Hepatology , Gastroenterology and Endocrinology

Table of contents :
Cover
Hepatology
Content
o Introduction
o Jaundice
o Ascites
o Liver cell failure (LCF)
o Acute viral hepatitis
o Acute (Fulminant) Hepatic Failure (FHF)
o Fatty liver
o Chronic hepatitis
o Liver cirrhosis
o Manifestations of liver cell failure
o Liver function tests: Investigations of liver cell failure
o Portal Hypertension
o Hepatic Bilharziasis (Hepatic Schistosomiasis)
o Amebic hepatitis & amebic liver abscess
o Hepatocellular carcinoma (HCC) (Hepatoma)
o Hepatic transplantation
o Drugs induced liver injury
o Differential diagnosis of organomegaly
o Gall bladder stones
o Cholecystitis
o Pancreatitis
o Pancreatic carcinoma
Gastoenterology
o Dysphagia
o Dyspepsia (indigestion)
o Vomiting
o Diarrhea
o Constipation
o Acute abdomen
o GIT bleeding
o Intestinal polyposis syndrome & Protein Losing Enteropathy
o Esophageal Achalasia (cardiospasm)
o Gastroesophageal reflux disease (GERD)
o Gastritis
o Peptic ulcer disease (PUD)
o Functional gastrointestinal disorders
o Irritable bowel syndrome (IBS)
o Inflammatory bowel diseases (IBD)
o Malabsorption syndrome
o GIT infections : Intestinal Amoebiasis, Shigellosis, Bilharziasis
o Familial Mediterranean Fever (FMF)
o Intestinal Tuberculosis
o Tuberculous Peritonitis
o Intestinal ischemia
o GIT malignancy : Esophageal carcinoma, Gastric carcinoma, Colorectal polyps & carcinoma
o Carcinoid tumor
Endocrinology
o The pancreas
o Diabetes Mellitus (DM)
o Pancreatic Endocrine Tumors
o The pituitary gland
o Hyperpituitarism
o Gigantism
o Acromegaly
o Hyperprolactinemia
o Syndrome Of Inappropriate ADH Secretion (SIADH)
o Hypopituitarism
o Levi-Lorain, Froelich's & Laurence Moon Biedl Syndrome
o Simmond's disease & Sheehan Syndrome
o Diabetes Insipidus
o The thyroid gland
o Thyrotoxicosis & Myxedema
o The Parathyroid gland
o Hyperparathyroidism
o Hypoparathyroidism, Hypocalcemia, Tetany
o The suprarenal glands (The adrenal glands)
o Hyperaldosteronism
o Gushing syndrome
o Congenital adrenal hyperplasia (adrenogenital syndrome)
o Pheochromocytoma
o Adrenocortical insufficiency (adrenal failure)
o Multiple endocrine neoplasm (MEN)
o Autoimmune polyendocrine (polyglandular) syndromes (APSs)
o Disorders :
o Disorders of growth
o Disorders of puberty
o Disorders of weight: Obesity & metabolic syndrome
o Hirsutism
o Polycystic ovary syndrome (PCOS)
o Gynecomastia

Citation preview

AND

Endocrinology

Mahmoud Sewilan Kasr Al-Ainy School of Medicine Cairo University ‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

‫‪HI‬‬

‫‪'/aTi‬‬

‫‪0‬‬ ‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Hepatology Topic

Page

o Introduction

1

o Jaundice

2

o Ascites

10

o Liver cell failure(LCF)

15

o Acute viral hepatitis

16

o Acute(Fulminant) Hepatic Failure(FHF)

22

o Fatty liver

24

o Chronic hepatitis

26

o Liver cirrhosis

30

o Manifestations of liver cell failure

38

o Liver function tests: Investigations of liver cell failure

47

o Portal Hypertension

50

o Hepatic Bilharziasis(Hepatic Schistosomiasis)

55

o Amebic hepatitis & amebic liver abscess

57

o Hepatocellular carcinoma(HCC)(Hepatoma)

59

o Hepatic transplantation

61

o Drugs induced liver injury

62

o Differential diagnosis of organomegaly

63

o Gall bladder stones

65

o Cholecystitis

67

o Pancreatitis

69

o Pancreatic carcinoma

73

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Introduction

tal lobule

: ?A■^ o

Bile duct

Hepatic lobule . wv'.V

,

Branch of

A

Acinus

>1,0" hepatic artery ; XU^Portal area Krjiicl! of

Central vein

portal vein^

Central vein

Portal triad

& ■POftal

portal venute .bile ductule N.

Kupffer cell

sinusoid ZormX

centra)

stellate cell

space of Disse hepatic arteriole

h epat ocyte

^ end othe iial cell

Most mi^tonts absortXKi by tbe Hepatk ^ery

imsMlfMi pass througb tbe INor. wbloh as s filter that can remove

poientlaMy bamnfut xertobiotlcs

before tbey get into the syaiemkc circulation.

Aorta-

Stomach

Ci^iartaa of Uvar

Small Intestines

Colon

Oigei^ve tract arbHiea

Capiileriee of digeettve tract: atomach. huteatlnea.

pancreaa. arKt spleen

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Symptomatology

Jaundice

Definition:

o

Yellowish discoloration of skin and mucous membrane due to increased total bilirubin.

o Jaundice is clinically evident when the serum bilirubin exceeds 2.5-3 mg/dl. i.e. manifest jaundice o Subclinical jaundice : 1—> 2.5- 3 mg/dl o Normally total bilirubin :0.2 -1 mg/dl ❖ Production & metabolism of bilirubin:

Macrophage RBCi

Giobln

^

I

Iron

Amtno f—

I tdlnibtiv

t atldi Binds to

uaoifcfTin Amino

Untonjugated bitirvibln

acids

Bilirubin + albumin

Indirect Bilirubin = Hemobilirubin = Unconjugated Bilirubin

—>-1

Conjugation (gtucuronyl transferase)

Conjugated I bilirubin

Direct Bilirubin = Cholebilirubin = Excretion

Conjugated Bilirubin

in bile

Enterohepatic

Stercobiiinogen

circulation

Urobiiinogen

Stercobiiin

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

*1* Production & metabolism of bilirubin:

1. Pre-hepatic:

o o o

Bilirubin is derived from catabolism of old RBCs, with separation of the hemoglobin into hem (iron & protoporphyrin)& globin. Protoporphyrin is oxidized into biliverdin Biliverdin via biliverdin reductase give rise to bilirubin. 2. Transport of bilirubin

o In plasma, biiirubin is tightly bound to albumin called indirect bilirubin = hemobilirubin = uiiconjugated bilirubin

o

It forms 60 - 80 % of total normal serum bilirubin.

o

Hemobilirubin has high molecular weight & is water insoluble (not excreted by the kidney) 3. Hepatic metaboiism of biiirubin:

1. Uptake :

o Dissociation of albumin occurs and bilirubin is bound to specific cytoplasmic called ligandins(Y)and Z proteins. 2. Conjugation : o Being water insoluble, unconjugated bilirubin should be changed into water soluble fraction in order to be easily secreted in bile.

o This occurs by glucuronyi transferase enzyme which conjugate bilirubin with glucuronic acid giving rise to direct biiirubin = cholebilirubin = conjugated bilirubin 3. Excretion : occurs by active process (energy dependent) of conjugated bilirubin

❖ N.B.: the last step is the rate limiting step, because it's the most susceptible when liver impairment occurs. 4. Post-hepatic intestinal phase of bilirubin:

o Conjugated bilirubin is transformed into stercobiiinogen by the action of bacteria in terminal part of the small intestine and the colon,

o

It passes in three routes :

a. Major part passes in stool, to be oxidized into stercobiiin (normally: 50-200 mg/day) giving stool its brown color. a. Reabsorbed to liver to be re-excreted with bile again into intestine (entero-hepatic circulation) b. Reabsorbed to kidney to be excreted as urobilinogen (normally: 0.5-2 mg/day, colorless) Classifications: Obstructive Jaundice

❖ Hemolytic Jaundice

Intra

Hepatocellular Jaundice

m

Gall Bladder ; Carcinoma

Ampullary Carcinoma

L

Extra

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Hemolytic Jaundice

o

Obstructive (cholestatic) Jaundice ❖ Etiology • Causes of obstructive jaundice = causes of biliary (cholestatic)

I. Corpuscular causes: All are hereditary except PNH is acquired

cirrhosis :

1. Cell wall defect:

o

o 3.

