of dicarboxylic acids. Diagnosis is confirmed by enzyme assay in fibroblasts. • SCAD deficiency presents in the neonatal period with failure-to-thrive, hypotonia, and metabolic acidosis. Hypoglycemia is not a common feature. Hyperammonemia and lactic acidosis have been reported. • The plasma acyl-carnitine profile reveals elevated short-chain acyl carnitine esters. Urine organic acids show increased excretion of short-chain organic acids (ethylmalonic acid) and butyrylcarnitine. Diagnosis is confirmed by enzyme assay in fibroblasts. • Some patients may present in infancy or childhood with myoglobinuria or as adults with exercise-induced muscle pains and rhabdomyolysis. • Rarely, affected infants can present with acute cholestatic jaundice or massive total hepatic necrosis in infancy. Differential Diagnosis • Metabolic acidosis • Dilated cardiomyopathy • Carnitine deficiency • Hypoglycemia • Reye syndrome • Other disorders of very-long-chain fatty acid oxidation (VLCAD) • Respiratory chain defects (complex I deficiency) Investigations • Blood glucose and urine ketones. • The hallmark biochemical feature of this condition is acute hypoketotic hypoglycemia. Collect urine ketones in the acute episode. • CPK, ammonia, uric acid, liver enzymes, and lactic acid may all be elevated. • Urine organic acids: Depending upon the cause particular type of organic acid profile may be obtained. • Plasma carnitine levels and acylcarnitine profile: Depending upon the cause particular type of acyl carnitine profile may be obtained. • Serum fatty acid analyses may be diagnostic. • Fatty acid oxidation studies and enzyme assay are also diagnostic. • Molecular studies: Molecular studies to identify the common mutation are available and help to pinpoint the underlying mutation.

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• Prenatal diagnosis: Prenatal diagnosis using biochemical studies has been attempted. In appropriate families in whom the molecular defect is known, prenatal diagnosis also is possible by mutation analysis. • The newborn screen assays for plasma acyl carnitine levels by tandem mass spectrometry or genetic study must be done in family members. • Pathological evaluation has revealed microvesicular and macrovesicular accumulation of fat in skeletal muscle, heart, and liver. Necrotic myopathy without steatosis has been described, as well as degeneration of muscle fibers. Hepatic cirrhosis also has been observed. • Ultrastructurally, the mitochondria appear to be increased in size and number with swollen appearance. Condensation of the mitochondrial matrix and irregular cristae is noted. Imaging Studies • Chest X-ray may reveal cardiac enlargement if cardiomyopathy is present. • Echocardiogram may reveal cardiac enlargement, poor contractility with decreased ejection fraction, and pericardial effusion in some cases. Other Tests • Skin biopsy to obtain cultures of skin fibroblasts for fatty acid oxidation studies or specific enzyme assay is necessary for confirmation of diagnosis by molecular analysis. Diagnosis of VLCAD, LCAD, and SCAD is confirmed by enzyme assay in fibroblasts. With the advent of genetic studies, this has lost its relevance. • Muscle biopsy, though not necessary for diagnosis, may be performed because lactic acidosis present in this condition may suggest a respiratory chain defect. Treatment • Early diagnosis and treatment are essential for an improved prognosis. • If left untreated, these conditions may result in significant disability and, ultimately, death. • Most of these conditions are chronic, with lifelong episodes of hypoglycemia. • For most fatty acid oxidation disorders, including MCAD, management involves long-term monitoring of serum glucose, a low-fat, high-carbohydrate diet, avoidance of fasting, and aggressive support during illness, and carnitine supplementation. • It is strongly recommended that infants under the age of 1 year be fed around the clock every 2–4 hours. • Treatment of SCAD is not effective, but the restriction of fats and supplementation of carnitine has been tried. MCAD Deficiency • MCAD deficiency is the most common of the disorders with an incidence of 1/6000 to 1/10,000. • Deficiency of VLCAD, LCAD, and SCAD is rare compared to MCAD. • In the first years of life this deficiency, will become apparent following a prolonged fasting period.

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Fatty acid oxidation disorders Very common in our practice Failure to thrive Unexplained recurrent vomiting Hypoglycemia Hyperammonia and coma Hepatomegaly Diagnosis: Acyl carnitine profile Mutation study

• Symptoms include vomiting, lethargy, and frequently coma. Excessive urinary excretion of medium-chain dicarboxylic acids as well as their glycine and carnitine esters is diagnostic of this condition. • In the case of this enzyme deficiency, taking care to avoid prolonged fasting is sufficient to prevent clinical problems. LCHAD Deficiency • There is an isolated LCHAD deficiency, which results in the inability to metabolize long-chain fatty acids. • Thus, the clinical features may result from either toxicity due to long-chain acyl-­ CoA esters that cause cardiomyopathy and cardiac arrhythmias or from a block in long-chain fatty acid oxidation that leads to an inability to synthesize ketone bodies and/or ATP from long-chain fatty acids. • The gene for the protein has been cloned and a common mutation, G1528C, has been identified in 87% of mutant alleles.

Case 23: A 3-Year-Old Boy with Failure to Thrive and Progressively Stiffening Muscles

24

A 3-year-old boy was seen for failure to thrive and progressively stiffening muscles. He was a full-term child, third in the family, born of non-consanguineous marriage. He was noted to have some jerky movement of the limbs and had a fixed position of both upper and lower limbs. He also had failure to thrive. He was seen by a pediatric orthopedic surgeon who diagnosed arthrpgryposis multiplex. Physiotherapy was recommended but this did not make much difference. He had delayed milestones. He continued to have jerky movements of his limbs and there was persistent failure to thrive. On examination, he had a dysmorphic face. His face and the whole body appeared swollen. The skin had thick and rough texture. There was depressed bridge of the nose. Both his height and weight were below third centile. Abdomen showed mild hepatosplenomegaly, CNS showed fixed position of both elbow and knee joints and the muscles appeared very stiff. There appeared to be Myoclonus. He appeared to recognize his parents and near relatives. Vision and hearing appeared to be normal on gross examination. CVS and RS were normal. Investigations showed mild microcytic hypochromic anemia. LFT showed mild elevation of SGPT. Renal functions and electrolytes were normal. What is your thinking here? What further tests would you do? The child looked so dysmorphic that lysosomal storage disorder was most likely. It could be mucopolysaccharidosis or mucolipidosis. The next step, therefore, is to look for these by urine analysis, blood analysis, and enzyme assays as appropriate. It turned out to be mucolipidosis type-II. Mucolipidosis Mucolipidosis (ML) is a group of inherited metabolic disorders that affect the body’s ability to carry out the normal turnover of various materials within cells.

© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2021 M. K. Ghoda, Neonatal and Pediatric Liver and Metabolic Diseases, https://doi.org/10.1007/978-981-15-9231-7_24

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24  Case 23: A 3-Year-Old Boy with Failure to Thrive and Progressively Stiffening…

Genetics Mucolipidosis has an autosomal recessive pattern of inheritance. Genes responsible for all four types of MLs have been identified. Types They are of 4 types. Pathogenesis • Because a particular enzyme is deficient, small chains containing a sugar-like material accumulate in neurons, bone marrow, and various cells that defend the body against infection. Clinical Features • Symptoms are either present at birth or develop within the first year of life. • In many infants with ML-I, excessive swelling throughout the body is noted at birth. • There may be coarse facial features, such as a flat nasal bridge, puffy eyelids, enlargement of the gums, and macroglossia. • Many patients suffer from failure to thrive and from recurrent respiratory infections. • There may be hepatosplenomegaly. • There may be skeletal malformations such as hip dislocation. • There may be impaired vision, cherry-red macules. • They may be ataxia tremors, and seizures. Myoclonus may be present. Hypotonia and mental retardation that is either initially or progressively severe. • Most infants with ML-I die before the age of 1 year. • ML-III produces less severe symptoms and progresses more slowly. • Some individuals with ML-III survive until their fourth or fifth decade of life. • A rare form of sialidosis—sialidosis type 1—occurs in children and adolescents and is often referred to as the juvenile form of the disorder. Children usually begin to show symptoms during the second decade of life, and myoclonus and cherry-red macules are often the initial symptoms. Patients usually develop seizures and progressive deterioration of coordinated muscular and mental activities. Diagnosis • Diagnosis of ML-I, II, and III can be confirmed by enzyme assay in the white blood cells or cultured fibroblasts from patients’ skin. For ML IV, no culture is required but DNA is obtained directly from the amniocytes and analyzed for specific mutations. • ML-IV is suspected when cells from conjunctiva are found to have numerous inclusions. • Measurement of the level of gastrin in the blood, which is significantly increased in ML-IV patients, helps to confirm the diagnosis. • Prenatal diagnosis for ML is accomplished using a procedure known as chorionic villus sampling done around the eighth or tenth week of pregnancy.

24  Case 23: A 3-Year-Old Boy with Failure to Thrive and Progressively Stiffening…

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Treatment • Therapies are generally geared toward treating symptoms and providing supportive care to the child. • For individuals with corneal clouding, surgery to remove the thin layer over the eye has been shown to reduce the cloudiness in the eye. • Nutritional supplements, especially iron and vitamin B12 for patients with ML IV.

Case 24: A 2-Month-Old Child with Neonatal Ascites

25

A 2-month-old child was referred for neonatal ascites. He was the first child born of a non-consanguineous marriage. His birth weight was low and on regular follow up, he had failure to thrive for which he was investigated and found to have hepatocellular damage and raised prothrombin time and ammonia. Liver was just palpable, spleen was not palpable and CVS, RS, and CNS were normal. TORCH titer was within normal range and urine for metabolic screening was normal. Total plasma galactose in mother’s milk was within normal range. He was thought to have neonatal hepatitis and treated with supportive treatment and asked to come after a week. One week on, his jaundice was persistent; there was no appreciable change in serum ammonia and prothrombin time and now there was some abdominal distention due to ascites. Liver was just palpable; CNS, CVS, and RS were all normal. The child appeared well but there was a failure to thrive with his weight actually showing a progressive decreasing trend. A small dose of diuretic was added and the child was seen again after a week. Now the ascites had increased, LFT showed hepatocellular damage, both PT and ammonia were high, renal functions were normal, electrolytes were normal. Patient was sent for further opinion. On examination, he appeared very weak and cachexic. There were obvious jaundice, mild hepatomegaly, and ascites. No other physical findings were noted. • USG of abdomen confirmed ascites and mild hepatomegaly but nil else. • Serum albumin: ascitic fluid albumin gradient was less than 0.8 and there were only a few cells. • Bilirubin was 15 mg with 70% direct, SGPT was 762, and ALP was 308 i.u. • PT was 27/14 sec. • Ammonia was 131, electrolytes were normal. • Creatinine 1.4 mg. • HB 7.3 gm, MCV 78 fl, MCH was 21, retics were 1.8%. WCC was 10,200 with 75%polys. A few vacuolated lymphocytes were seen. © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2021 M. K. Ghoda, Neonatal and Pediatric Liver and Metabolic Diseases, https://doi.org/10.1007/978-981-15-9231-7_25

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25  Case 24: A 2-Month-Old Child with Neonatal Ascites

How will you proceed now? What is your differential diagnosis? • Neonatal ascites has many causes and diseases of the urinary tract are one of the commonest cause. Following clinical analysis will help you in narrowing down the possibilities fairly accurately. • In our experience, rapid liver failure in a neonatal jaundice is almost always secondary to metabolic disorders. Infection or structural diseases take a longer time to produce liver failure. • Then there was failure to thrive, also suggestive of metabolic disease. • Sonography did not reveal a large distended urinary bladder or hydronephrotic kidneys, which is seen in urinary ascites. • Gall bladder and biliary tree appeared normal so there was little chance of it being biliary ascites. • For it to be cardiac ascites you should find cardiac abnormalities in physical examination and there may be hepatic congestion, dilated hepatic veins, etc. • For it to be infective or secondary to perforation there may be some peritonism. Metabolic Liver Diseases of the Newborn Here hepatosplenomegaly is not very prominent but there is moderate to severe hepatocellular dysfunction. • Galactosemia: Hyperbilirubinemia, initially even unconjugated, is seen. GAL-­1-T is diagnostic. • Hepatorenal tyrosinemia: Here plasma tyrosine levels are high and urinary succinyl acetone is high. • Hereditary fructose intolerance (HFI): Appears only with the introduction of fructose. Lactic acidosis, hypoglycemia, hyperuricemia. • Glycogen storage diseases type-IV: Cirrhosis early in the disease, hypoglycemia, and myopathy. In this case, both liver and spleen were enlarged as against only liver initially in GSD type IV and cirrhosis takes few years to develop and there is prominent hypoglycemia also. So this was also ruled out. • Peroxisomal disorders: Developmental delay, failure to thrive, seizures, hypotonia. In this case, there was no neurological involvement and muscles appeared normal and hence this was thought unlikely. • Mitochondrial disorders: Severe Hepatocellular dysfunction, myopathy, lactic acidosis, multisystem involvement. • Neonatal hemochromatosis. • Storage disorders: Urine was screened for metabolic disorders. Sialic acid level in urine was measured and it was 30 times the normal, suggesting sialic aciduria or Salla disease. This patient was treated with diuretics and supportive treatment for his liver failure; but he had convulsions and GI bleed and died within a fortnight.