Hereditary spherocytosis spectrin & ankyrin) Hereditary elliptocytosis (J. spectrin & glycophorin) Hereditary stomatocytosis(| stomatin) PNH: Paroxysmal nocturnal hemoglobinuria Enzymatic defect: Glucose -6- phosphate dehydrogenase deficiency (G6PD). Pyruvate kinase deficiency. Hemoglobin defect:

o

Thalassemia.

o

Sickle cell anemia

o o o 2. o

11. Extra-corpuscular causes: o All are acquired 1) Immunological:

1. A. o

B.

Intrahepatic biliary obstruction: Primary biliary cirrhosis(PEC). Intra & extra hepatic biliary

liver, Causes :

3.

Cholestasis of pregnancy. Cholestatic type of viral hepatitis Chronic hemolytic anemia.

4.

Cancer liver: HCC or secondaries.

1. 2.

5.

Chlorpromazine, Contraceptive pills (CCPs), Chemotherapy, oral hypoglycemic drugs e.g.

Chlorpropamide & anabolic steroids. 6.

Helminthes: Fasciola.

7.

Hereditary disorders (stasis without true obstruction): Dubin Johnson syndrome: Hereditary defect in bile excretion

A. o

B. o

Rotor syndrome: Hereditary defect in bile excretion with normal color of the liver,

A. Prosthetic valves or calcific

ii.

valves

B. March hemoglobinuria: o

Affect marathon mnners or

army recmits after mnning on hard surface for long time, o It's transient process. C. Microangiopathic hemolytic anemia(MAHA): o Due to hemolysis of RBCs

Cause:

■ ■ ■

Malignant hypertension Hemolytic uremic syndrome Thrombotic thrombocytopenic purpura

5) Miscellaneous:

o Hypersplenism, liver disease & renal disease

Same causes of chronic liver failure.

HI.

Extra-hepatic biliary obstruction (surgical):

Familial unconjugated hyperbilirubinemia:

1. Gilbert's syndrome: o It is due to a defect in the uptake (I Z & Y proteins) & conjugation of hilirubin by the liver cells.

2. Crigler - Najjar syndrome: o It is due to a deficiency of the conjugating enzyme (glucuronyl o ■ ■

transferase). Types: Type I: absent enzyme Type II: deficient enzyme

3. Lucey - Driscoll syndrome: 1.

It is due to inhibition of the

conjugating enzyme by a substance in the maternal serum

4. Breast milk jaundice: 2.

It is due to inhibition of the

conjugating enzyme by a substance in the breast milk.

1. In the lumen:

o

Ascaris worms.

o

Gall bladder stones:

■

GB stones impacted in the common hile duct or common hepatic duct —>■

superimposed bacterial infection leading to ascending cholangitis (Charcot's triads right upper quadrant pain, Jaundice & fever with rigors)

o Characteristics: fragmented RBCs(schistocytes) and thromhocytopenia Die & Scleroderma

o

Chronic:

liver. Causes :

exposed to rough vascular

■

II.

❖ Obstruction of bile ducts outside the

intima

o

Same causes of acute (fulminant) liver failure.

with greenish black liver.

clostridium welchii

3) Toxic causes: snake or spider venom & lead poisoning. 4) Mechanical trauma:

o

Acute:

obstmction:

or warm hemolytic anemia. incompatible blood transfusion, RH incompatibility(hemolytic disease of new bom) 2) Infective: sepsis, malaria, p hemolytic streptococci &

1.

Primary :

Primary sclerosing cholangitis Secondary : Intra-hepatic biliary obstruction (medical): Obstruction of biliary radicles in the

A. Autoimmune antibodies: Cold B. Alloimmune antibodies:

Hepatocellular Jaundice

2.

In the wall:

o o

Strictures: e.g. post-operative, Tumors: e.g. cholangiocarcinoma.

3.

Pressure from outside:

o o o

Cancer head of pancreas, Cancer ampulla of Vater. Enlarged LN in porta hepatis.

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Pathogenesis:

1 Hemolytic Jaundice: liiiimr'ii irr ■

ttt Hemobiiirubin

02

t urobilinogen -» f urobilin (Urine is normal in color but darkens on standing)

51 02

C stercobilinogen -> f stercobilin ^ dark stools.

2. Obstructive jaundice:

Dark urine Hemobiiirubin

ttt Cholebilirubm

Frothy urine

Istercobilmogen —> pale stools & steatorrhoea

ttt Bile salts

3. Hepatoceilular jaundice:

t Cholebilirubin: Dark urine

t Hemobiiirubin

t Cholebilirubm

t urobilinogen

t urobilin

Istercobilinogen —>■ slightly pale stools

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Pathogenesis Increased hemolysis of RBCs —>

Biliary obstruction will prevent

increased hemobilirubin.

cholebilirubin to reach the intestine,

The liver cannot uptake all the

therefore:

increased hemobilirubin

Chloebilirubin regurgitates into the blood —> increased serum bilirubin —> jaundice.

completely, therefore: Part of hemobilirubin is retained in the blood ^ increased serum bilirubin —> Jaundice. Excessive hemobilirubin will be

2.

converted to cholebilirubin &

—> dark urine.

excreted by the liver to the

Bile salts: regurgitate into: Blood ^ Pruritus, Bradycardia Urine —>■ J, surface tension of urine frothy urine There is decreased stercobilinogen, decreased urobilinogen —> no urobilinogen in urine.

intestine —»increased 3.

from intestine —> increased

urobilinogen, therefore: urine is normal in color but darkens on

Liver cells are not able to uptake,

2.

conjugate & excrete all the bile pigments. A part of hemobilirubin is retained in

the blood & a part of cholebilirubin regurgitates into the blood ^

Bile does not reach the intestines ^

pale stools (clay-colored, bulky, offensive, and greasy). Excessive cholebilirubin appears in urine

stercobilinogen —> dark stools. Increased stercobilinogen absorbed

1.

increased serum bilirubin ^

jaundice. 3. Stercobilinogen is decreased —> slightly pale stools. 4. Cholebilirubin appears in urine —» dark urine.

5.

Increased urobilinogen occurs because the diseased liver cannot

fully re-excrete the absorbed stercobilinogen.

standing as urobilinogen will be converted to urobilin .

Bilirubin is not present in urine:

Acholuric jaundice Clinical picture

Jaundice: is usually mild (lemon yellow).

1. 2.

Stools: dark. Urine: normal in color but darkens

5.

on standing. Features of hemolytic anemia e.g. HSM, gall stones, leg ulcers, hemolytic crises. Features of the cause e.g.

3. 4. o o

Jaundice: is usually deep (olive green). Stools: pale & feature of steatorrhea (clay-colored, bulky, offensive, greasy) Urine: dark (frothy). Features of obstructive jaundice: Pruritus, Bradycardia, Bleeding tendency (J,Vit K), Bone affection (J,Vit D)

1. 2.

Jaundice: is usually moderate (orange yellow). Stools: pale.

3.

Urine: dark.

4.

Features of liver cell failure.

5.

Features of the cause e.g. Familial hyperbilirubinemia (asymptomatic or mild intermittent jaundice)

t Cholesterol: atherosclerosis & xanthelasma

5.

Thalassemia

Features of the cause e.g. gallstones

Hcnioh tic .laundice

Hcpatocell 111 ill- .laundice

Obstructive .liuindicc

❖ Investigations:liver function tests

1 AST & ALT

Normal

Normal, t later T

Total bilirubin

T

Direct bilirubin

Normal

T

Indirect bilimbin

t

Normal

I TTT T T T T 30 K.A.U.

GOT

Normal

5 - nucleotidase

Normal

TTT TTT

Albumin

Normal

Normal

o

Normal in acute liver disease

Globulin

Normal

Normal

o o

J. In chronic liver disease In acute & chronic liver disease : t

Normal

Normal

o

Normal in acute liver disease.

Albumin/ Globulin ratio

T T

o

J. or even reversed In chronic liver disease

Stercobilinogen in stool Urobilinogen in urine

T

Bilirubin in urine

absent

i i

i T

Present

Present

T

❖ Blood:

1 Blood pieture :

o

Of hemolytic

1

o

Macrocytie normoblastic anemia

o

Anemia of LCF(see later)

Coagulation profile

o

Prolonged PT time & decreased PC concentration that is corrected by

o

Prolonged PT time & decreased PC concentration that is not corrected by parenteral vitamin K.

Lipid profile

o

Increased cholesterol with normal

anemia.

parenteral vitamin K o

esterification.

Normal cholesterol with decreased esterification.

❖ Investigation of the cause :

1 Serology:

o

Coomb's test for autoimmune

0

hemolytic anemia Hb electrophoresis for thalassemia

A. Anti-mitochondrial antibodies for PBC

I o o

Hepatitis markers for viral hepatitis Antibodies for autoimmune hepatitis

B. Imaging: ultrasonography & CT: o Extra-hepatic obstruction: dilated Intrahepatic biliary radicles o Intra-hepatic obstruction: no dilatation of intrahepatic biliary radicles

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Clinical approach to jaundiced patient Hepatocellular Jaundice

Hemolytic Jaundice

Calcular

|

Malignant

Personal history

1. Age

o

Children

0

Adults

o

Old age

2.

o

Any sex

o

Females

o

Males

Sex

3. Special habits

o o

Any age Any sex

o

Alcoholic

o

Middle age

o

Any sex

Present history 1.

o

Onset

Gradual with acute

o

Acute

o

Gradual

0

Acute

o

Gradual

o

Intermittent

o

Intermittent or

0 Regressive

o

Progressive

o

o

Long

episodes of hemolytic crisis 2.

o

Course

Intermittent

progressive o

Long

3.

Duration

o

Variable

o

Variable

4.

Stool

o

Dark

o

Pale & feature of steatorrhea

5.

Urine

0

Normal but darkens

o

Dark

6.

Fever

o

Shot

o Pale

1

on standing

During hemolytic

o

Charcot's

o

Low grade fever

fever

crisis

0 High fever at the pre-

o

Low grade fever

-ve

o

-ve

Dull

o

-ve

icteric

stage 7.

Marked loss of

o

-ve

o

-ve

o

-i-ve

o

o

Abdominal, back &

o

Biliary colic

o

Epigastric pain radiating to

o

weight 8. Pain

bony pains

aching pain in the right hypochond

back

rium &

epigastriu m

9.

Pruritus

o

o

-ve

o May be present

+ve

1

| I

Past history o

Drug intake

o

Biliary colic

o

Alcohol

o

Blood

o

Viral hepatitis

transfusion

& repeated injection

1

Family history o

+ve

0

-ve

o

Manifestations of

0

Scratch marks, Xanthomata, bradycardia

0

-ve

0

-ve

I 1 I

o -ve

General examination hemolytic anemia e.g. leg ulcers & skin pigmentation.

0 0

o

Manifestations of

Cachexia

liver cell failure:

Edema of

e.g. palmar erythema & spider naevi.

lower limbs due to IVC o

obstruction

Skin

pigmentation & clubbing in primary biliary cirrhosis

1

Abdominal examination 1.

May be enlarged

Liver

2. Splenomegaly 3.

4.

5.

Ascites

Gall bladder

Others

+ve

-ve

Pigment stones

|

enlargement

Enlarged, tender, hard & irregular

tender & soft

Shrunken & sharp edge

-ve

-ve unless there is

+ve in 20% of

+ve

lymphoma

cases

+ve due to

-ve

-i-ve

malignant deposits in the peritoneum Enlarged &

-ve

-ve

Marked

-ve

Small, tender, not palpable

Enlarged,

palpable Abdominal masses

Portal hypertension e.g. dilated abdominal wall veins

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Investigation for jaundice 1. Laboratory investigations :

Hemolytic Jaundice Obstructive (cholestatic) Jaundice Hepatoceliular Jaundice Investigations: see before.

2. Imaging: 1. Abdominal ultrasonography & CT: o

Ascites

o Liver: cirrhosis, tumors, portal vain dilatation

o Biliary system: dilated intrahepatic biliary radicles in extra-hepatic obstruction, o

Gall bladder: stones,

o Spleen: splenomegaly, o Pancreas: cancer head of pancreas.

2. FIbroscan: elastography that maps the elastic properties and stiffness of soft tissue for staging hepatic fibrosis. 3. Visualization of the biliary system: This is done mainly in extrahepatic obstruction A. Magnetic Resonance Cholangiopancreatography(MRCP): o Accurate visualization of the biliary & pancreatic systems B. Endoscopic retrograde cholangiopancreatography(ERCP)

C. Percutaneous Transhepatic Cholangiography(PTC)

IP a. Method

o Injection ofthe radio-opaque substance in the biliary tract by a side view

b. Value

o Visualization of the biliary system &

o Percutaneous injection of radio-opaque substance into the intra-hepatic bile ducts

duodenoscope

o Visualization of the intrahepatic bile ducts.

pancreatic system

0 Obstructive jaundice e.g. biliary stones or

c. Indication

d. Therapeutic use e. Complications

cancer head of pancreas. 0 Stone removal by sphincterotomy

0 Cholangitis & pancreatitis

o Obstructive jaundice to differentiate intrafrom extra- hepatic obstruction o Biliary drainage by a stent o Infection & hemorrhage.

3. Liver biopsy: Performed percutaneously under ultrasound or CT guided ❖ Contraindication

Indication

1. 2. 3. 4. 5.

Some cases ofjaundice Chronic hepatitis Unexplained hepatomegaly Diagnosis of storage diseases Diagnosis of infiltrative diseases

o

Ascites

o Bleeding tendency o Platelets < 80,000 /mm^ o

PC 1 type ofjaundice): 1. Long standing hemolytic jaundice : o End in obstructive jaundice due to formation of pigment stone or thrombi (inspissated bile syndrome) 2. Long standing obstructive jaundice:end in hepatocelluiar jaundice 3. Viral hepatitis : o hepatocelluiar and obstructive jaundiee

j B. Causes of postoperative jaundice : Hemolytic Jaundice

A. B. C. o 0

Hepatocelluiar Jaundice Infection : sepsis Ischemic or hypoxic injury latrogenic: Halothane hepatitis Drug induced

0

Post blood transfusion

Obstructive Jaundice

o Incompatible blood transfusion (acute & delayed hemolytic reaction)

A. Postoperative pancreatitis B. Postoperative cholecystitis

o

C. Retained CBD stone

A. Large hematoma (the commonest cause) B. Hemolysis :

Crisis: sickle cell crisis

C. Medical Causes of itching (pruritus):

1. 2.

Obstructive jaundice Primary biliary cirrhosis

3. Bilharziasis

4.

Drug hypersensitivity

7.

5.

Diabetes mellitus

8.

6. Chronic renal failure

Hemolytic anemia Polycythemia

9. Leukemia & Lymphoma

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Ascites

❖ Definition:

Accumulation offree fluid in the peritoneal cavity ❖ Etiology : 1. Hemorrhagic ascites: A. Acute pancreatitis

B. Malignant ascites : primary : peritoneal mesothelioma, secondary : in GIT, pancreatic or ovarian tumors C. Hemorrhagic blood diseases e.g. Hemophilia. D. Rupture spleen as in trauma E. Rupture ectopic pregnancy 2. Transudative ascites:

o All causes of generalized edema (cardiac, hepatic, renal, nutritional, allergic) o Myxedema

o Meigs' syndrome: ovarian fibroma, ascites & right sided hydrothorax o All causes of portal hypertension (mention them) especially liver cirrhosis & hilharzial fibrosis 3. Exudative ascites:

o Peritoneal causes: TB , spontaneous bacterial peritonitis (SBP).

o Pseudomyxoma peritonei: ruptured mucocele of appendix or GB or pseudomucinous cystadenoma of ovary 4. Chylous ascites : o Rupture or obstruction of thoracic duct by, trauma, tumor & filariasis. Grades of ascites:

A. Mild

C. Severe (tense)

B. Moderate

0 Detected only by ultrasound o Clinically: Puddle sign

o Moderate symmetrical abdominal distension

o Clinically: shifting dullness

o Marked symmetrical abdominal distension with respiratory distress o Clinically: fluid thrill

Clinical picture:

1. Symptoms:

1. Abdominal distension & discomfort

2. Dyspepsia & dyspnea 3. Hernia

4. Symptoms of the cause e.g. liver cell failure. 2. Signs:

Tympany Tympany

D

A. Primary signs of ascites

Transnion point

fiansifton

.:->w

J

Dulhiess

Dullness

1. Inspection : o

Generalized abdominal distention with fullness in flanks, umbilicus is shifted downwards, everted ± umbilical hernia

o Wide subcostal angle o o

Divarication of recti Dilated veins on abdominal wall

2. Palpation: o

Transmitted fluid thrill in tense ascites

o Liver & spleen: felt by dipping method in tense ascites o Abdominal masses: may be felt in TB or malignancy 3. Percussion :

o Shifting dullness in moderate amount of ascites o Dullness around umbilicus in knee-elbow position in mild amount of ascites

10

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

4. Auscultation :

A. 1. 2. 3. 4. 5. 6.

Puddle sign: for detection of mild ascites(120ml): Patient lies prone for 5 minutes Patient then rises into knee-elbow position Apply stethoscope to most dependent part of the abdomen One flank is percussed by repeated light flicking of constant intensity The stethoscope is gradually moved toward the flank opposite the percussion Sharp increase in the intensity of the sound picked up by the stethoscope indicates fluid level.