25  Case 24: A 2-Month-Old Child with Neonatal Ascites

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Neonatal Ascites Fetal or neonatal ascites is rare and occurs in about 1:3000 pregnancies. In neonatal period, it is usually due to: • Metabolic diseases –– Lysosomal storage disorders –– Hepatorenal tyrosinemia type-I –– Neonatal hemochromatosis. –– Carbohydrate deficient glycoprotein syndrome • Urinary ascites • Biliary ascites • Chylous ascites • Cardiac ascites In older children, due to: • • • • • • • • •

Trauma Infection, particularly tuberculosis Hepatocellular disease Budd-Chiari syndrome Pancreatic ascites Gynecologic GI abnormalities Neoplasia Miscellaneous causes

Biliary Ascites • Biliary ascites in neonates are rare. • It almost always occurs in infants younger than 3 months. • Hepatobiliary isotope scanning demonstrates radionuclide in the peritoneal cavity. • Ultrasonography is usually necessary to rule out congenital anomalies and obstructing lesions. • Paracentesis reveals elevated bilirubin levels in the fluid. • The treatment of biliary ascites due to spontaneous perforation is drainage, either open or laparoscopic. • The perforation usually seals in a few weeks in the absence of obstruction. Chylous Ascites • Chylous ascites is rare. • Most cases occur in infancy, with a male predominance, and are of congenital origin. • The diagnosis is confirmed with paracentesis; the fluid has a markedly elevated triglyceride content (>1500 mg/dL) and a predominance of lymphocytes (>75%).

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25  Case 24: A 2-Month-Old Child with Neonatal Ascites

• After surgical causes, e.g., malrotation, obstruction, and neoplasia, have been ruled out with appropriate imaging studies, more than one half of the patients respond to nonoperative treatment with parenteral nutrition and bowel rest for 2–4 weeks. • Initial use of diets rich in medium-chain triglycerides instead of complete bowel rest may also help. • Refractory chylous ascites to nonsurgical treatment mandates exploratory laparotomy or laparoscopy. Administration of a high-fat diet or whole milk with Sudan dye immediately before surgery may help in identifying the site of leakage. • Idiopathic neonatal chylous ascites is associated with a high mortality rate. Hepatocellular Diseases • Storage disease, neonatal or viral hepatitis, alpha1-antitrypsin deficiency may result in ascites. • Paracentesis reveals the presence of fluid with a high serum-to-ascites albumin gradient (>1.1 g/dL). • Treatment of the ascites consists of sodium and fluid restriction and diuretics. • Repeated therapeutic paracentesis may be necessary. • Long-term management may require the placement of a peritoneovenous shunt or liver transplant. Peritoneal Infection • May lead to excess peritoneal fluid. • Appendicitis is common in patients in developed countries, whereas tuberculous fluid collections and Salmonella organisms are observed in patients in the developing world. • Treatment is directed at the underlying condition. Pancreatic Ascites • Either from trauma or pancreatitis. • Paracentesis reveals fluid with markedly elevated amylase and lipase levels. • Bowel rest and TPN are the initial therapies, with the administration of somatostatin analogs. • ERCP with or without nasopancreatic transampullary stenting is the usual initial treatment. • Exploration and repair may be required if medical management fails. Iatrogenic Ascites • Ascites may occur (particularly while the patient is in the neonatal intensive care unit [NICU]) as a result of iatrogenic gastric perforation from gastric catheters and/or tubes and with intraperitoneal feedings. • Similarly, umbilical catheter perforation may result in the leakage of parenteral nutritional fluid into the peritoneal cavity. • Treatment usually requires exploration and repair of the injury site.

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Some Useful Clues for Diagnosis • If a large bladder or a myelomeningocele is present, the ascites is probably urinary. • If vomiting occurs or if bowel loops are abnormal even though not distended, gastrointestinal causes are likely. • If there is impressive peripheral or body wall edema, consider infection, heart disease, liver disease, erythroblastosis, and other causes of hydrops fetalis. • If hepatomegaly is present, metabolic causes of liver diseases are most likely.

Ascites confimed? Any obvious pathology? e.g. jaundice, cardiac problem, urinary problems, Glabnormalities.

Yes?

No?

Investigate along those lines

Ask Sonologist to look for

Liver:

Urinary tract:

• • • • • • •

1. 2. 3. 4.

Echo texture Billary tree and GB Hepatic veins Portal vein Splenic vein IVC SOL

Still no clue OR Confirmation required.

Distend bladder Distended ureters Ureterocele Hydronephrosis

Bowel • Dilatation • Peristaltic activities • Calcification

Diagnostic ascitic tapping for routine, microscopy, culture, cytology, amylase, lipase or diagnostic laparoscopy

Lysosomal Storage Diseases (LSD) • Lysosomes are membrane-bound intracellular organelles containing substrate-­ specific hydrolases. • These enzymes help to degrade both cellular components and extracellular material ingested either by phagocytosis or pinocytosis, and are most abundant in those cells actively involved in phagocytosis, for example in the reticuloendothelial system.

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25  Case 24: A 2-Month-Old Child with Neonatal Ascites

• LSD occurs when there is a deficiency in one or more of the lysosomal hydrolases and breakdown of cellular components cannot proceed in a normal fashion. • Undigested cellular components then accumulate within the residual bodies, which form vacuoles or vesicles within the cytoplasm and have a characteristic appearance on light and electron microscopy. LSD can be divided into three broad categories depending on the type of material stored: • Sphingolipidoses. • Mucopolysaccharidoses. • Oligosaccharidoses. Diagnosis • Characteristic urinary excretory products. This is most easy to perform. • By the characteristic histological findings on light and electron microscopy. • The characteristic enzyme defects found in the cells from these patients. • Coarsening of the trabecular pattern is seen to a greater or lesser extent in all patients and but particularly well marked in the patient with sialidosis. Thinning of the cortex and lack of modeling were also observed, particularly in the patient with GM I gangliosidısis. Salla Disease • Refers to LSD first reported in a geographically restricted area in northern Finland. • The enzyme defect in this condition has not been well documented as yet. • Increased levels of free neuraminic acid are found in the urine. • Abdominal distension due to varying amounts of ascites and hepatosplenomegaly may be the presenting feature. • The cause of ascites is obscure. • The radiographic skeletal changes in these patients may alert the radiologist to the true cause for the ascites in these otherwise often puzzling patients. • The diagnosis can then be confirmed by characteristic histological findings on light and electron microscopy as well as characteristic cellular enzyme defects and urinary excretory products in these patients. LSD Coarse facial features Organomegaly +++ Slow progress Neurological and skeletal involvement

Case 25: A Patient with Sickle Cell Anemia with Sudden Onset of Jaundice

26

A 15-year-old boy was referred for sudden, severe jaundice. He was diagnosed as sickle cell anemia when he was three-years old and had sudden severe abdominal pain. Since then he was under a hematologist for the same. He was on regular folic acid treatment. A week or so ago he was noticed to have jaundice and hence referred to a surgeon for possible choledocholithiasis causing jaundice. Apart from deep jaundice, he had no complaints and his physical examination was normal. Investigations at that Time Showed • CBC: HB 10.2, WCC 4385, retics: 2.2%. Peripheral smear was unremarkable. • Bilirubin: 45 mg. with 43 mg. conjugated, SGPT 23 I.U., SGOT 40 i.u., ALP: 123 I.U., PT 13/14 sec. • HAV, HEV, HBsAg, HCV antibodies were negative. • USG: Multiple GB stones, CBD normal in its entire length, no IHBR dilatation. • He was referred to us. We corroborated the above history. Physical examination was normal except for deep jaundice and mild splenomegaly. A repeat sonogram conformed GB stones, CBD, and IHBR both appeared normal. • Bilirubin was 48 mg. with 45 mg as conjugated. • ALT/SGPT and AST/SGOT and ALP were minimally deranged. • Hb was 10.2, retics were 2% and no premature cells were seen in peripheral smear. • ANA, AMA, LKM, and ASM were negative. • Virology screening: HBsAg negative, Anti HCV negative, HIV test negative. • Hemoglobin electrophoresis showed: HbF 3%, HbS 35%, and HbA2 2.2%. © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2021 M. K. Ghoda, Neonatal and Pediatric Liver and Metabolic Diseases, https://doi.org/10.1007/978-981-15-9231-7_26

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26  Case 25: A Patient with Sickle Cell Anemia with Sudden Onset of Jaundice

How Will you Explain these Abnormalities? Our analysis was as follows: • Obviously, this patient had cholestasis but no obstruction. • There were no features of hepatocellular damage, as seen by normal ALT and AST and normal PT. • There was no evidence of hemolysis as seen by normal Hb and reticulocyte count. • Acute episodes of the disease selectively affect the liver in 10% of patients, causing hepatic crisis with abdominal pain, nausea, fever, jaundice, and transaminase elevation. This patient had no pain and no enzyme elevation ruling out the “crisis.” Viral hepatitis is often clinically indistinguishable from hepatic crisis, but in viral hepatitis the abdominal pain is usually less, the jaundice tends to be more severe, and the transaminase elevation is more prolonged. The two can be distinguished by serology and liver biopsy. • Furthermore, acute cholecystitis or choledocholithiasis may have clinical and laboratory features similar to sickle cell hepatic crisis or viral hepatitis. Sonography helped to rule out these conditions. • We concluded, by exclusion, that this patient could have cholestasis, due to sickle cell disease, but without any hepatic crisis. This is benign cholestasis due to sickle cell disease. We had no evidence of either obstruction or viral hepatitis. • Having said that, sickle cell intrahepatic cholestasis was not the first in our list of differential diagnosis, first due to its rarity, and secondly due to the fact that this patient had a fairly uncomplicated sickle cell anemia over several years of his life, with no history of vaso-occlusive crisis or regular exchange transfusions. But absence of IHBR or CBD dilatation in spite of very high bilirubin was pointing toward cholestasis and no other cause looked remotely possible. Progress: He was treated conservatively with supportive treatment and appeared to do well with slow but steady reduction in his bilirubin over the next 3 months to 18 mg. with 80% being conjugated. Sickle Cell Disease (SCD) The hepato-biliary complications of the sickling disorders can be separated into broad categories of: • Disorders related to hemolysis, cholelithiasis/biliary Sludge. • The problems of anemia and transfusion, like iron overload and viral hepatitis B or C. • The consequences of sickling and vaso-occlusion. • Defects unrelated to hemoglobin S. • Cholelithiasis/Biliary Sludge: • The onset of cholelithiasis could start as early as 2 to 4 years of age. Prevalence increases progressively with age, reaching a frequency of nearly 30% by 18 years of age.

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• The co-inheritance of alpha-thalassemia appears to reduce the frequency of stones by lowering the degree of hemolysis. • Sludge is often found with stones, but sludge alone may or may not progress to stone formation. Vascular Occlusion The hepatic complications attributed to vascular occlusion encompass a variety of clinical syndromes. • The liver is generally enlarged. • Liver histology invariably shows Kupffer cell hyperplasia with erythrophagocytosis, sinusoidal distension with aggregates of sickled erythrocytes and fine fibrosis in the space of Disse. • The “hepatic crisis” or “right upper quadrant syndrome,” consisting of right upper quadrant pain, fever, jaundice, elevated AST/ALT, and hepatic enlargement is said to occur in as many as 10% of patients with acute vaso-occlusive pain. This is akin to acute hepatic ischemia or infarction. The AST/ALT falls rapidly, differentiating this condition from the slower decline characteristic of acute viral hepatitis. Treatment with supportive care is the only modality needed. • Hepatic sequestration: –– This syndrome is characterized by a rapidly enlarging liver accompanied by a decrease in hemoglobin/hematocrete and a rise in reticulocyte count. The liver is smooth and variably tender. –– Bilirubin may be very high with a predominance of the conjugated fraction. The alkaline phosphatase can be very high or normal. The transaminases are only minimally elevated and often are normal. –– Recurrence is common. –– Ultrasonography and CT scanning show only diffuse hepatomegaly. –– Exchange transfusion is preferred but careful monitoring is required. –– Acute hepatic failure has been reported in several cases where massive hepatic necrosis was seen in the absence of markers for viral hepatitis. Exchange transfusion was followed by rapid improvement in clinical and biochemical features. • Cholestasis: Cholestasis can occur when the hepatic vein pressure abruptly increases, exceeding the maximal bile secretory pressure of 20-mm Hg. • A benign cholestatic picture has been described in which there are striking elevations of bilirubin with only modest elevations of alkaline phosphatase and transaminases. Importantly, no impairment of hepatic synthetic function occurs, as reflected in the coagulation times (PT/PTT). The patients are asymptomatic with the exception of jaundice and/or pruritus. Fever, abdominal pain, and gastrointestinal upset are conspicuously absent. In all instances, resolution of cholestasis occurred within months in the absence of specific therapy.