B. Venous hum in portal hypertension

B. Secondary signs of ascites :

1. Pleural effusion:

o o 2. o o o

Usually in right side Due to leak of ascitie fluid through diaphragm Signs of elevated diaphragm by ascites: Congested neck veins Dullness at base of lung Displaced apex of heart up & out

3. Lower limb edema:

o LL edema occurs before ascites except in ascites precox (ascites before lower limb edema)e.g. pericardial effusion, constrictive pericarditis, tricuspid incompetence & tricuspid stenosis C. Signs of the cause: 1.

2. a.

b. o

Signs of liver cell failure. Sign of malignancy: Malignant ascites is massive, hemorrhagic, rapidly accumulating after tapping Sister Mary Joseph Nodule: Bulging nodule in the umbilicus due to metastasis of a malignant cancer in the pelvis or abdomen. Differential diagnosis :

A. Differential diagnosis of cause of ascites: depends on examination, tapping, & US & laparoscopy. B. Differential diagnosis from other causes of apparent veins on abdominal wall: 1. Just visible veins

2. a) b) C. 1.

Abnormally dilated veins: Portal veins obstruction: portal hypertension (caput medusa) Systemic veins obstruction(SVC or IVC obstruction) Differential diagnosis from other causes of abdominal distension: Fluid : ascites , ovarian cyst B. Ovarian cyst

A. Ascites

2. 3.

a. Distention

o

Diffuse Shifted downward

o Mainly central o Shifted upward

b. Umbilicus

o

c. Percussion

o

Central resonance & dull flanks

o

d. Shifting dullness e. By US

o

Bilateral

o

Free fluid

o May be unilateral (fluid in cyst) o Encysted fluid

Central dullness & resonance flanks

Full urinary bladder : put a catheter Flatus: hyper-resonance all over the abdomen.

4.

Feces (intestinal obstruction): hyper-resonance all over the abdomen. X-ray show fluid levels

5.

Fat(obesity): Umbilicus is tucked in & no shifting dullness

6.

Fetus: signs of pregnancy

7.

Fibroid or other tumor e.g. liver, spleen & kidney.

11

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Investigations: Rough liver margin

1. For the cause:

o

For liver cirrhosis : liver function test

o For heart failure : eehocardiography o For TB & Malignancy : biopsy 2. Ultrasonography: o

Detect minimal ascites

o

Detect cause

Cirrhotic

liver tissue

o Differentiate free from encysted ascites 3. Tapping : diagnostic abdominal paracentesis: analysis of fluid for : A. Hemorrhagic ascites blood stained with many RBCs B & C : Transudate & exudate:

o Aspect:

B. Transudative ascites:

C. Exudative ascites: o

o

Proteins

o Colorless, clear o 0.6

Yellowish turbid

o >3 gm/dl

proteins / Serum Proteins

o

Peritoneal Fluid LDH/ Serum LDH

o

WBCs

o Specific gravity

o < 1000 / mm^

o > 1000/mm'

o

o

1016

o 45 mg/dl o Glucose o >60 mg/dl o 1.1 g/dl : due to portal hypertension regardless 0 250 cells/mm^ o TB bacilli detected by ZN satin, o culture is positive for organism Lowenstein-Jensen medium, guinea usually gram negative organism pig inoculation

❖ Treatment:

ALDACrONP 100m

A. Treatment of the cause

Sf=fK>NOUlCTa^ ^—

B. Treatment of ascites in liver cirrhosis:

1. Bed rest: f renal perfusion —>■ diuresis. 2.

Diet:

a. Salt restriction < 2gm / day b.

Fluid restriction in tense ascites: 1/2 L 4

volume of urine / day + 1/2 L /1°C rise of temp.

c.

Protein :

o o d. 3. A. o

High protein diet to correct hypoalbuminemia Restricted in hepatic encephalopathy Follow up : daily estimation of urine output & body weight Drugs: Diuretics: Keep patient Wet & Wise rather than Dry & Drowsy Indication : given only if weight loss < 1 kg after 4 days on diet regimen

20 mg (lOmg/ft R only

leoofsus*

o At first spironolactone 100 mg/day: being mild & K"^ sparing o If no improvement: add furosemide 40 mg/day + KCL supplement o In resistant case : IV Mannitol & IV Dopamine B. IV albumin to increased plasma oncotic pressure & to correct hypoalbuminemia

12

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

wnl/20%

4. Tapping: therapeutic abdominal paracentesis:

o Indication :tense ascites i.e. marked abdominal distension with respiratory distress o

Contraindication:

a. b. e. d. o

CNS: encephalopathy CVS: hypotension Liver; liver cell failure (asterixis) Renal: hypokalemia & renal failure. Precaution : > 5 liter per session combined with IV albumin 6-8 gm/L removed

C. Treatment of refractory (resistant) ascites : I

Diuretic resistant ascites: Definition :

Ascites not responding diet management & intensive medical treatment with 400 mg spironolactone PLUS 120 mg ❖ Causes:

❖ Treatment:

o

o

Salt restriction

o

IV Albumin

Lack of salt restriction

o Hypoalbuminemia o Dilutional hyponatremia o Presence of underlying cause : malignant ascites, TB peritonitis & SBP

o

Fluid restriction & IV Mannitol

o

Treatment of Cause

Diuretic intractable ascites: Definition:

Ascites can't be treated by diuretics due to development of diuretic induced complications e.g. encephalopathy, that preclude the use of an effective diuretic dosage. Stop the drug & mange the complications D. Severe terminal cases is treated by: Hepatic vein

Stent

Portal vein

1. Lee veen shunt: o o

Peritoneo-venous shunt: one way valve between peritoneum & SVC Complication : hypervolemia, pulmonary edema & infection.

2. Ascites ultrafiltration & reinfusion: o

Ultrafiltration apparatus remove ascitic fluid, concentrates it & reinject it back to patient

3.

Transjugular intrahepatic portosystemic shunt(TIPS):

o

o o

4.

A special device is introduced through the jugular vein to the liver to put a stent communicating between the inflow portal vein and the outflow hepatic vein. It is used to lower portal pressure in portal hypertension Complications: infection, hepatic encephalopathy & TIPS stenosis Hepatic transplantation

13

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Spontaneous bacterial peritonitis(SBP) Definition :

Spontaneous inflammation of ascitic fluid in absence of secondary cause of peritonitis Etiology: o o

Diminished antibacterial activity of the ascitic fluid leading to bacterial translocation of gut flora to peritoneum. Enteric organisms especially gram -ve bacteria e.g. Bscherichia coli, Klebsiella & enterococcal species. Clinical picture:

1.

Clinical deterioration of general condition

2. Fever 3.

Abdominal pain and tenderness

4. Ascites 5.

❖

Hepatic encephalopathy & other features of liver cell failure Investigations:

1.

Diagnostic paracentesis for ascitic fluid analysis:

o

Turbid

o

Total leucocyte count > 500/mm^ or polymorphonuclear leukocytes > 250/mm^

2. Ascitic fluid culture ❖ Treatment: 1. Antibiotics: o

3"''' generation eephalosporin e.g. Cefotaxime : 2gm/8hour IV

2.

Ciprofloxacin : 200 mg/8hour IV Albumin infusion : improve survival & kidney function

o

E' day within 5 hours of detection : 1.5 gm/kg

o

3"* day: 1 gm/kg

o

WHM Wml/20%

Prophylaxis with norfloxacin (400 mg daily) or ciprofloxacin (250mg daily)

14

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Liver cell failure(LCF)= Hepatocellular failure(HCF)

Classifications & Etiology of Liver cell failure(LCF) 1.

11.

Acute liver cell failure

Chronic liver cell failure

A. Chronic hepatitis ❖ Etiology:

o Hepatitis A, B, C,D and E viruses o CMV,EBV,HSV, yellow fever

B. Liver cirrhosis

I

❖ Idiopathic(Cryptogenic) of unknown cause | ❖ Infection: I o HBV,HCV & HDV infection. o Post viral hepatitis cirrhosis(B, C, D) | ❖ Inflammatory: Nonalcoholic steatohepatitis(NASH) 1

viruses

❖

latrogenic : drug induced liver injury :

A. Alcohol &INH

B. Acetaminophen (Paracetamol): >10 gm i.e. >20 tab

B. Alpha-methyl dopa C. Nitrofurantoin

C. Amiodarone & methotrexate

C. Anesthetic : Halothane

D. Phosphorus, Carbon tetrachloride, DDT (Dichloro-diphenyltrichloroethane) ❖ Ischemic:

0 Acute Budd-chiari syndrome

0 Budd-chiari syndrome

❖ Immunological: A. Autoimmune hepatitis: lupoid hepatitis

B. Biliary (Cholestatic) cirrhosis: primary biliary cirrhosis & primary sclerosing cholangitis ❖ Cardiac cirrhosis *1* Metabolic & miscellaneous: A. Wilson disease

1

B. Acute fatty liver of pregnancy

B. Hemochromatosis

C. Reye's syndrome

C. Alpha one antitrypsin deficiency

❖ Malignancy : primary or secondaries(iymphomas - leukemia - metastatic tumors)

15

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

|

Acute viral hepatitis

❖ Definition: Diffuse liver inflammation lasting < 6 months. Etiology:

o Hepatotropic viruses; mainly hepatitis A, B, C,D,E viruses o Non hepatotropic viruses: less commonly: CMV,EBV,HSV, yellow fever viruses. ❖ Synonyms

A. Hepatitis A

B. Hepatitis B

C. Hepatitis C

D. Hepatitis D

o

o

o

o

Infective

hepatitis

Serum

hepatitis

Post

E. Hepatitis E o Epidemic/

Delta

hepatitis

transfusion

Enteral

hepatitis 1. Nature

Enterovirus

o

0

RNA

0

27 nm

o

Feco-oral

o Parenteral (blood, needles)

o

2. Mode of transmission

Hepadna

o

o

DNA

o

RNA

o

42 nm

o

30-60 nm

o

Elavivirus

hepatitis

0 Incomplete

o

Calicivirus

virus

o

RNA

o

RNA

o

27 nm

o

35 nm o

Feco-oral

o

2-6 weeks

Sexual

o Vertical (intrauterine) 3. Incubation

o

2-6 weeks

o

2-6 month

period

4. Epidemiology

0 Sporadic or epidemic

o Sporadic

o Epidemic

5. Age

o

o Any age

o

Children or

young adults 6. Acute

Children or

young adults

o

Mild

o

Severe

o

No

o

Yes

o

Mild

o

o Mild except

Severe

in pregnancy

infection

7. Chronicity &

o

No

liver cancer 8. Passive immunization

9. Active

o Non specific immunoglobulin (Ig)

o Specific Ig

o

o

HAV vaccine

immunization

o Non specific Ig

HBV

o

HBV vaccine

vaccine ^■ntlpa t

yHMAg

❖ N.B.:

1. Hepatitis D:

/

o o

It is incomplete virus that requires HBsAg surface coat for its infection (hybrid particle) ' Accordingly, infection with HDV requires the previous exposure to HBV infection

o

The infection mav take two forms:

A. Super infection: this represents super added infection of HDV in a chronic HBV carrier. B. Co- infection: this represent simultaneous infection by HDV and HBV which results in severe acute infection 2. Hepatitis G:

o

It is an RNA virus similar to HCV that is frequently detected in patients with chronic liver disease, but without significant liver disease 3. Hepatitis T: the most recent identified carcino-virus, it's role in liver disease not yet established. o*

❖ Pathology:

I—

A. Initial viremia with inflammation of GIT mucosa

B. o o ■

Intrahepatic localization leads to : Diffuse centrilobular necrosis, with cellular infiltration around portal tracts Swelling of hepatocytes due to inflammatory edema leads to: Obstruction of intrahepatic biliary canaliculi —> obstructive (cholestatic)jaundice


■ necrosis. ■** Clinical picture:

1. Hepatic encephalopathy with cerebral edema: o It is the first sign without other features of liver involvement o In early stage, the patient presents with personality changes & restlessness —>■ the condition may be misdiagnosed as neurological or psychiatric disorder, o In late stage : drowsiness & hepatic coma 2.

Jaundice:

o Mild in early stage and then become deep in late stages, o 3. 4. o o

Death may occur before jaundice develops Fetor hepaticus & asterixis Multi-organ failure: Acute Respiratory Distress Syndrome (ARDs), Acute renal failure Bleeding tendency: coagulopathy

o

Die

o o o

Electrolytes: hypokalemia, hypocalcemia, hypomagnesemia Endocrine: hypoglycemia Septicemia

o

Shock

5. Features of the underlying cause may be present.

22

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Investigations : 1. Liver function tests: o

AST & ALT

o

Bilirubin

o

Albumin

o o o o

In early stages: t|t In late stages : due to massive necrosis of hepatic cells t both direct & indirect and used as a prognostic marker Normal(Long life span)

o

Globulin

o

Increased

o

Albumin/ Globulin ratio

o

Normal

o Coagulation profile : Prothrombin time: o Prolonged used as a prognostic marker 2. For organ involvement: A. Laboratory: o Blood glucose level o

Serum urea and creatinine

B. Imaging: o Chest X-ray and ABG

o CT & MRI brain: may show cerebral edema, and excludes other neurological causes for coma PARACETAMOL

3. For the cause e.g. hepatitis markers

TABLETS BP SOO mg Effi'c.tive Pain

Treatment

1. 2. 3. A. B. 4. 5. o o

tit

Hospitalization in ICU & care for the comatose Treatment of the cause e.g. N-acetylcysteine for paracetamol toxicity. Symptomatic treatment for: Hepatic encephalopathy (see later) Multi-organ failure e.g. mechanical ventilation, hemodialysis & glucose infusion Liver support using artificial biological liver. Liver transplantation: The one year survival rate after transplantation is 60%. Survival without transplantation is 10%.

^cetylcystein® Injection

❖ Prognostic markers: King's college criteria for poor prognosis in ALP (predicts > 90% mortality rate): A. Paracetamol over-dose:

B. Non paracetamol over-dose:

1. pH 100 seconds

2. or all of three of the followina:

2. Or Anv three of the followins:

o Encephalopathy (grade 3 or 4) o PT > 100 second(INR > 6.5) o Serum creatinine > 3.4mg/dl.

o o o o o

Etiology non A,non B hepatitis, halothane, drug reaction or Wilson disease Jaundice to encephalopathy time > 7 days Age 40 years Bilirubin > 17.5mg/dl PT > 50 second(INR > 3.5)

23

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Fatty liver Definition

Healthy liver

Steatosis

Steatohepatitis

Fibrosis/cirrhosis

o Excessive deposition offat in the liver > 5 % of liver weight o

Spectrum :

A. Hepatic steatosis; fatty infiltration without inflammation i.e. simple fatty liver B. Steatohepatitis : fatty infiltration with inflammation that may lead to progressive fibrosis and eventually cirrhosis

Pathology :

o Characterized by presence of large vesicles containing triglycerides occupying most of hepatocytes and displacing nucleus, o In long-standing cases, accumulating fat induces an oxidant stress leading to necrosis of fat-laden hepatocytes and hepatic inflammation (non-alcoholic steatohepatitis), fibrosis and eventually cirrhosis Etiology 1.

Macrovcsicular Steatosis:

A. Alcoholic fatty liver disease : Alcoholic steatosis & alcoholic steatohepatitis B. Non-alcoholic fatty liver disease(NAFLD): non-alcoholic steatosis & non-alcoholie steatohepatitis(NASH)

ii i. Primary : idiopathie cause ii. Secondary: 1. Type II DM 2. Obesity(60-90% of cases)& Hypertriglyceridemia 3. Rapid weight loss

4. Malabsorption, gastric & jejunoileal bypass 5. Parental nutrition

6. Drugs e.g. amiodarone, eortieosteroids, contraceptive pills, Valproic acid & Tetracycline II.

Microvesicular Steatosis:

1. Acute fatty liver of pregnancy :

o Abnormal fatty acid metabolites produced by homozygous fetus enter cireulation and overcome maternal hepatic mitochondrial oxidation system o Presents in the last trimester with fulminant hepatic failure o Immediate delivery may save both baby and mother 2. Reye's syndrome:

o Seen in children secondary to viral infection & toxic agents especially aspirin o Inhibition of p oxidation & uncoupling of oxidative phosphorylation in hepatic mitochondria leads to diffuse microvesicular fatty infiltration, o Presents with fulminant hepatic failure.