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26  Case 25: A Patient with Sickle Cell Anemia with Sudden Onset of Jaundice

• In contrast, progressive cholestasis in the absence of cirrhosis has been reported in a small number of cases. These cases are characterized by right upper quadrant pain, extreme elevation of bilirubin, striking elevation of alkaline phosphatase, and variable elevation of transaminases. Importantly, renal failure, thrombocytopenia, and severely prolonged coagulation times develop. Mortality due to uncontrollable bleeding or to hepatic failure is common.

Case 26: A 7-Year-Old Boy with Recurrence of Jaundice

27

A 7-year-old boy came for consultation with jaundice. He was previously fit and well and did not abuse drugs, tobacco, etc. He had no injection or blood transfusion. Some 6 weeks ago he had traveled quite extensively with his parents, eating out in roadside hotels. Some 4  weeks ago he developed intestinal symptoms, anorexia, nausea, dark urine, and jaundice. He was examined by another Gastroenterologist who found his liver slightly enlarged and tender. • His bilirubin was 3 mg, ALT 1004 i.u., GGT 575 i.u., ALP 182 i.u. Infective hepatitis was diagnosed. He was prescribed vitamins; bed rest and his symptoms gradually subsided. Repeat LFT’s in 2 wks time showed: • S. bil 1.5 mg, ALT 300 i.u., GGT 343 i.u. and ALP 142 i.u. Six weeks later repeat LFT’s showed: • S. bil 2 mg, ALT 940 i.u., 447,565 i.u., ALP 152 i.u. He was feeling very well and had already put on all the weight he had lost. On examination he had jaundice; there were no stigmata of chronic liver disease. Liver was slightly enlarged. Rest of the examination was normal. How Will you Proceed Now? Our analysis was as follows: • In a previously fit and healthy individual without any predisposing factors for hepatitis-B, this is a classic story for fecal-oral type of infective hepatitis namely type-A and E, both of which are sporadic and epidemic.

© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2021 M. K. Ghoda, Neonatal and Pediatric Liver and Metabolic Diseases, https://doi.org/10.1007/978-981-15-9231-7_27

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27  Case 26: A 7-Year-Old Boy with Recurrence of Jaundice

• Type-C hepatitis was a remote possibility, very remote as only 25% become symptomatic and ALT infrequently rises above 1000 I.U. • LFT’s in this patient shows classical relapse, which is mainly biochemical. It is more common with hep-A, about 8–15% patients relapsing. Typically, the relapse is around 30–70 days and takes place before the ALT levels have touched the baseline normal. This is believed to be due to a particular strain of the virus as there are no definite host-related factors present consistently in such cases. • This relapse may be biochemical only, i.e., only the blood tests may be abnormal without any new symptoms or it could be symptomatic also. • Viral serology, HAV-IgM, is helpful and if positive as was the case in this patient, clinches the diagnosis. • An important point, I would like to make out here for the reader is that it is unhelpful to obtain serial LFTs in someone who is distinctly improving or who does not have any symptoms or significant clinical findings, say for example massive hepatomegaly or ascites. • Not only it is useless but also many a time it is psychologically devastating for the patient who constantly keeps making mathematical calculations about the speed of recovery and gets perturbed if his calculations are not matching “his” mathematical model. Many a time the transaminases take up to 6 months to hit the baseline normal. My advice is that unless the patient has persistent fever, persistent nausea or vomiting, edema, or ascites or prolonged PT in spite of vitamin K, or that the patients is confused or agitated, there is little to be gained by repeating the tests even for once. • Finally, a small comment about widely prescribed advice about glucose ingestion. It is not a natural substance and ingestion of a large amount of glucose invariably leads to nausea, bloating, and vomiting! • Encourage natural diet and fruits and that should provide liver enough glucose. Hepatitis a (HAV) Infection HAV is a 27–32 nm diameter, non-enveloped virus belonging to genus Hepatovirus in the Picornaviridae family. Pathogenesis • The virus is not directly cytopathic. Hepatocyte injury results from a host immune response. • Nonspecific immune mechanisms may also play a role. Incubation period: Around 15–45 days.

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Pathology • Hepatocytes show balloon degeneration, most prominent in zone III. • There may be collapse of the reticulin network but lobular architecture remains intact facilitating an orderly pattern during recovery. • Portal tracts are expanded by a mixed inflammatory infiltrate, mainly mononuclear, and lymphocytes but may also contain plasma cells, neutrophils, and eosinophils. • There is marked Kupffer cell proliferation. • Cholestasis may be pronounced. Features Seen more Frequently in Acute Hepatitis A • It is transient in children, but it could have a prolonged course in adolescent and adults, with higher morbidity. • Relapse is more common, up to 15%, between 4 and 10 weeks, and occurs before SGPT has returned to baseline. • Cholestasis is more prominent. • Chronicity or sub-acute liver failure is not seen. Extrahepatic manifestations: Are less frequent in acute HAV infection and only prolonged illness appears to have a higher frequency of extrahepatic manifestations. • Transient rash. • Arthralgia and arthritis mainly occur in the lower limbs and leukocytoclastic vasculitis was typically seen on the legs and buttocks. Both are due to cryoglobulinemia which contain IgM anti-HAV. • Glomerulonephritis. • Rarely, toxic epidermal necrolysis, myocarditis, renal failure, optic neuritis, transverse myelitis, and polyneuritis. These may be immune-complex related. • Thrombocytopenia, aplastic anemia, and red cell aplasia. Complications • A post-hepatitis syndrome is characterized by prolonged malaise, elevated serum aminotransferase levels, and persistence of HAV- IgM. • Rarely development of type 1 autoimmune hepatitis. • Acute liver failure, although rare, occurs mainly over the age of 40 years or under the age of 10 years or in those with underlying chronic liver disease. • Prognosis: Is excellent and mortality is less than 0.1% and at the extremes of age.

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27  Case 26: A 7-Year-Old Boy with Recurrence of Jaundice

Vaccination Is possible with formaldehyde killed HAV and immunity is long. Combined vaccines for A and B viruses are now available. HAV infection Very common Epidemics seen Transient or even anicteric in children Could be prolonged in adults Up to 15% relapse between 30 and 70 days

Case 27: An 8-Year-Old Boy with Recurrent Jaundice

28

An 8-year-old boy was referred for recurrent jaundice. He was well before 3 months when he first fell ill with fever and chills, headache, and slight nausea. He was treated with paracetamol. In a couple of days’ time he was noticed with jaundice. His blood tests, reported below showed jaundice and he was treated with supportive treatment. He continued to have fever and hence he was given injectable Chloroquine and amoxycillin, which he took for 2 days and then stopped, as he felt better. His bilirubin and SGPT normalized. About a month later, he again developed jaundice with minimal fever for which he took Ciprofloxacin and remaining doses of Chloroquine left over from the first time. He felt better over a few days and returned to work. He felt unwell for the third time about a month later and was found to have jaundice. There was no associated fever, nausea, or vomiting. On examination, he appeared well although slightly jaundiced. There was no anemia, no nodes, and no stigmata of chronic liver disease. Liver was not palpable and spleen was just palpable. Keyser-Fleischer ring was absent by slit lamp examination. Sonography revealed mild splenomegaly but no evidence to suggest chronic liver disease. Liver profile is shown below.

© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2021 M. K. Ghoda, Neonatal and Pediatric Liver and Metabolic Diseases, https://doi.org/10.1007/978-981-15-9231-7_28

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28  Case 27: An 8-Year-Old Boy with Recurrent Jaundice

1st episode

2nd episode

3rd episode

4th episode

4.5 mg.

1.5

5.0

4.0

(3.0 Direct)

(1.0 Direct)

(3.5 Direct)

(3.0 Direct)

SGPT:

104.I.U.

42

68

56

ALP:

122 i.u.

....

114

108

S.Bilirubin

(Up to 125) Hb:

12.4

....

12.0

HBsAg: negative

TC:

7.0

....

6.4

HAV-lgM: negative

P.S. for M.P.

Neg

Albuminc:

Neg. 4.0 g

What differential diagnosis you would consider? What further tests would you consider? What is your final diagnosis? Our analysis was as follows: • This patient has recurrent “cholestasis,” but no obstruction on sonography and normal ALP and hence obstructive jaundice is unlikely for all practical purposes. • Hepatitis-B and C need keeping in mind as both can give recurrent jaundice and of course Wilson’s disease, alcohol, etc., although LFT’s did not suggest chronic liver disease. • Drugs can sometimes give rise to jaundice but there was no such history. • One noticeable thing was that he had fever treated with antimalarials which he did not finish as half-way through the treatment he felt better. • Falciparum malaria could give rise to this picture and this needs ruling out. • We see two types of liver, involvement of the liver with falciparum malaria and many other illnesses where there is large amount of cytokines like TNF alpha and interleukins are secreted, resulting in a “hepatopathy” better known as cholestasis of inflammation, where there is predominantly a direct hyperbilirubinemia and SGPT, which is generally less than three times normal. The other, the “hepatitic” picture is almost indistinguishable from viral hepatitis. • Falciparum liver involvement almost always starts with fever and headache but nausea, vomiting, etc. are not very prominent. In endemic area, it is now

28  Case 27: An 8-Year-Old Boy with Recurrent Jaundice

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mandatory to include falciparum malaria, dengue fever, and enteric fever in differential diagnosis of acute hepatitis. A somewhat similar picture is also seen in septicemia, major trauma, electrocution, etc. • Fortunately for us, his falciparum was picked up straight away in our laboratory and he responded to appropriate therapy. Final diagnosis is Falciparum-induced cholestasis (of inflammation). Cholestasis of Inflammation Conjugated hyperbilirubinemia ALT and AST < 3 times upper limit of normal ALP is normal Caused by sepsis, endotoxins, chemokines like tumor necrosis factor alpha

Case 28: A 3-Year-Old with Huge Liver and Abnormal Liver Functions

29

A 3-year-old girl was referred for huge hepatomegaly and persistently abnormal liver function tests. She was the first born, full-term normal delivery. There was no consanguineous marriage and there was no significant family history. The mother’s health during pregnancy was excellent. At birth a pediatrician had seen her and nothing unusual was found. At 6 months, her abdomen was noted to be distended due to an enlarged liver, which was non-tender, and with rounded edges. Spleen was not enlarged. Ultrasound confirmed the findings; portal and splenic veins were of normal size, lymph nodes were not enlarged. Cardiovascular, respiratory and neurological examination was normal. She appeared intellectually normal and all her milestones were normal. • S. Bilirubin: 1.8 mg, ALP: 351 I.U., SGPT: 98 I.U., GGT: 84 I.U. PT 18/15 sec. • Fasting blood sugar: 88 mg. • Antibodies against TORCH, HAV, HBV, and HCV were all negative. Her development for next 2 years. Was normal with normal milestones and intellectual development, normal hearing, and normal vision. No bony deformity was detected but repeated liver function studies showed elevated bilirubin and liver enzymes. She was advised liver biopsy but the parents were concerned and opted for further opinion. On examination, the child looked normal except huge hepatomegaly. Liver function showed abnormality similar to her earlier reports. CBC, renal functions and bloods sugar were normal. Examination of eye including slit lamp examination was normal. Sonography as reported above.

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• What do you suspect? • How will you proceed further? • Would you do a liver biopsy? This was an interesting case. Our analysis was as follows: • Her hepatomegaly was detected soon after birth and all known viruses were negative. • Liver was huge and no developmental defect was noted and hence all in all some form of storage disease of mild severity was most likely. • Repeated normal sonography rules out any structural lesion of the liver. • Most of the glycogen storage diseases have recurrent hypoglycemia and/or acidosis, muscle pain, and poor physical growth. This patient had none of these. • Most of the mucopolysaccharidoses (MPS) have associated splenomegaly, mental retardation, corneal clouding, bony deformities, etc. in various combinations. The milder variants may not have these associations. We thought therefore that this child must have MPS of milder variety. • Recently, we have seen moderate to large hepatomegaly due to macrovesicular fat deposits probably from lipoprotein lipase deficiency and/or Apo B/c deficiency. Here also spleen is not enlarged and there is no hypoglycemia. This patient was investigated in collaboration with a molecular geneticist. Preliminary screening ruled out glycogen storage disease and attention was focused on MPS. Her urine showed dermatan sulfate and subsequently leucocytes aryl sulfate was found to be low. In clinical terms this is mild form of type VI MPS, “Martaux-Lamy,” where normal development is possible. Abnormal liver enzymes are because of infiltration of dermatan sulfate. As diagnosis could be made this way liver biopsy was not indicated. 13 years on the child is doing well. Genetic study if easily available could help to pinpoint the genetic mutation in such cases with ease. Mucopolysaccharidoses Mucopolysaccharidoses (MPS) is a group of autosomal recessive metabolic disorders caused by the absence or malfunctioning of lysosomal enzymes needed to break down glycosaminoglycans (GAG), the building block of bone, cartilage, tendons, corneas, skin, and connective tissues.