24

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Clinical picture: 1. Asymptomatic in the majority of cases. 2. Pain in the right hypochondrium in the minority of cases 3. Presentation:

A. Acute liver cell failure (fulminant hepatic failure) in acute fatty liver of pregnancy & Reye's syndrome B. Chronic hepatitis & cirrhosis in alcoholic & non-alcoholic steatohepatitis(NASH). 4. Abdominal examination :

o Liver: enlarged, soft with smooth surface & may be tender. 5. Clinical features of the cause.

Investigations: 1. Laboratory : A. Liver function test:

o

t AST, ALT & GOT

o

Serum bilirubin & albumin: Normal

B. o 2. o o 3. o

Lipid profile: t Cholesterol & triglycerides Imaging : Abdominal ultrasound shows enlarged bright homogenous liver MRI is the most sensitive noninvasive method to detect fatty infiltration. Instrumental: Liver biopsy It detects the presence of inflammation, necrosis and cirrhosis.

Treatment:

2.

Treatment of the cause e.g. DM and hyperlipidemia Gradual reduction of body weight & low fat diet(rapid reduction may cause liver damage)

3.

Antioxidants as vitamin E to reduce the oxidant stress imposed by accumulating lipids.

1.

25

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Chronic hepatitis ❖ Definition:

o Diffuse liver inflammation without improvement lasting > 6 months. ❖ Etiology :see before: page 15. ❖ Classifications : according to histopathology:

m

Portal infiltration

Piecemeal necrosis

Fibrous septa:

Bridging necrosis

Cirrhosis

rosettes

1. o o o

Chronic persistent hepatitis: Chronic inflammatory infiltrate confined to portal tract, Slight-to-absent hepatic fibrosis Preserved lobular architecture (no cirrhosis)

2. Chronic lobular hepatitis: scattered necrosis throughout the hepatic lobule 3. Chronic active hepatitis: A. Mild form :

B. Severe Form : Features described in the mild form plus:

0 There is cellular infiltration ofthe portal

0 Fibrous septa extending into the liver cell columns with isolation of groups of liver cells in the form of rosettes. 0 Intrahepatic fibrous bridging (bridging necrosis) either portaleentral, central-central or portal-portal is seen. 0 Progress to liver CIRRHOSIS is common

tracts.

0 The infiltrate extends into the periphery of the liver lobules.

0 Piecemeal necrosis of the periphery of the lobules.

❖ Clinical picture of the cause e.g.:

Chronic

Uver

Hepatitis

Orrhoslj

liver Cancer

I"'*

I V iZ

A. Of autoimmune hepatitis: see later. B. Of chronic viral hepatitis: 1. Asymptomatic : Accidental discovered

2. Constitutional symptoms : low grade fever, fatigue, headache, anorexia & malaise 3. Manifestation of:

a. Chronic infection can lead to liver CIRRHOSIS with liver cell failure & portal hypertension ^ hepatoeellular carcinoma in late cases b. Abdominal examination :

o In early cases there are hepatosplenomegaly o In late cases there are shrunken liver & splenomegaly

4. EXTRA-HEPATIC COMPLICATIONS are present in small number of cases(MENTION THEM)

26

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Investigations: A.

B.

Of autoimmune hepatitis: see later. Of chronic viral hepatitis :

1. Liver function tests: chronic liver cell failure:

o

AST & ALT

o

ttt

o

Bilirubin

o

t total, both direct & indirect

o

Albumin

o globulin

o

Decreased

o

Increased

Albumin/ Globulin ratio o 1 or even reversed o Coagulation profile : Prothrombin time: o Prolonged o

2. Detection of viral marker: o

3.

HCV antibodies & HCV RNA.

o HBsAg, HBeAg & HBV DNA. Abdominal ultrasonography:

o

In early eases there are bright hepatomegaly & may be splenomegaly. In late cases there are shrunken liver (cirrhosis) & splenomegaly

4.

Assessment of degree of fibrosis :

o

A. Non invasive : detect degree of fibrosis onlv o

Fibrosis markers e.g. APRI: AST-to-platelet ratio index

o

Fibroscan: elastography that maps the elastic properties and stiffness of soft tissue for staging hepatic fibrosis.

B. Invasive : Liver biopsv: detect both inflammation & fibrosis : o

According to histopathology: 3 types (mention them) The Metavir scoring system for hepatitis C: Staging according to Metavir Score

Portal tract fibrosis Portal fibrosis

Portal nbrosis

with few septa

Septa! fibrosis

Cirrhosis

a) Activity grade: indicates the degree of inflammation o AO: no activity o A1: mild activity o A2: moderate activity o A3: severe activity

b) Fibrosis stage: indicates the severity of fibrosis or scarring. o

FO: no fibrosis

o Fl: portal fibrosis without septa o F2: portal fibrosis with few septa o F3: numerous septa without cirrhosis. o

F4: cirrhosis

❖ Treatment:

A. Of autoimmune hepatitis; see later. B. Ofchronic viral hepatitis: HBV & HCV

27

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

1. Treatment of HBV :

HBeAg

❖ Indications to treat:

Negative

Positive

HBV DNA

Ik.

3E

>2000

< 20,000

> 20,000

3r

IT

31

Ik.

ALT: upper limit normal(ULN):35 U/L for cj, 25 U/L for $

IT

o

Normal:

l-2xULN: Biopsy &

3r

o > 2 ULN: TTT

Monitor TTT if>A2 or>F2

❖

Normal:

l-2xULN: Biopsy &

Monitor

TTT if>A2 or>F2

ly > 2 ULN:

N.B.: Patients with HBV cirrhosis need treatment, with any detectable HBV DNA level and regardless of ALT levels.

1. HBeAg

2. ALT level:

A. Negative

3. Decision

upper limit normal (ULN):35 U/L for (?,25 U/L for 2

B. Positive

HBV DNA lU/ml a. < 2000

a) 20,000

O

1-2 ULN

o o ❖ o

Monitor ALT & HBV DNA level every 3 -6 months Monitor HBeAg every 6-12 months Consider liver biopsy: Age > 40 years

o Family history of HOC o Extra-hepatic complications ❖ Treatment if moderate to severe inflammation & fibrosis

o

❖ Treatment

>2ULN

❖ Drugs used for treatment of HBV infection : I.

SC Interferon :

II.

Oral antiviral treatment:

❖ Advantages 1. Limited duration of therapy (48 1. More HBV DNA suppression 2. More normalization of ALT weeks) 3. Maintained on treatment of viroiogical response 2. More chance for HBsAg loss 3. More chance for sustained

HBsAg seroconversion 4. Sustained off treatment

viroiogical response ❖ Drugs:

2. Pegylated

1. Alpha Interferon

1. Tenofovir

2. Entecavir

300 mg daily

0.5 mg daily

3. Telbivudine

4. Lamivudine

600 mg daily

100 mg daily

5. Adefovir

interferon-

alpha-2a ♦> Dose 10 million

180 pg SC weekly

10 mg daily

units SC

weekly ❖ Side effects

o o

Flu-like symptoms Fatigue

o

Autoimmune disorders

Lactic acidosis Pancreatitis

Fanconi

Fanconi

syndrome

syndrome osteomalacia

28

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Recent guidelines recommend choosing either pegylated interferon-alpha-2a, tenofovir, entecavir, as a first line therapy for HBV infection. ❖ Duration :for several years or lifelong to achieve virologieal endpoints ❖ Response to treatment in chronic HBV infection: o Loss of HBV DN A by PGR in blood o Loss of HBeAg & appearance of HBe Ab

J

^ 2. Treatment of HCV :

❖ Indications to treat:

o All patients with chronic HCV infection except patients with short life expectancies that can't be remediated by treatment of HCV,by transplantation or by other directed therapy.

❖ N.B.: the choice of treatment regimen depends on the genotype, there are 6 genotype of HCV,genotype 4 the most common genotype of HCV in Egypt.