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Huge hepatomegaly * GSD: Usually Hypoglycemia is present, spleen is not enlarged till cirrhosis sets in * MPS: Spleen may be enlarged ++ No hypoglycemia * Hepatoblastoma: No Hypoglycemia and no splenomegaly, sudden onset and fast progression

Lysosomal enzymes are a group of enzymes, not a single enzyme, each having a specific function in the metabolic degradation of GAG. In MPS either there is deficiency of one of the 11 enzymes or a defunct enzyme that does not work properly. As a result GAG accumulate in the cells, blood and connective tissues resulting in progressive cellular damage which affects the physical appearance, and malfunctioning of a group of target organs most prominent amongst them being the CNS and musculoskeletal system. Since many more metabolites need lysosomes in their degradation, they are also affected by the absence of lysosomal enzyme or abnormality and from lysosomal point of view; all these disorders are therefore justifiably designated as lysosomal storage diseases (LSD). Clinical Features • Depending upon the type of defect and the severity of the defect the clinical features and natural history of the disease could vary. • The disease may not be apparent at birth but progresses as storage of GAG increases. • Patients may have coarse facial features, thickened skin, excessive body hair, a flat nasal bridge, thick lips, enlarged mouth, and macroglossia. • There may be short stature with disproportionately short trunk, skeletal dysplasia, and other skeletal abnormalities. • CNS complications include damage to neurons as well as pain and impaired motor function due to compression of nerves or nerve roots in the spinal cord or in the peripheral nervous system. Affected patients may have varying degrees of

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mental retardation, developmental delay, and behavioral problems. There may be hearing loss, either conductive or sensory neuronal or both. Communicating hydrocephalus is common in some of the MPS. The cornea often becomes cloudy from intracellular storage, and glaucoma, and degeneration of the retina are important features. • There is generally hepatosplenomegaly, sometimes massive, and hernias. Short and often claw-like hands, progressive joint stiffness, and carpal tunnel syndrome can restrict hand mobility and function. • Recurring respiratory infections are common, as are obstructive airway disease and obstructive sleep apnea. • There may be heart disease, often involving enlarged or diseased heart valves. MPS VI (Martaux-Lamy) • It is caused by the deficient enzyme N-acetylgalactosamine-4-sulfatase. • Patients usually have normal intellectual development. • It has a variable spectrum of severity. • Neurological complications include clouded corneas, deafness, thickening of the dura and pain caused by compressed or traumatized nerves and nerve roots. • Growth is normal at first but stops suddenly around age 8 years. By age 10 years, children have developed a shortened trunk, crouched stance, and restricted joint movement. • In more severe cases, children also develop a protruding abdomen and forward-­ curving spine. • Skeletal changes, particularly in the pelvic region, are progressive and limit movement. • Many children also have umbilical or inguinal hernias. Nearly all children have some form of heart disease, usually involving valve dysfunction. Diagnosis of MPS • A clinical diagnosis is sometimes very obvious. • Urine is the first test, usually used as a screening test. Azure-A test is less reliable. False positives are high. Thin layer chromatography may detect the GAG in the urine and typing is also possible. • Enzyme assays are used to provide definitive diagnosis. • Prenatal diagnosis using amniocentesis and chorionic villous sampling is possible. Genetic testing and counselling: Very important and accurate way of diagnosing these conditions and it should be offered to the family members.

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Treatment • Supportive therapy is all one can offer. • In coming days, enzyme replacement will hold the clue. • Bone marrow transplantation (BMT) and umbilical cord blood transplantation (UCBT) have had limited success.

Case 29: A 15-Year-Old Boy with Prolonged Jaundice

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A 15-year-boy came for consultation with jaundice. He was previously fit and well and did not use drugs, tobacco, alcohol, etc. He had no injection or blood transfusion. Some 4 months ago he had travelled rough for holidays. On return from holidays he developed jaundice. He was seen by a physician who found his liver slightly enlarged and tender. • Bilirubin was 4 mg, ALT 1500 I.U., GGT 900 I.U., ALP 147 I.U. • HAV-IgM was reactive. • HBsAg was non-reactive. Acute infective hepatitis-A was diagnosed. He was prescribed vitamins; bed rest and his symptoms gradually subsided but did not go completely. Repeat LFT’s in 2 wks time showed: • Bilirubin 7.5 mg, ALT 851 I.U., GGT 447 I.U., and ALP 243 I.U. He had anorexia and had lost 2 kg in weight. He was treated with more supportive treatment and IV dextrose and multivitamins. He failed to improve and had more anorexia, weakness, nauseous feeling, and mild abdominal distension, which was confirmed to be ascites. At 8 weeks repeat LFT’s showed: • S. bil 12 mg, ALT 94 I.U., AST 65 I.U., and ALP 252 I.U. He was seen by another gastroenterologist who thought he had HAV related cholestasis and prescribed Cholestyramine. He continued to remain unwell with anorexia, nausea, and progressive distention of abdomen and had lost further 4 kg weight and hence the referral. There was no significant past history or family history especially of any liver diseases. He was not taking any drugs or alcohol. On examination he appeared deeply jaundiced. There was mild ankle edema and moderate ascites. Liver and spleen were not palpable. © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2021 M. K. Ghoda, Neonatal and Pediatric Liver and Metabolic Diseases, https://doi.org/10.1007/978-981-15-9231-7_30

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There were no stigmata of chronic liver disease. CNS, CVS and RS were all normal. Bilirubin was 44 mg, ALT 75 I.U., GGT 69 I.U., and ALP 255 I.U. PT 17/13 sec. Albumin 2.56 Gms, globulin 2.2 Gms. Ascitic fluid showed transudative picture with SAAG of 2.6 and no cells. HAV-IgM was reactive. IgM antibodies to HBsAg, HCV, HEV, HIV, and Leptospira, were non-reactive. • ANA, AMA, LKM, and ASM were negative. • Serum Ceruloplasmin, 24-hour urinary copper, K.F. ring in the eye were all within the normal range. • USG showed moderate ascites but echo texture of liver was normal, spleen was mildly enlarged and both portal vein and splenic vein were not dilated. • • • • •

How Will you Proceed Now? This was tricky and our analysis was as follows: • In a previously fit and healthy individual this is a classic story for fecal-oral type of infective hepatitis namely type-A and E both of which are sporadic and epidemic. • Type A was conclusively confirmed and type E was negative. • But type A hepatitis does not go into failure like in this case and secondly cholestasis is asymptomatic apart from itching, but this patient had features of liver failure, so cholestasis was not likely explanation. Similarly relapse also should not be symptomatic, to this extent at least, nor should produce the failure. • This patient had to have dual disease, one chronic asymptomatic which must have been triggered of by the acute insult. But what could this chronic disease be? All other routine markers were negative. Could he have hemochromatosis? We did serum ferritin levels and transferrin saturation. Ferritin was 4000 mcg/L and transferrin saturation was 98%. This transferrin saturation is crucial as ferritin being an acute phase reactant could be high in any acute illness and hence elevated ferritin need not mean hemochromatosis. But if the transferrin saturation is more than 50% for males and 45% for females then it is highly suggestive of hemochromatosis together with ferritin more than 1000 mcg/L. • MRI of liver suggested iron overload. • Lip biopsy suggested iron overload. –– So all in all we were dealing with hemochromatosis with acute hepatitis A infection. Treatment and Progress Patient had 4 sessions of plebotomy with removal of total 1.2 liters of blood. He had progressive fall of hemoglobin over 3  months and at the end of this period his

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bilirubin touched normal base line for the first time in 6 months. Ferritin decreased from 4000 to 2700 mg. The patient was totally asymptomatic and had regained all his weight back. Hemochromatosis • It is a genetic disease with multisystem involvement. • It is the most common genetic disease in Caucasian populations who have a rate of one in 227. • The diagnosis can be elusive because of the non-specific nature of the symptoms but with the discovery of the HFE gene, diagnosis is possible with minimum difficulty. Genetics Commonest cause of primary hemochromatosis is mutation in the HFE gene. These are C282y or H63D.  Other mutations are also possible. In India we do not have library of mutations in HFE gene. Clinical Features • Many patients are asymptomatic for a considerable period or may even present with cirrhosis only. • Hepatomegaly is common physical signs but may not be present in the young asymptomatic homozygote. • A clinical presentation with marked elevations in liver enzymes and elevated iron tests is uncommon and suggests an alternate diagnosis. • HCC is seen in about 20% of the affected population. • Other symptoms include diabetes, arthralgia, fatigue, pigmentation, and endocrine problems. Some of these symptoms may be sequelae of cirrhosis. Diagnosis • The fasting transferrin saturation > 45% in women and > 50% in men is suggestive but not diagnostic. • Marked elevation of ferritin (>1000 μg/L). As ferritin could be raised in other inflammatory conditions also, its correlation with transferrin saturation is important. • Liver biopsy has previously been the gold standard diagnostic test but nowadays used mainly for estimating prognosis and concomitant disease. • MRI can demonstrate moderate to severe iron overload of the liver. The techniques are improving and may be ideally suited to exclude iron overload in a doubtful patient. • Genetic Testing for the C282Y and H63D mutations of the HFE gene has become an important basis for investigating a suspected patient with hemochromatosis. Treatment • The goal of therapy is to remove excess iron to prevent any further tissue damage.

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• 500 ml. of blood is removed weekly under standard conditions. When the hemoglobin decreased to 2. Cell count could be high with mainly lymphocytes; and total fat content is around 3.5 to 4 Gms/dL. –– Chyliform ascites—Fluid with a lecithin–globulin complex due to fatty degeneration of cells. –– Pseudochylous ascites—Fluid that is milky in appearance due to the presence of pus. • Microscopy, ADA activity, culture, and PCR for tuberculosis and other similar infections. • CT scan, lymph node biopsy, lymphangiography, peritoneoscopy, and Scintiscanning may be required for detection of lymphatic leak. • Echocardiogram, color Doppler, and other related tests for heart related etiology. Complications Sepsis is the most common complication with occasionally sudden death. Treatment • Supportive: –– Repeated paracentesis. –– Diuretics and salt and water restriction. –– Elevation of legs with use of supportive stockings. –– A low-fat diet with medium-chain triglyceride supplementation. Medium-­ chain triglyceride oil is administered orally at a dose of 15 mL 3 times per day at meals may help. –– Octreotide 100 mcg, S.C., 8 hourly may help. –– Bowel rest and the institution of total parenteral nutrition should be tried in refractory cases.

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36  Case 35: A Young Boy with Failed Renal Transplant and Sudden Onset of Ascites

Definitive • Surgical repair, open or laparoscopic. • Relief of cardiac temponade or heart failure. • Appropriate intervention for malignancy. • TIPS for cirrhosis and lastly. • Peritoneo-venous shunting. Prognosis: Depends upon the underlying condition.

Case 36: A 2-Year-Old Boy with Diarrhea, Failure to Thrive, and Hepatomegaly

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A 2-year-old boy presented, with a chief complaint of diarrhea. During the previous 2  weeks, he averaged 6 loose, non-bloody stools per day, exhibited poor energy, poor appetite, and decreased urine output over the past 24 h. His mother reported a history of fever with body temperature up to 102 °F and emesis 1 week before presentation. His parents were concerned that he had shown no weight gain or linear growth during the past 6 months despite nutritional supplementation. His review of systems was otherwise negative. He had a history of patent ductus arteriosus and received indomethacin treatment. His history was also notable for nephrolithiasis on previous ultrasound and sizable urinary crystals observed by the parents. Family history was significant for nephrolithiasis in his maternal grandmother. There was no consanguinity between the parents. There had been no recent travel, sick contacts, or foreign visitors. He had a history of developmental delay and did not walk until 17 months of age. He was not receiving any medications. There was no history of allergies. On physical examination, his height and weight were both below the fifth percentile. Heart rate of 130, his vital signs were within normal range. Head, eyes, ears, nose, and mouth examination were normal. His lung examination was unremarkable. His heart examination was normal. His abdomen was round and protuberant with a soft liver palpable 6–7 cm below the right costal margin. There was no splenomegaly. He had normal bowel sounds. His skin revealed no rashes, jaundice, cyanosis, or bruising. His neurologic examination revealed mild hypotonia in his lower extremities, with 2+ deep tendon reflexes bilaterally. He had mild speech delay. • • • • •

CBC with differential: Normal. Coagulation studies: Normal. Stool for bacterial, viral, and parasitic stool cultures did not show any growth. Glucose level of 41 mg/dL. ALT/SGPT: 247 IU/L.

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AST 182 IU/L. Albumin level of 2.4 g/dL. Urinalysis revealed moderate ketones with a pH of 6. Abdominal and chest X-rays were normal.

What Is the Differential Diagnosis? Ok, we analyzed as follows… Other than infectious causes, the differential diagnoses that would explain hepatitis include: • • • • •

Inflammatory conditions (e.g., autoimmune hepatitis). Metabolic disorders (e.g., fatty acid oxidation defect, and tyrosinemia). Storage disorders (e.g., glycogen storage disease and Niemann-Pick disease). Mitochondrial disorders. Malignancy.

Differential Diagnosis • Diarrhea of this duration associated with a history of fever could be consistent with any type of bacterial, viral, or parasitic gastrointestinal infection. • Infections in the gastrointestinal tract can manifest with both diarrhea and hepatitis. Infections with hepatitis A virus, Epstein-Barr virus, cytomegalovirus, or enterovirus could have led to this patient’s clinical and laboratory findings. A post-infectious enteropathy as a result of inflammatory damage to intestinal mucosa, thus compromising appropriate absorption of fluids and nutrients, could also present in this fashion. • Although acidosis and hypoglycemia are not unexpected in a dehydrated child with infectious diarrhea, increased liver enzyme levels should raise red flags for metabolic or storage disorders. • The patient’s small stature, failure to thrive, and developmental delay also point to possible metabolic dysfunction. Metabolic disorders, such as tyrosinemia, fatty acid oxidation defects, and mitochondrial disorders, all should be considered. Given the patient’s hepatomegaly, storage disorders involving the liver, such as glycogen storage disease (types I, III, VI, and IX), need to be excluded. • If he had exhibited splenomegaly, storage disorders involving the reticuloendothelial system such as Niemann-Pick or Gaucher’s disease would need to be ruled out. Infiltrative processes, such as lymphoma/ leukemia, neuroblastoma, or tumor metastases; hepatic cysts; and congestive disorders, such as congenital heart disease and Budd–Chiari syndrome, appear to be less likely in this child.

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• Autoimmune hepatitis, although less common at this age, could present with this degree of liver enzyme elevation. Last, the patient’s prematurity increases the likelihood that he underwent prior umbilical catheterization, which increases the risk for thrombosis or cavernous transformation of the portal vein, although he has no splenomegaly as would be expected in that setting. What Additional Diagnostic Tests Would you Perform? Additional diagnostic tests that could be helpful in this setting include Doppler ultrasound and laboratory studies: • • • • •

Serum amino acids. Urine organic acids and amino acids. Plasma acylcarnitine profile. Lactate/pyruvate. Uric acid, creatine kinase, fasting lipid profile with triglycerides and cholesterol. • PT, APTT, and INR. The best initial diagnostic test to evaluate for hepatomegaly in this patient with failure to thrive and diarrhea is abdominal ultrasonography. Doppler ultrasound is useful in assessing appropriate flow and direction in the portal and hepatic veins and hepatic arteries. Ultrasound examination: The liver was diffusely enlarged, but normal in echo texture; there were no focal masses. • The gallbladder and intrahepatic/extrahepatic ducts were normal. The spleen was normal in size, and the pancreas was normal in appearance and size. Doppler flow study was unremarkable. • Serum amino acids, urine organic acids, and plasma acylcarnitine profile were within normal limits. • Uric acid level was elevated at 7.7 mg/dL (range, 1.8–5 mg/dL). • Creatine kinase level was low at 1.5 in patients with hepatic encephalopathy, or INR >2.0 in patients without encephalopathy. Why Acute Liver Failure in Neonates Assume Significance? • Acute liver failure (ALF) is potentially a devastating process. • It progresses fast resulting in death or transplant if not arrested with appropriate treatment. Important Lesson is that once ALF it is diagnosed there is no time to lose. Another important issue is hypoglycemia soon after birth. • Perinatal events, Galactosemia, GSDs, Organic acidemia, and PHHI • Hypoglycemia starting late in infancy or early childhood: FAOD, PHHI, HFI, Insulinoma, and GSDs What About Acidosis, Which Is Anion Gap Acidosis Here? • Anion gap = AG = [Na+] + [K+] − [Cl−] − [HCO3−]. • Normal range: 8–16 mmol/L • In anion gap metabolic acidosis: Consider • Organic acidopathy • Lactic acidosis • Ketoacidosis So in this case we are looking for any of these three causes. What are your priorities here? How will you manage this case if you receive such a neonate? Understand this carefully, it may save many, many lives throughout your career. Priorities in such cases are as follows: Simultaneously...

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• Correct any immediate life threatening complication/events. • Start investigations to arrive at a diagnosis and treat accordingly. • Arrange for a speedy and safe transport if your center is not geared for such emergencies. Etiology of Neonatal Liver Failure • In neonates and infants, metabolic diseases are the main cause of ALF. Among non-metabolic causes, HSV is common and it is an emergency. • In older children, viruses, drug-induced hepatotoxicity and autoimmune hepatitis are the most common identified causes of ALF. Do all Causes of Neonatal Liver Failure Have the Same Intensity or Timeframe of Presentation? The answer, as we have discussed earlier, is no. • Neonatal Hemochromatosis • Zellweger syndrome • Mitochondrial liver diseases may be present at birth. Whereas • • • •

Tyrosinemia Galactosemia Hemophagocytic Lymphocytic syndrome HSV hepatitis

may take a few days to weeks to manifest. Important learning point here is therefore that the time of presentation may provide a clue as to the underlying etiology. Overall What Features Should Make You Suspect Metabolic Disease? If you see a child with: • • • • • • •

Intermittent illness. Recurrent unexplained vomiting. Failure to thrive. Aversion to certain food or the illness starting with particular food. Rapid deterioration for no obvious reasons. Rapidly progressive encephalopathy of obscure origin. Hypotonia, seizures, especially if hard to control.

Or if the Child Has • Apnea or respiratory distress • Sepsis, particularly with Escherichia coli

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Unusual odor Jaundice Dysmorphic features Organomegaly

When you have suspected metabolic disease, remember you have following tests available in India: • • • • • • • • • • • • •

Sugar Urinary reducing substances, urinary ketones Ammonia Urea Total Galactose, Galactose phosphate/Gal-1-T Lactate Ferritin and transferrin saturation Triglycerides Alpha-fetoprotein Acyl carnitine profile Plasma amino acids Urinary organic acids Urinary GAG estimation You may order them judiciously to arrive at a firm diagnosis.

What Basic Treatment a Pediatrician Needs to Start Irrespective of the Cause if Metabolic Cause Is Suspected? The basic principles for treatment of suspected metabolic disorders are: • Prevent catabolism by using IV dextrose. • Limit the intake of the offending substance, if possible, through manipulation of the diet. Limit protein in urea cycle disorders, fatty food in FAOD. • Stabilize the patient without bothering to find out the cause of illness if the patient is acutely ill. Do you know important non-metabolic causes of neonatal liver failure? • HSV hepatitis. • Hemophagocytic Lymphohistiocytic syndrome. • Neonatal Hemochromatosis which is an alloimmune disorder. How and When to Suspect HSV Hepatitis? • Could be confused with bacterial sepsis. • Vesicular skin lesions are the most predominant symptoms consistent with neonatal herpes.

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• Later on DIC, hepatitis, pneumonitis, and seizures. • Remember!! HSV hepatitis is an emergency and once suspected treatment is mandatory. Hemophagocytic Lymphohistiocytosis (HLH) • Rare but potentially fatal. • Fever, hepatosplenomegaly. • Pancytopenia, lymphadenopathy. • Cutaneous involvement occurs in as many as 65% of patients. • An inherited more prevalent with parental consanguinity. Non-metabolic investigations of neonatal liver failure: Infectious • Culture from cutaneous lesions or oropharynx for HSV viral markers. • Cytomegalovirus PCR. • IgM varicella zoster virus. • IgM Epstein-Barr virus. • HIV 1 and 2. Hemophagocytosis • Serum triglyceride • Cholesterol • Ferritin • Bone marrow biopsy There are some newer concepts in management of Liver failure, which you should be familiar with. To Prevent Hepatocyte Damage • N-acetyl cysteine (NAC) infusion in non-acetaminophen causes of ALF at 100 mg/kg/d in all cases of ALF irrespective of the etiology. To Prevent Cerebral Edema • Prophylactic infusion of 3% saline to maintain sodium at 145–155 mmol/L is preferred over mannitol. • If neurological signs or ICP is above 25 mm Hg, a bolus of IV mannitol (0.25–1 g/ kg, 20%). Repeated, if serum osmolality 2 times ULN

HBeAg+ Anti HBe+ DNA: 2 times ULN

Case 42: A Case of Neonatal Hepatitis and Failure to Thrive

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A 2-month-old female was referred for persistent jaundice. First by order of birth, FTNVD, no consanguinity/noted to have jaundice by parents at 15 days or so parents were reassured by the treating pediatrician. However, there was progressive deepening of jaundice with failure to thrive. On Examination • Deeply jaundice. • No edema or ascites. • Liver ++ 2 fingers below costal margin. • Splenic tip palpable. • No visible veins. • Diapers were stained yellow. • Stool color on personal inspection was yellow. Investigations • S. Bil: 10.2, 70% conjugated. • ALT: 376 i.u. • GGT: 240 i.u. • ALP: 357 i.u. • S. Alb: 2.81. • S. Glob: 2.45. • INR: 1.9, corrected to 1.2 after vitamin K. • Hb: 9.8, normochromic normocytic picture. • WCC: 10,200 with 65% polys. • Plt: 150,000. • RFT: urea 32, creat: 0.9. • USG: Mild hepatomegaly, slightly altered parenchymal pattern. • PV and SV were normal in size. • Spleen mildly enlarged. © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2021 M. K. Ghoda, Neonatal and Pediatric Liver and Metabolic Diseases, https://doi.org/10.1007/978-981-15-9231-7_43

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GB distended. CBD and IHBR seen and not dilated. HBsAg: Non-reactive. HAV: Non-reactive. HEV Non-reactive.

We stop for a while at this point and remember what we have learnt so far. Neonatal jaundice is not a homogenous entity and therefore we need to know: • If it is a case of unconjugated hyperbilirubinemia or a case of conjugated hyperbilirubinemia? –– Sick child –– With gross metabolic disturbances –– Coagulopathy –– Ascites/edema • Or a non-sick looking child with –– No gross metabolic disturbances. –– Coagulopathy, if present, is reversible. –– Ascites/edema is a late event. 3. Timing of onset of jaundice? Here it a case of conjugated hyperbilirubinemia, so we have following etiologies to consider: • • • • •

Pregnancy related. Structural defects. Metabolic diseases. Viral diseases other than those related to pregnancy. Unknown.

So when you see a patient with jaundice, you may have to process information simultaneously, • Jaundice soon after birth… Progressively increasing… coagulopathy... Ascites... Edema... stool yellow. • Jaundice detected after a few days, progressively increasing… pale stool… no edema, no ascites… no FTT. • Jaundice detected after a few days, progressively increasing… initially yellow but now pale stool…no edema, no ascites…some FTT. • Jaundice... developed in late infancy... no failure to thrive... severe itching... coagulopathy reversible with vitamin K stool intermittently yellow and white.

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Useful Investigations • USG: Structural defects, biliary atresia, spontaneous perforation of bile duct. • TORCH+ Viral markers. • Septic screen: For Cholestasis of inflammation. • Galactosemia and Tyrosinemia screen. • TMS and Acyl carnitine profile: FAOD, UCD, Tyrosinemia. • ECHO: PPH. • Fundus examination, X-ray spine for butterfly vertebrae. • Liver biopsy. • Lap/op cholangiogram. • If you have Next Generation Sequencing (NGS) available, it helps tremendously in limiting your differential diagnosis. It is fast, accurate, and becoming progressively cost effective. Coming back to our case... • • • • •

Cytomegalo IgM: Positive. GALIPUT: Within normal range. Alpha-feto protein was not significantly elevated. Fundus: Normal. ECHO: Normal.

Should a pediatrician accept this as evidence of Cytomegalo virus infection as the cause of hepatitis in this patient? • • • •

The answer is a clear no. CMV is ubiquitous and not everybody who develops manifest infection. False-positive results are common. PCR to confirm the activity and to ascertain the magnitude of the viral load are required to initiate therapy.

If PCR was high in this case would you treat this patient? Treatment criteria for suspected CMV infection are: • Immunocompromised are at risk of developing life- and sight-threatening CMV disease. Or if the patient has Cytomegalo Inclusion Disease (CID). • IUGR. • Hepatosplenomegaly. • Hematological abnormalities particularly severe thrombocytopenia. • Cutaneous manifestations, including petechiae and purpura.

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The most significant manifestations of CID involve the CNS. • • • • •

Microcephaly. Ventriculomegaly. Cerebral atrophy. Chorioretinitis. Sensorineural hearing loss.

This patient had very high CMV viral load and hepatosplenomegaly and during the next month developed hematological abnormality requiring Valgancyclovir treatment with resolution of his jaundice.