I ❖ Drugs used for treatment of HCV infection: I. Old regimen : Interferon & oral antiviral treatment e.g. ribavirin for 48 weeks 11. Recent regimen called :

o All oral interferonfree regimen or direct acting antiviral drugs(DAAs)regimen Classifications :

1. NS3-4A protease inhibitors e.g. paritaprevir 2. NS 5A inhibitors e.g. velpatasvir, ledipasvir 3. NS 5B polymerase inhibitors e.g. sofosbuvir ii.

Drugs & doses :

2. HCV with decompensated liver compensated liver cirrhosis cirrhosis (Child B or C) (Child A) A. Daily fixed combination of sofosbuvir(400mg)/ velpatasvir (1 OOmg)for ... o 12 weeks o with ribavirin(600mg)for 12 1. HCV with or without

3. HCV with decompensated liver cirrhosis with ribavirin

ineligible o

24 weeks

o

24 weeks

weeks

B. Daily fixed combination of sofosbuvir(400mg)/ ledipasvir(90 mg)for ... o 12 weeks o with ribavirin (600mg)for 12 weeks

❖ Response to treatment in chronic HCV:-ve PCR

3. Hepatic transplantation

29

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Liver cirrhosis

❖ Deflnition «& pathology: ^ lnfidlT10Q

Normal

Fibrotic

Cirrhotic •^vjr

f®' V

•

vs.'..-

\

-V'

o

1. 2.

"A

•

Diffuse liver affection characterized by : Degeneration of hepatocytes Formation of regeneration nodules

3. Fibrosis which leads to disturbed liver function & blood flow 4.

IRREVERSIBLE LOSS of hepatic architecture (cirrhosis). Etiology: see before: page 15.

❖ Pathogenesis : o Long standing injury to the liver lead to stimulation of Kupffer cells ^ release of cytokines —> stimulate hepatic stellate cells (ito cells)^ excessive release and deposition of collagen fibers^ irreversible loss of hepatic architecture (cirrhosis) Classification:

1. According to etiology: e.g. alcoholic cirrhosis. 2. According to pathology: micronodular, macronodular, and mixed. 3. According to clinical picture: compensated or uncompensated cirrhosis.

Clinical picture: I.

Compensated liver cirrhosis (latent cirrhosis): The patient is asymptomatic

The patient is discovered accidentally when hepatomegaly and/or splenomegaly is discovered during examination for unrelated condition. 11.

Uncompensated liver cirrhosis (manifest cirrhosis):

Normal

Chronic hepatitis

liver

with fibrosis

cancer

cirrhosis

1.

Manifestations of the cause

2.

Manifestations of liver cell failure due to progressive deterioration of liver functions Manifestations of portal hypertension: o Liver cirrhosis increases resistance to blood flow and leads to higher pressure in the portal venous system,

3.

4. 5.

resulting in portal hypertension. Manifestations of hepatocellular carcinoma Abdominal examination may reveal: A. Hepatomegaly

B. Hepatosplenomegaly C. Hepatosplenomegaly + ascites D. Shrunken liver with sharp border + splenomegaly + ascites 111.

Features of the underlying cause.

30

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Investigations: 1. Investigations for the cause

2. Investigations of chronic liver cell failure (mention them in details, will be discussed later); including: A. Liver imaging e.g. abdominal ultrasound to know the size & pattern of liver cirrhosis. B. Assessment of degree of fibrosis : i. Noninvasive : detect degree of fibrosis only o Fibrosis markers e.g. APRI: AST-to-platelet ratio index

o Fibroscan: elastography that maps the elastic properties and stiffness of soft tissue for staging hepatic fibrosis. o o 3. 4.

ii. Invasive : Liver biopsy: To confirm the cirrhosis(mention the pathology) To detect the etiology e.g. Iron deposition in hemochromatosis Investigations of portal hypertension

ro A O

Investigations of hepatocellular carcinoma e.g. Alpha feto-protein ❖ Treatment 1. Treatment of the cause

2. Treatment of liver cell failure

3. Treatment of portal hypertension 4. Treatment of hepatocellular carcinoma

5. Drugs to reduce hepatic fibrosis: Penicillamine (), collagen synthesis)& Colchicine(t collagen destruction) 6. Hepatic transplantation

❖ Prognosis : 1. Child-Turcotte-Pugh Scoring System: ❖ 1 point

❖ Parameters

❖ 2 point

❖ 3 point

1. Ascites

o

None

o

2. Albumin

o

>3.5

Medically controlled o 2.8-3.5mg%

3. Bilirubin

o

J, hepcidin level —> iron overload due to f ferroportin mediated iron efflux from storage & f gut iron absorption. 2.

lL-l,8&TNF-a.

4.

Normally, dietary copper is absorbed from the stomach and proximal small intestine and is rapidly taken into the

The disease is autosomal recessive with

Production of toxic metabolites called

adducts during conversion of acetaldeliyde to acetate. 2. Immune reaction against liver cells altered by alcohol 3. Release of inflammatory cytokines e.g.

1

Primary (Hereditary) licmocliromatosis:

Nutritional deficiency may lead to decreased amount of hepatotropes

liver, where it is stored and

incorporated into ceruloplasmin, which is secreted in the blood.

Secondary (acquired) heniochromatosis (hemosidrosis):

In Wilson disease:

The disease is autosomal recessive

This results from excessive iron load in the

with point mutation of ATP7B gene

body due to: Hemolytic anemia & siderohlastic anemia Dietary iron overload (Bantu siderosis) Repeated blood transfusion or iron injection

located in chromosome 13.

There is failure of ceruloplasmin synthesis with loose binding of cooper to albumin.

The copper will be deposited in tissues and lost in urine

❖

o 0 o

Mitochoiidrial swelling Mallory bodies (eosinophilic inclusions) & steatosis (fatty infiltration) Pathology of cirrhosis

3.

History of alcoholism. Clinical picture of alcoholic cirrhosis Other features of alcoholism e.g.

A.

CNS:

1.

2.

1) Wernicke-Korsakoff syndrome. 2) Ataxia, peripheral neuropathy, myopathy, epilepsy & coma. B. CVS: Cardiomyopathy

o

o

A. o o

B. C.

Patbologv:

Deposition of iron occurs in the periportal hepatocytes & then extends to all hepatocytes Pathology of cirrhosis ❖ Clinical picture

o

The disease is more common in:

o

o

Deposition of copper in the liver, eye. and nervous tissue

Pathology of cirrhosis

Middle age male patient(40-60y) Female starts to manifest after menopause as monthly blood loss was protecting them. Clinical picture of liver cirrhosis Specific features: CNS: panhypopituitarism & peripheral

The disease is common in young patients with combined neurological and hepatic manifestations 1. CNS: Deposition of copper in basal ganglia may lead to: A. Extrapyramidal manifestations: athetosis, parkinsonism, & chorea

neuritis

B.

Dementia

CVS: cardiomyopathy, arrhythmia 2. Eye: Eatty liver, Eulminant hepatic failure. o 3. Chest: interstitial lung fibrosis o Kayser-Fleiscber ring : deposition of Alcoholic hepatitis: fever,jaundice & o 4. Liver cirrhosis with LCF & portal HTN copper at the comeal margin with 5. enlarged tender liver. Pancreas: fibrosis with development of DM greenish brown discoloration by slit Alcoholic cirrhosis o lamp 6. Supra-renal: Addison's disease D. GIT: 7. Renal: renal tubular dysfunction 3. Liver: 8. Gcnitalia: impotence and testicular atrophy A. Recurrent episodes of acute hepatitis 1) Enlargement of parotid gland B. Acute hepatic failure 2) Gastritis, peptic ulcer, gastric carcinoma 9. Joints: Chondrocalcinosis & pseudo gout 10. Skin: Bronze pigmentation (melanin C. Liver cirrhosis with LCF & portal 3) Malabsorption syndrome & pancreatitis E. Blood: deposition) and ulcers HTN Macrocytic anemia, tlirombocytopenia, N.B.: MRl can differentiate between primary 4. Blood: hemolytic anemia. leucopenia & hyperuricemia. 5. Renal: tubular dysfunction & secondary as it shows that the pancreas is E. Others: Dupuytren's contracture spared in secondary iron overload. Investigations: General investigations for liver cirrhosis + investigations of the cause: Investigations of the cause: Gamma-Glutamyl Transferase(GGT): Investigations of the cause: A. Low serum ceruloplasmin. markedly A. Laboratory: f serum iron, j" transferrin saturation, f serum ferritin &[serum High IgA level B. Copper level: transferrin, J, TIBC o ], in serum B. Abdominal CT & MRl: excess iron o t urine C. Liver biopsy: confirm cirrhosis & deposition in liver. show high level of copper in liver C. Liver biopsy confirm cirrhosis & show tissue heavy iron deposition D. DNA analysis : mutation in HFE gene C.