Case 43: An Infant with Sudden Onset of Unilateral Ptosis and Jaundice

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A 3-month-old child was referred because of jaundice and altered coagulation not corrected by vitamin K and plasma. He was a second child of a non-consanguineous marriage, FTNVD. First sibling, a girl, was normal at 4 years of age. At about one month, his parents noted that he was not putting on weight and appeared yellow. They also noted that he was irritable and was crying excessively. The child was seen by a local pediatrician who reassured them that jaundice will disappear by 3 months. A day before he was referred, parents noted that he was not opening his left eye. Local pediatrician confirmed this finding and also noted that the jaundice had worsened and hence the referral. Let us pause here and think what could be going on. Do you have any idea? O.K. He had complete ptosis of his left eyelid with dilated pupil, without any other neurological features like paralysis. We thought it was third nerve palsy and a pediatric neurologist confirmed it. What Next? What Possibly Could Be the Cause of This? Next was MRI. The neurologist had expected intracranial hemorrhage in the middle cerebral artery in the territory of 3rd nerve nucleus causing partial 3rd nerve palsy. MRI confirmed this. Can you guess why this happened? Obviously, there was coagulopathy associated with jaundice causing this hemorrhage. Investigations • CBC: Unremarkable • Bilirubin: 10.2, ALT 545, Albumin 2.8, Globulin 2.6 • PT: 34/13.5 sec • RFT: Unremarkable • RBS: 78 mg © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2021 M. K. Ghoda, Neonatal and Pediatric Liver and Metabolic Diseases, https://doi.org/10.1007/978-981-15-9231-7_44

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• USG: Slightly altered parenchymal echo texture, Collapsed GB, normal CBD, portal vein, and splenic vein normal. Spleen was normal, minimal free fluid seen. • Thyroid functions: Normal • Urine for reducing substance was negative. • TORCH titer was negative for all four viruses. Progress The child was given vitamin K and FFP but his coagulopathy would not correct. On daily vitamin K and FFP his average INR remained around 2.5. He also remained jaundiced and had failure to thrive. What other tests you would do now? Obviously, this child is in liver failure and coagulopathy is difficult to correct. As we have discussed before, at this age two important things need be looked at, first is galactosemia even though urine for reducing substances is negative; and the other is hepatorenal tyrosinemia type I, although there was no renal involvement here. Alpha-feto protein is said to be very high, in tens of thousands, in tyrosinemia but this is not diagnostic and in our experience any liver pathology where there is massive necrosis and regeneration, alpha-feto protein is elevated. The diagnostic test is urinary succinyl acetone, which was very high here, thus clinching the diagnosis. Nitisinone (NTBC) is a very effective drug which can be lifesaving. Unfortunately this patient did not avail this drug, but another patient who also had hepatorenal tyrosinemia with renal involvement in form of Fanconi syndrome did manage to take this drug with reversal of liver function abnormality. Take home message is that liver involvement in neonatal age with early decompensation is almost always metabolic in origin except HSV infection and neonatal hemochromatosis. Difficult to correct coagulopathy should alert one to the possibility of hepatorenal tyrosinemia. Hepatorenal Tyrosinemia • This is caused by decrease in the activity of fumarylacetoacetate hydrolase. • It is autosomal recessive. • The gene has been cloned and mapped to chromosome 15q23-25. Clinical Profile The clinical course generally followed is one of the two patterns: • An acute • A chronic form An acute presentation is predominant. Symptoms develop in early infancy, and they are those of acute hepatic decompensation with death occurring usually before the first birthday. However, some patients with an acute presentation end up being in the chronic form. If untreated, one-year mortality for those presenting with symptoms by 2 months is about 60%; those presenting between 2 and 6 months it is 20% and for those presenting after 6 months it is 4%.

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Liver Is the Prime Target • There is jaundice, failure to thrive, abdominal distension, and there may be vomiting and/or diarrhea. • The tempo is usually very fast with associated liver failure resulting in ascites, edema feet. Coagulopathy is difficult to control with vitamin K. • There may be associated hypoglycemia. • There may be GI bleed, epistaxis, or sometimes-intracranial bleed. This may be the presenting feature in a few. • A boiled cabbage-like odor in some patients has been related to a metabolite of methionine. • Transaminase levels in the blood may be normal or slightly elevated. • Elevation over 1000 IU/L indicates substantial damage to hepatic cells. • Alpha-fetoprotein may be markedly elevated, ranging from 100,000–400,000 ng/ mL but this is not diagnostic. The Chronic Liver form • It is in the form of hepatic cirrhosis with elevated bilirubin, altered albumin/ globulin ratio, and coagulopathy. If patient survives then there is the development of hepatocellular carcinoma. • Renal involvement is another characteristic feature of chronic form. It takes the form of enlargement of the kidneys, nephrocalcinosis. The renal tubular disease is that of a typical renal Fanconi syndrome in which there is phosphaturia, aminoaciduria, and often glycosuria. There may be proteinuria. • Systemic metabolic acidosis may result from renal tubular dysfunction. The phosphate losses lead to hypophosphatemia and clinical rickets, which may be vitamin D resistant. • There may also be a variable reduction in glomerular function. Neurological Involvement • They are independent of Liver disease. • Neurologic crises of pain and paresthesia are a result of peripheral neuropathy. • Muscular weakness may progress to paralysis requiring artificial ventilation, self-injurious behavior has been observed. • Some patients have seizures. • Death may occur. • Most crises subside in one to seven days and resolve slowly, but there may be residual weakness. Intelligence is usually normal. Diagnosis • The gold standard in the diagnosis is the demonstration of succinylacetone in the urine. • Where the mutation is known or where a small number of mutations are responsible, molecular testing is the preferred method. This is done by Next Generation Sequencing.

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• Heterozygote detection has been carried out by the assay of fumarylacetoacetate hydrolase activity in fibroblasts and lymphocytes. • Prenatal diagnosis has been accomplished by assay of the enzyme in cultured amniocytes or chorionic villus material. • Direct assay of succinylacetone in amniotic fluid is thought to be the method of choice. • Tyrosinemia has recently been incorporated into expanded tandem mass spectrometry (MS/MS) programs with tyrosine as the key analyte. • A combination of hypoglycemia, coagulopathy, tyrosinemia, succinylacetone, and very high fetoprotein is diagnostic.

Tyrosine 4-OH phenyl pyruvate NTBC Methylacetoacetate Succinyl acetone +++

Fumerylacetoacetate

Fumarate

Acetoacetate

Fumeryl acetoacetate hydrolase (FAH)

Block in Tyrosinemia type 1

Galactosemia and Tyrosinemia

Both cause neonatal jaundice and sickness but Tyrosinemia causes difficult to control coagulopathy and has very high alpha-feto protein and has renal involvement whereas Galactosemia has none of the above and improves promptly on withdrawl of galactose/milk Treatment The advent of therapy NTBC/Nitisinone has changed the natural history of the disease. The dose is 1 mg/kilogram/day for lifelong period. Results are excellent. Fibrosis and adenoma formation have been known to revert also.

Case 44: A Neonate with Rapidly Deteriorating Liver Functions

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A 5-day-old neonate was transferred to our care for rapid deterioration of his general health and altered liver functions. He was born at term to a healthy mother after a normal pregnancy. Birth weight was 2.7 kg. The mother was reported to be in good health during pregnancy. Apgar score of 9 and 9 at 1 and 5 min, respectively, and physical examination at birth was unremarkable. On the fourth day of life, the infant was admitted locally with fever, lethargy, and moderate respiratory distress. Sepsis workup was performed and pending result was treated with Ampicillin and cefotaxime and oxygen through a nasal canula. Investigations • CBC: Hb 12.3, WCC 10200 • C-reactive protein 19 mg/L • Liver enzymes: AST: 312 U/L, ALT: 201 U/L • Chest X-ray showed bilateral infiltrates Next day, a vesicular eruption in the right leg area was noted. He was still febrile and the severity of the respiratory distress was increasing requiring a nasal CPAP; and subsequently, he was intubated and placed on conventional mechanical ventilation. However, due to severe desaturation and respiratory failure, he was shifted to high-frequency oscillatory ventilation (HFOV). He also developed hypotension for which dopamine and dobutamine infusions were started. Investigations on Day 5 • Thrombocytopenia 39,000, WCC 1800. • C-reactive protein level 33 mg/L.

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• AST 5186, ALT: 1174, INR 4.0. • USG: Showed derangement of the liver parenchymal architecture, CBD was normal, no intrahepatic duct dilatation was seen, the gallbladder was partially collapsed with sludge inside, the spleen was mildly enlarged, and there was an evidence of portal hypertension. What are you thinking? Let us analyze this case. In our experience any skin lesion, particularly vesicular with liver failure should straight away raise the possibility of herpes simplex. Added to this, respiratory failure, fulminate hepatic failure, in combination with leukopenia, thrombocytopenia, and fever, raised the possibility of viral infection; top-most again being disseminated herpes simplex virus infection. Remember this, disseminated herpes simplex infection with liver involvement is an emergency and as soon as you suspect it, obtain necessary samples and start treatment there and then without waiting for results. We started intravenous acyclovir at 20 mg/kg, 8 hrly after obtaining the blood and CSF sample for the HSV PCR test. In addition, infusion of FFP, platelet, PRC, clotting factors, GCSF, and IVIG were also started. Result of blood and CSF HSV PCR was positive for HSV-II virus. His mother and father were tested for HSV and both came as positive for HSV-II antibody. His stay was very stormy. He developed fulminated liver failure with cholestatic jaundice. Now What? He was treated with N-acetylcysteine, 3% NaCl and propranolol, FFP and vitamin K. He was fed parentally for about 24 days, and enteral feed was introduced gradually till full feed through NGT. IV Acyclovir was continued for 4 weeks when his blood and CSF PCR for HSV was negative. His liver enzymes gradually improved until almost normalized by the age of 3 months. Repeat ultrasound at the age of 3 months revealed a complete recovery. Disseminated HSV Infection with Hepatitis • Disseminated HSV disease is the most lethal form of neonatal herpes infection. Mortality without treatment was 85%, and with treatment 57%. • Neurological impairment is very common. • HSV infection should be considered in the differential diagnosis of acutely unwell neonate. • Early and prompt administration of acyclovir improves survival and outcome.

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• Even after successful parenteral treatment, the recurrence of HSV can occur and may be a lifelong problem. Therefore, some experts recommend long-term suppressive therapy with oral acyclovir to reduce skin or eye recurrences during infancy. • Severe hepatitis, caused by either HSV strains, may cause potentially fatal, acute liver failure in neonates with disseminated disease. • Liver transplantation may be required.

Case 45: A 6-Month-Old Child with Hematemesis

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A 6-month-old child was referred for UGI endoscopy with upper GI bleed. Upper GI endoscopy showed large varices with stigmata of recent bleed. In view of very narrow passage, endoscopic sclerotherapy was performed instead of band ligation. The child was born premature at 30 weeks. He was delivered by cesarean section because of decreased fetal movement and increased pelvic pressure. Apgar scores at birth were 8 and 9 at 1 and 5 min, respectively. Review of antenatal sonography showed IUGR. The baby had developed respiratory distress, liver failure, and coagulopathy early in life. Investigations • Hb: 9.2, WCC 10,000, platelets 74,000. • APTT/PT 47/32 sec, PT 31/13 sec. • Bilirubin 7.9, 70% conjugated. • GAL 1 T for galactosemia, Urinary succinyl acetone for tyrosinemia and plasma amino acids for Urea cycle disorders were negative. • TORCH titers were negative. Diagnosis of Idiopathic Neonatal Hepatitis was made and supportive treatment was started. The patient remained stable and was taken home by parents against medical advice. Do You Agree with This Diagnosis? Why? At the age 6 months, he developed hematemesis and referred for UGI endoscopy. Large varices were seen and since the passage was very narrow, endoscopic sclerotherapy was performed instead of endoscopic band ligation.

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What More Would You Do Now? Do You see Cirrhosis at This Age? Cirrhosis at this age is distinctly uncommon and has to be a metabolic disease. Congenital hepatic fibrosis, etc. may produce portal hypertension but liver involvement is usually minimal. It could be autoimmune, may be neonatal hemochromatosis or some similar illness in view of negative work up for common metabolic problems. One thing I would like to emphasize is that do not consider Wilson’s disease at this age. In our experience minimum age for Wilson is 5 years, literature says 3 years, but not below one year. So we try on this line. Investigations • ANA, anti-SMA and anti-LKM1 and 2 were negative. • Markedly elevated ferritin and transferrin saturation. • An MRI showed signal abnormalities in liver and pancreas compatible with iron deposition. • He was started on intravenous immunoglobulin although we thought it was already too late. • Lip biopsy showed excessive iron deposition. • Liver biopsy was not done. Patient deteriorated late that evening and died. Postmortem examination of the liver showed subtotal collapse of parenchyma, diffuse interstitial fibrosis, intrahepatic cholestasis, and marked iron deposition in hepatocytes. There was marked iron depositions in pancreas, myocardium, respiratory secretory glands, thyroid, brain, kidneys, and adrenal glands. No reticuloendothelial iron accumulation was seen. Diagnosis: Neonatal Hemochromatosis. Neonatal Hemochromatosis • Neonatal Hemochromatosis (NH) is a clinical condition in which severe liver disease in the newborn is accompanied by extrahepatic siderosis. • It is not a genetic disease but a Gestational Alloimmune Liver Disease (GALD). • During the pregnancy, the mother is exposed to a fetal antigen that she does not recognize as “self” and subsequently begins to produce IgG antibodies that are directed against fetal hepatocytes. • It may result in congenital cirrhosis or acute liver failure with and without iron overload and siderosis. • Extrahepatic siderosis in NH is most frequently seen in the acinar epithelium of the exocrine pancreas, myocardium, epithelia of thyroid follicles, and the mucosal or minor salivary glands of the oronasopharynx and respiratory tree. • The reticuloendothelial system is relatively spared, so spleen, lymph nodes, and bone marrow contain very small quantities of stainable iron. • In fetuses with GALD, liver injury results in significantly decreased production of hepcidin which has negative feedback on iron absorption and as a result excess iron is transported from the placenta to the fetal liver.

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• Renal hypoplasia and other abnormalities are also described. • Occasionally, the NH phenotype can arise from non-GALD diseases including perinatal infection, trisomy 21, and mitochondrial DNA depletion syndrome due DGUOK gene mutations. • Presentation could be anytime from 18 weeks gestation to 3 months post-delivery. • The majority of infants present with liver failure within hours of birth. • There may be hypoglycemia, coagulopathy, and jaundice. • Renal involvement produce oliguria. • 25% have a history of intrauterine growth restriction, oligohydramnios, and prematurity. • Rarely liver disease may take days to weeks to be present. • Rarely there would not be any clinical disease. • LFTs may show varying degrees of abnormality, from birth in most of the cases. However, aminotransferases rarely exceed 100 IU/L. • Alpha-fetoprotein levels are very high as in many liver diseases with massive necrosis. This is not diagnostic. • Iron studies reveal high serum ferritin levels, low transferrin levels, and high iron saturations. Again this is not diagnostic as ferritin being acute phase reactant, it is high in many liver diseases. • Differential diagnosis includes mitochondrial diseases, bile acid synthetic defects, tyrosinemia, Hemophagocytic lymphohistiocytosis, ABCB11 gene mutations, hereditary galactosemia, hereditary fructose intolerance, and infection. • It is the evidence of fetal insult and neonatal liver failure, which strongly suggest NH. Combined with resistant coagulopathy and low serum aminotransferases, diagnosis should be vigorously persuaded. • The above, with evidence of extrahepatic siderosis easily detected in punch biopsy of lip is diagnostic. • T2-weighted MRI can also be used to document siderosis. Together, they have a sensitivity that approaches 80. Treatment • High-dose intravenous immunoglobulin (IVIG) (1 g/kg) with or without double-­ volume exchange transfusion to remove existing reactive antibody is the treatment of choice. • Sometimes IVIG must be given pending confirmation of the diagnosis. • Recurrence of severe NH can be prevented by treatment with IVIG during gestation at 14 weeks, 16 weeks, and then weekly from the 18th week of pregnancy until the end of gestation.

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Neonatal Hemochromatosis Possible pathophysiology M Mother is exposed to fetal cells and develops alloantibodies

F Alloantibodies attack fetal liver cells

Fetal liver cells produce Hepcidin, which regulates iron transport across placenta, and Ferroportin which regulates iron movement out of liver cells. Net result is unregulated movement of iron across placenta and failure to export iron out of liver cells resulting in massive iron overload.

Prognosis: If treated as above in time, prognosis is very good.

Case 46: A Young Child with Persistent Elevation of SGOT/SGPT

47

A 2-year-old male was referred by pediatrician for persistent elevation of AST and ALT. The child had developed acute hepatitis A and serial monitoring showed persistent elevation of AST and ALT. The child was born of non-consanguineous marriage. He was the only child. The child had no symptoms. Milestones were on target. There was no significant past medical history. Investigations • CBC: Normal • LFT: S. Bil 0.6, ALT 830, AST 925, ALP: 125, Albumin 3.9, Globulin 2.4 • PT 11.2/12 sec • RFT: Normal • Bl. Sugar (random) 84 mg • HBsAg, HCV: Non-reactive • Ceruloplasmin and 24-h urinary copper: Within normal range • ANA, Anti-SMA: Within normal range • TTGA: (For Celiac disease) Normal • Ferritin: Within normal range • USG: Normal liver, spleen, and portal vein The child remained well but AST and ALT remained elevated. Liver biopsy was offered. Patient was lost to follow up. Three years later, the relatives returned with complaint that the child keeps falling and they are ready for the biopsy of liver. Would You Do Liver Biopsy Now? Let us analyze this case. The child was almost incidentally found to have raised AST and ALT but he was asymptomatic otherwise. Liver functions and USG failed to

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come up with any answer. This is a standard MRCP/DM gastro examination case, which we would get right ten times out of ten. But in real life I failed! Complaint of repeated falls cleared the issue immediately. This child must have muscular problem, motor neuron disease or something like that. ALT and AST both were coming from muscle, simple! The child was referred to neurologist and diagnosis of motor neuron disease was confirmed. No liver biopsy is required now.

Case 47: An Infant with Persistent Vomiting

48

A 3-month-old male infant was referred for persistent vomiting, feeding difficulty, and dehydration. He was the first child of a non-consanguineous marriage delivered at full-term vaginally. Initial few days were without any problem but since then the child progressively became irritable with excessive crying and occasional vomiting. This progressively got worse. The child was seen by a local pediatrician who admitted him because he found the child dehydrated. Investigations • CBC: Hb11, WCC 12,000, PLT 2,34,000 • CRP: 12 • RFT: Na; 121, K: 5.9, Cl: 88, Creat 0.8, urea 21 • LFT: Bil. 0.6, ALT 21 • RBS: 53 • Urine: Normal, no reducing substances The child was infused normal saline and dextrose and appeared to settle and hence discharged with problems recurring soon after discharge and hence he was shifted to our care. History was corroborated. Child looked cachetic with weight of 2.0 kg, pulse was thready, and blood pressure was barely recordable at 50 mm Hg systolic. Abdomen was soft, no organs were palpable. CVS and RS were normal. Investigations • CBC: Hb10.8, WCC 14,000, and PLT 2,00,000 • CRP: 16 • RFT: Na; 117, K: 5.5, Cl: 89, Creat 1.1, urea 22 • LFT: Bil. 0.9, ALT 22 • RBS: 44 © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2021 M. K. Ghoda, Neonatal and Pediatric Liver and Metabolic Diseases, https://doi.org/10.1007/978-981-15-9231-7_48

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• • • •

48  Case 47: An Infant with Persistent Vomiting

Urine: Normal, no reducing substances Blood culture was obtained CXR: Normal ECHO: Normal

What Would You Do Now? Any Thought on Diagnosis? This was not difficult. The child was severely dehydrated with low sodium, high potassium, and hypoglycemia. Blood pressure was almost unrecordable. Cortisol/ Adrenal insufficiency was our diagnosis. He was transferred to PICU and started with saline and dextrose to counter hypoglycemia. After obtaining spot cortisol and ACTH and 17-hydroxyprogesterone sample, hydrocortisone was administered. The child made quick recovery. Pending reports: • USG showed adrenal hypoplasia. • High ACTH, low cortisol, and normal. • 17-Hydroxyprogesterone levels, thus confirming our diagnosis. X-linked Adrenal Hypoplasia Congenita (X-linked AHC) • It is characterized by infantile-onset acute primary adrenal insufficiency at an average age of three weeks in 60%. • In 40% onset is in childhood. • Rarely, it may present in adulthood. • Clinically, it presents acutely with dehydration and shock caused by salt wasting. • Hypoglycemia and seizures may be seen. • Cortisol may be low or within the normal range, which is inappropriately low for a sick child. • In older children, adrenal failure may be precipitated by intercurrent illness or stress. • Affected males typically have delayed puberty or arrested puberty caused by hypogonadotropic hypogonadism (HH). • Carrier females may very occasionally have adrenal insufficiency or hypogonadotropic hypogonadism as a result of skewed X-chromosome inactivation. • Primary adrenal failure characterized by hyponatremia, hyperkalemia, acidosis, and an elevated serum concentration of ACTH in the presence of normal or low serum concentration of 17-hydroxyprogesterone presenting in a male in the first month or two of life strongly suggests X-linked AHC. • Nearly 100% of affected individuals with a positive family history consistent with X-linked inheritance have an identifiable pathogenic variant in NR0B1, the only gene in which pathogenic variants are known to cause X-linked AHC. • Approximately 50% of males with AHC who have no other affected family members have an identifiable pathogenic variant in NR0B1.

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Management Is Twofold • Treatment of acute illness with IV saline, glucose, and hydrocortisone. • Secondly, we need to replace glucocorticoids and mineralocorticoids and oral supplements of sodium chloride in younger children. Steroid replacement must be increased during periods of illness or stress. • Affected individuals with hypogonadotropic hypogonadism are likely to need increasing doses of testosterone to induce puberty.

Case 48: A Case of Fever and Jaundice

49

A 12-year-girl was referred for jaundice and skin rashes. She was well before some 7 days when she developed fever, retro-orbital pain, backache, and vomiting. Since there was an epidemic of dengue going on, her pediatrician admitted her and investigated for dengue fever. On admission, she had fever of 104 F, pulse 104, B.P. 110/70, she looked unwell. There was no jaundice, no petechiae, no ankle edema, and no ascites. Liver and spleen were not palpable. RS and CVS were both normal. Investigations • CBC: Hb 10.9, WCC 11,000, Plt, 2, 40,000, HCT 33, no malaria parasite seen • Urea 23, Creat 0.8, Na 136, K 3.9 • Bil: 0.7, ALT 62, AST 64, ALP 125, Alb 3.6, Glob 2.0 • Dengue NS 1 antigen: positive, Dengue IgM: non-reactive She was diagnosed as a case of Dengue fever. Supportive IV fluids with encouragement to drink oral fluids and paracetamol were started. Fever continued almost continuously requiring round the clock paracetamol and tepid sponging. She continued to remain anorexic, and now she had right upper quadrant pain. Jaundice was detected in her eyes. • • • •

Bil: 3.2, ALT 1035, AST 1100, ALP 143, PT 16/12.3, Albumin 2.9 CBC: Hb 9.0, HCT 39 Creat 1.2, Urea 61, Na 144, K 3.3, RBS 84 HBsAg, HAV IgM, and HEV IgM were non-reactive

In view of increased hematocrete IV fluid was pushed and patient was encouraged to take as much oral fluids as possible.

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Will You Accept This as a Case of Dengue Fever? What Do You Think Is Responsible for Her Jaundice? • Yes, we can accept this as a case of dengue because dengue IgM takes time to develop, initially only Dengue virus PCR and NS1 antigen will be positive. • Dengue is responsible for hepatitis as the progression so far with reactive NS 1 antigen is conclusive of dengue. Involvement of Liver in Dengue Fever Anicteric hepatitis: • The commonest abnormality detected has been raised transaminase levels. • Elevation in AST is more than ALT, especially during the first week of infection. • The increased AST/ALT ratio is useful for differential diagnosis from acute hepatitis caused by the hepatitis A, B, or C viruses where it is rarely observed. • Levels are mostly mildly elevated and more than a 10-fold rise is seen in a tiny minority. • Liver damage has been found to be more common among females. • Coagulation abnormalities have been found also. Hepatitis pattern: • This is more common in DF than DHF. • RUQ pain, anorexia, and nausea/vomiting. • Clinical jaundice has been detected in 1.7–17%. • Hepatomegaly may be present with elevated transaminases. • Hepatomegaly is more common with children. Acute liver failure: • Dengue-related ALF has been well described in children, with dengue being responsible for ALF in about 20% of patients. • The presentation can be varied, either classical presentation of dengue with hepatitis and shock syndrome or there may be less classical dengue characteristics. Worsening of chronic liver disease: • Dengue has also been well recognized as the cause of worsening of chronic liver disease. Management: Mainly supportive. Oral and where required intravenous fluids are pushed to avoid hemoconcentration. Fever is dealt with paracetamol only. Any complication is dealt with as per standard guidelines of affected organ management.

Case 49: A Neonate with Jaundice and Enlarged Liver

50

A 3-month-old girl was referred for jaundice. This was detected when she was about 2 months old. Various pediatricians treated her locally without any diagnosis being made. She was first child from a non-consanguineous marriage. Pregnancy was uneventful with normal vaginal delivery. Since birth, the child was on breast-­feeding and was thriving well. There was no history of fever, convulsions, vomiting, loss of consciousness, etc. On examination, the child was obviously jaundiced. Liver was firm and enlarged 3 fingers below costal margin and was non-tender. Spleen was not palpable. Rest of the examination was normal. Investigations • CBC: Normal. • Urea creatinine and electrolytes were normal. • Random blood sugar 65 mg. • Bil: 4.3 mainly conjugated, ALT/SGPT 149, AST/SGOT 83. PT 15/13 sec. Albumin 3.5, Globulin 2.0. • Urine for reducing substances was negative. • USG: Liver enlarged, portal and splenic vein normal. • Eye checkup: No cataract, no chorioretinitis, no cherry red spot, and no posterior embryotoxon. Few other tests were done and the patient was advised to eat frequent meals and get admitted immediately if there was even a trivial infection. She was regularly followed up with improvement in her jaundice, which disappeared completely, but the liver remained enlarged as before. Roughly two years on, she was rushed from her hometown to us with 4–5 days history of diarrhea and vomiting. When she arrived at our hospital, she was comatose.

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How Can You Explain This? What Is Your Likely Diagnosis? Let us apply some logic here... • This child had neonatal jaundice with enlarged liver from which she recovered symptomatically. • If we go back to classification of neonatal liver diseases, obviously she does not have fulminant liver disease so mitochondrial liver disease and neonatal hemochromatosis and those sorts of disorders are very unlikely. • Jaundiced regressed completely so biliary atresia is not possible. • Once infective causes like cytomegalovirus infection have settled they do not recur, so they are also not likely. • She was given dietary advice and she deteriorated very fast once she picked up infection. So all in all, metabolic disease seems very likely. But this could not be galactosemia or tyrosinemia because they have definitive treatment, which might have been started and these diseases have relentless progress if not treated appropriately. • Urea cycle disorder or fatty acid oxidation disorders (FAODs) are seen locally and they seem likely. • On second admission, she had severe hypoglycemia but simultaneous urine did not show any ketones! So this is a case of hypoketotic hypoglycemia. Ammonia was not very high. In hypoglycemia, fat metabolizes and produce ketones, which are used as a source of energy. So absence of ketones is surprising and could be because of underlying Fatty Acid Oxidation Disorder (FAOD). Urea cycle disorders are therefore is out of question. • FAOD are routinely seen locally and could be confirmed by Acyl carnitine profile by Tandem Mass Spectroscopy (TMS). • Here this test suggested Carnitine Palmolyl Transferase 1 (CPT-1) deficiency, which was confirmed by mutation study. Fatty Acid Oxidation Disorders • These are a group of disorders where there is incomplete fat oxidation in mitochondria resulting in liver disorders. • They are autosomal recessive in inheritance. • Right from entry in to cell and then in to mitochondria, there are several steps requiring various enzymes, which ultimately produce complete oxidation of fat and generation of ketones. • Various mutations in genes controlling all these steps/enzymes lead to various disorders that differ slightly from each other but ultimately result in hypo ketotic hypoglycemia. • Patient could be asymptomatic for a few years except for aversion to fatty food, and then they become symptomatic on acquiring trivial infection. Here they deteriorate dramatically. • Few patients present with neonatal hepatitis, which appears to settle down only to strike again on acquiring trivial infection.

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• Hypoketotic hypoglycemia should alert to the possibility of FAOD. • Acyl carnitine profile can lead you to the diagnosis and sometime to the level of enzyme arrested. • Molecular diagnosis is available now to confirm the disorder. • Treatment is to treat every infection vigorously with intravenous dextrose and appropriate antibiotics if necessary. • Patient should avoid fatty diet and needs counseling from a metabolic dietician. • Liver transplant is curative.

Fatty acid Outside cell FAT/CD36 + AMPK PKC PRARy

AMPK

FACS

ACC

MCD Malonyl -CoA

– Acyl carnitine

Fatty acyl CoA

Inside cell

Acetyl-CoA

– Fatty acid

Carnitine

CPT1 CAT CPT2 Fatty acyl CoA

+ β Oxidation

AMPK Acyl carnitine

Carnitine

Mitochondrial genes Fatty acid utilization genes Transcriptional regulation genes

PPARa

PPGC-1a

SIRT1 PGC-1a-Ac

Acetyl CoA Mitochondrial matrix

Nucleus

• Fatty acids enter cell and are converted to Fatty acyl CoA with the help of Fatty acid Acyl Co A synthase (FACS). • With the help of Carnitine Palmotyl Transferase 1 (CPT 1), Fatty acyl Co A is converted in to Acyl carnitine. • All this happens in the cytoplasm. • With the help of Carnitine Acyl Translocase (CAT), Acetyl carnitine is transferred inside mitochondria with carnitine coming from inside mitochondria to cytoplasm. • With the help of CPT 2, Acyl carnitine is again converted in to Fatty Acyl Co A, which then undergoes B oxidation to Acetyl Co A, which enters Krebs’s cycle for energy production. • FAOD prevents formation of Acetyl Co A at various stages, ultimately resulting in failure of fat to participate in Krebs’s cycle.

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50  Case 49: A Neonate with Jaundice and Enlarged Liver

Nuts and bolts of fatty acid metabolism

Formidable looking fatty acid metabolism could be made very simple to understand as follows…..

Fatty acid In cytoplasm Fatty acyl Co-A

Carnitine, CPT 1 and 2 and Carnitine translocase

Fatty acyl Co-A In mitochondria Acetyl CO-A

Investigating a child with neonatal jaundice who is not very sick or does not have decompensation/ liver failure/ metabolic disturbances Stool colour: Creamy or yellow

Galactose 1 transferase TORCH titres

Urine colour: yellow or white

Eye check up for choreoretinitis, Cherry red spot, posterior embryotoxon and Schwalbe’s line

Ultrasonography with special reference to biliary tree and gall bladder

X-ray spine for butterfly vertebrae

Echo cardiography for primary pulmonary hypertension

50  Case 49: A Neonate with Jaundice and Enlarged Liver

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Investigating a sick child with evidence of metabolic disturbances and/ or early decompensation/liver failure Stool colour: Creamy or yellow

Urine reducing substances other than glucose

Urine colour: Yellow or white? Urine ketones Ultrasonography: Special reference to biliary tree Herpes simplex virus antibodies

Arterial blood gases and pH

Urinary succinyl acetone Acyl carnitine profile and Tandem Mass Spectroscopy Lactate levels

Blood sugar and simultane ous urinary ketones Galactose 1 Transferase Some very useful investigations

Neonatal jaundice With sickness and early decompensation and metabolic disturbances

Mitochondrail disorders Galactosemia Tyrosinemia Neonatal hemochromatosis Herpes simplex Zelweger’s syndrome

Without much sickness and no early decompensation nor gross metabolic disturbances Biliary atresia Alagille’s syndrome Idiopathic Neonatal Hepatitis Choledochal cysts Toxoplasma, Cytomegalo and Rubella Parvo virus

Case 50: A Case of Huge Hepatomegaly but No Hypoglycemia

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A 3-year-old girl was referred for liver biopsy with a suspicion of glycogen storage disorder. She was the first child in the family of a non-consanguineous marriage. She was noted to have hepatomegaly when she had seen a local pediatrician for upper respiratory infection. • • • • • • • • • •

CBC: Normal Bilirubin 1.9 mg SGPT: 112 SGOT: 97 Alk. Phos 223 (up to 350) Alb: 3.6 Globulin: 2.1 Creat: 0.8 RBS: 104 mg USG: Huge liver that was brightly refractile suggestive of fatty liver; spleen +, portal and splenic veins were of normal caliber, biliary tree, and gall bladder were normal.

Comments from laboratory: Serum appears whitish and turbid. She was treated with vitamins and some hepatoprotective drugs. She continued to have enlarged liver which increased in size over a year and half for which she had repeated sonographies and LFTs which were essentially similar to above results. Now, the liver was so large she had difficulty in walking and she stopped walking. She was referred to a teaching hospital for further evaluation. History was confirmed. Development and vaccination were adequate. Intellect was normal. CNS did not reveal any localized weakness to account for her inability

© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2021 M. K. Ghoda, Neonatal and Pediatric Liver and Metabolic Diseases, https://doi.org/10.1007/978-981-15-9231-7_51

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to walk, which was thought to be very large liver. Spleen was palpable for 2 cms below costal margin. There were no stigmata of chronic liver disease. No cutaneous xanthomas were detected. LFTs were essentially similar to above results. FBS and PP2BS were respectively 76 and 119 mg%. Uric acid 3.2 mg. Fasting cholesterol 351 mg, Triglycerides 1295 mg, serum reported to be lipemic. • Viral serology for HAV, HEV, HBV, and HCV were all negative. • Ceruloplasmin was within the normal range. • USG confirmed huge liver with bright echo texture, spleen +, PV, and splenic veins were normal. Kidneys were of normal size and echo texture. • • • •

The child was suspected to have glycogen storage disorder in view of huge hepatomegaly and referred for liver biopsy. What Are Your Thoughts in This Case? To us various things looked unlikely. • Firstly, glycogen storage disorder was extremely unlikely for two reasons. First, the child had never had any episode of hypoglycemia and secondly, liver was palpable but soft to firm with gross elevation of triglycerides which suggested fatty infiltration. There was no kidney involvement, no physiognomy suggestive of GSD, no cardiac, and no muscular involvement. • We also want to emphasize that this is not the presentation of any of the known viral etiology, so perhaps virology work-up may not be done in these types of patients. Similarly work-up for autoimmune hepatitis is also not required. • Such huge hepatomegaly usually means infiltrative/storage disorders and recurrent hypoglycemia or kidney, liver, and muscle involvement would suggest GSD. Liver biopsy showed gross macrovesicular steatosis and foam cells and there were no features suggestive of GSD. This did not come as a surprise to us but was very surprising to the referring pediatrician. So, while investigating a case of huge hepatomegaly, episodes of hypoglycemia are very important differentiator and if absent, infiltrative disorders must be considered and investigated accordingly. This level of hypertriglyceridemia could be because of several causes and needs further evaluation. Several rare genetic disorders can be responsible including:

51  Case 50: A Case of Huge Hepatomegaly but No Hypoglycemia

• • • • •

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Familial combined hyperlipidemia and monogenic familial hypertriglyceridemia. Lipoprotein lipase (LPL) deficiency. Familial apolipoprotein C-II deficiency. Familial apo AV deficiency. Familial lipase maturation factor 1 (LMF1) deficiency.

Diagnosis Blood tests measuring lipoprotein lipase activity, Apo C 2 levels, Apo AV levels, and molecular diagnosis are required and patient maybe referred to centers, which specialize in this field. Treatment Dietary restriction and Fibrates and statins may help. An enlarged liver or spleen will usually shrink to normal size within one week of reducing triglyceride levels. Genetic counseling will be of benefit for affected individuals and their families. Glybera is the first approved gene therapy for lipoprotein lipase deficiency.

Case 51: Pregnant Lady with HBsAg Positivity: A Pediatrician’s Perspective

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A 22-year-old woman in the first trimester of pregnancy is found to be positive for hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg). The obstetrician referred her for further management. She was asymptomatic; there was no family history of liver disease. There was no history of blood transfusion or any surgery. Physical examination was normal. • HBV DNA >106 i.u./mL • ALT 22 i.u. Bilirubin 0.8 mg, Albumin 3.8, Globulin 2.0, PT 12/13 sec • USG: No hepatosplenomegaly The patient has questions about how to prevent perinatal transmission of HBV to her infant. Specifically, she requests information about the success of immunoprophylaxis with HBV vaccine and high-titer anti-HBs immunoglobulin (HBIg). She also requests information about the potential use of antiviral therapy. Will this reduce the risk to the infant? What is the effect on her disease? As a pediatrician, what is that you would like an obstetrician to have done before she delivers? Let us try... You want to have a child whose risk is minimized to contract hepatitis B. To reduce the incidence of perinatal transmission of HBV, the American Academy of Pediatrics and the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention recommend that all newborn infants receive HBV vaccine by 24 h of age. Infants born to mothers who are HBsAg positive require prompt administration of vaccine along with HBIg. They also urge post vaccination serologic testing (HBsAg and anti-HBs) of infants at age 9–12 months, born to HBsAg-positive women in order to assess the response of the infant to vaccination. Despite timely post-exposure prophylaxis, perinatal HBV transmission still occurs in 5–15% of infants and HBeAg-positive mothers with high HBV DNA © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2021 M. K. Ghoda, Neonatal and Pediatric Liver and Metabolic Diseases, https://doi.org/10.1007/978-981-15-9231-7_52

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levels are at greatest risk of transmitting HBV to their infants. This lady could transmit HBV infection to her child. What is the incidence of failure? The rate of immunoprophylaxis failure closely correlates with the maternal predelivery HBV DNA level. • • • •

Approximately 3% for levels >106 copies/mL. 7% for levels >107 copies/mL. 8% for levels >108 copies/mL. No perinatal transmission has been reported in infants born to mothers with viral loads 200,000 IU/mL. You expect the obstetrician to treat this lady as she has 3% risk of transmitting HBV to her offspring. When to Start Treatment? Antivirals must be started between 28 and 32 weeks and continued for at least 3 months postpartum. What Antiviral Agents to be Used? Both Tenofovir and Entecavir are found to be effective and safe for use in third trimester. While on any of this treatment HBV DNA levels do not fall, the drugs could be interchanged. At birth HBIg should be given immediately and vaccine within 12 h. Success rate with this regime is very high and nearly 98–99%.