Liver:

2.

General measures for treatment of

A. General measures for treatment of cirrhosis

cirrhosis

B. Treatment of the cause e.g. Iry

Treatment

2.

Stop alcohol intake

hemochromatosis:

1.

Venesection of 500 ml blood/week ^ J, serum iron as it's used for synthesis of new RBCs.(this may take > 2 years & is done as needed to keep serum ferritin normal usually 3-4 times/year). 2. Iron chelating agent: deferoxamine: furinary excretion of iron C. Symptomatic treatment e.g. DM.

34

A. General measures for treatment of cirrhosis.

B. Treatment ofthe cause:

1. Copper chelating agent: o D-penicillamine: "furinary excretion of copper. 2. Potassium metabisulphite: precipitates copper in the intestine & prevent its absorption

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Autoimmune hepatitis (Lupoid hepatitis)

Biliary (Cholestatie) cirrhosis Primary biliary cirrhosis

Primary sclerosing cholangitis

Definition

Chronic autoimmune disease ofthe liver leading to inflammatory damage to the liver causing scarring & eventually cirrhosis

Chronic autoimmune/inflammatory disease of biliary system (intra & extra hepatic) leading to narrowing and obliteration of biliary channels causing chronic cholestasis &

Chronic autoimmune

disease of the liver leading to destruction of

intrahepatic bile ducts causing chronic cholestasis & eventually cirrhosis Etiology

eventually cirrhosis

o

Autoimmune disease due to genetic predisposition (defect in T suppressor cells) leading to autoantibodies against the liver.

o

The disease is commonly associated with other autoimmune disorders.

o o

Pathology of chronic hepatitis Pathology of cirrhosis

❖

Pathology

o

Granulomatous reaction

o

o

damaging and destroying the intrahepatic bile ducts Pathology of cirrhosis

o

Concentric(onion skin) fibrosis destroying the intra & extrahepatic bile ducts

Pathology of cirrhosis

Clinical picture

2.

Incidence :

A. Incidence :

A. Incidence:

Not common in Egypt. More common in young aged females The disease has two types:

o

o

■

Type

I.

Type I

2.

■

Incidence

o

Pre and Post-

o

Type II Teens and

early Twenties

menopausal females ■

Antibodies

More common in females

More common in males

o o B. 1.

40-60 years old o 20-40 year old Smoking increases the risk o Smoking decreases the risk Features of obstructive jaundice : PRURITUS is the most common initial symptom followed by obstructive jaundice by months or years. 2. t Cholesterol:

0

ANA

0

Anti EKMA-I

o

Atherosclerosis

o

ASMA

0

Anti-EC-l

o

Xanthelasma with xanthomatous deposition in the eye lids, hand creases

o

AAA

0

Anti SEA/EP

o

p-ANCA

o

anti SEA/EP

and over the elbow.

Presentation :

3. Malabsorption leading to : o Fatty stool : Steatorrhea o Fat soluble vitamin deficiency e.g. a. (.Vitamin K : Bleeding tendency

o

Acute hepatitis and jaundice,

b. (Vitamin D: Bone affection : osteoporosis & osteomalacia (hepatic

o

Chronic liver disease & cirrhosis

4.

Associated with auto-immune &

4.

Abdominal examination :

extra-hepatic manifestations e.g.:

o

In early cases there are tender hepatomegaly & splenomegaly.

o

In late cases there are cirrhotic liver with LCF & portal HTN

3.

osteodystrophy)

o

Amenorrhea

o

Autoimmune hemolytic anemia & ITP

o

RA & SEE

5. Skin Pigmentation 6. Clubbing

.j.

7.

o

Celiac disease & ulcerative colitis

o o

DM,autoimmune Thyroiditis & Graves disease Fibrosing alveolitis.

Associations: autoimmune

diseases e.g. SEE & Sjogren's syndrome

5.

Acute Cholangitis leading to right upper quadrant pain,jaundice & fever with rigors (Charcot's triads) t risk of Cholangiocarcinoma Associations: In 75% irritable bowel

disease especially ulcerative Colitis

Investigations: General investigations of liver cirrhosis + 2. A. B.

Liver function tests: as chronic hepatitis Serology : High IgG levei Type I: positive:

o

ANA : Anti-nuclear antibodies

o

ASMA : Anti-smooth muscle antibodies

o o

AAA : Anti-actin antibodies

p-ANCA (atypical): Perinuclear - antineutrophil cytoplasmic antibodies Anti-SEA/EP : Anti-soluble liver antigen/liver-pancreas antibodies

A. General investigations of OBSTRUC TIVE .lAUNDlCE Investigations of the Investigations of the cause: cause: i. Serology: 1. High IgM level High IgM level 2. Anti-M itochondrial Negative AMA antibodies(AMA) Perinuclear - antineutrophil especially M2 antibodies cytoplasmic antibodies(p-ANCA): are specific (positive in positive in 60% of cases. 95% of cases) 4. Positive ANA & ASMA. Positive ANA & ASMA. ii. ERCP,MRCP & liver biopsy: Eiver biopsy: destructive Inflammation, fibrosis & sclerosing cholangitis: damage & loss of biliary tract of small bile ducts with Beading of wall of biliary radicals ductular proliferation B.

o

Type II: positive Anti-EKMA-I: Anti-Elver kidney microsomal antibodies type I

o

Anti-EC-l: Anti liver cytosol antibodies type 1

o

Anti-soluble liver antigen/liver-pancreas antibodies

1.

General measures for treatment of cirrhosis

A.

General measures for treatment of cirrhosis

Prednisolone:

B.

Treatment of the cause:

C.

Treatment 2. o

30 mg/day is given for one week, then 15 mg/day as a maintenance dose for 6 months to 3 years according to the

Ursodeoxycholic acid : improving the symptoms by competing with bile acid at their ileal reuptake sites

response. 3.

Azathioprine:

o

This is given with prednisolone in a dose of50 mg/day to potentiate the effect of prednisolone & reduce its dose.

2.

Cholestyramine: improvement of pruritus by binding bile salts in the

3.

Symptomatic treatment e.g. supplements of fat soluble vitamin 4. Endoscopic stents & surgical

intestine and increase their excretion in stool

excision of strictures

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬ 35

❖ Cardiac (congestive) cirrhosis Definition:

o Cirrhosis from prolonged severe hepatic congestion. Inferior Aorta vena cava

Hepatic vein

Hepatic irtery

Liver

❖ Etiology:

sinusoids

1. Right ventricular failure 2. Tricuspid valve disease(TR & TS) 3. Pericardial effusion & constrictive pericarditis

yj rij/ '—'

Ii V —

4. rVC obstruction

5. Hepatic outlet obstruction syndromes: Veno-oeclusive syndrome & Budd-Chiari syndrome.

❖ Veno-occlusive syndrome (sinusoidal

❖ Budd-Chiari syndrome

obstruction syndrome) ❖ Definition

o Hepatic congestion due to obstruction of small and o Hepatic congestion due to obstruction of large hepatic medium sized hepatic veins veins ❖ Etiology 1. Idiopathie 1. Idiopathie in one half of cases. 2. Irradiation & chemotherapy 2. Intra-abdominal malignancy e.g. liver, kidney or supra 3. Thrombosis due to : renal gland. o Senecio alkaloids (Heliotropium plants) used as herbal 3. Thrombosis due to : tea in Jamaica o Anti-thrombin III defieieney & protein C or S deficiency o PNH, Polycythemia vera

o Oral Contraceptive pills. Clinical picture 1. Acute obstruction:

o Sudden onset of acute abdominal pain with ascites and even acute fulminant hepatic failure 2. Chronic obstruction:

o Tender hepatomegaly, ascites, and features of liver cirrhosis 3. Signs suggesting hepatic vein/proximal IVC thrombosis : A. Ascites more than LL edema

B. Non pulsatile tender hepatomegaly C. Absent of hepatojugular reflux to differentiate from RSHF D. Direction of refilling blood flow : filling from below upwards Investigation

1. 2. a. b.

Investigations of liver cirrhosis Investigations of the cause: Abdominal ultrasound : enlarged liver with homogenous nature Other imaging : Hepatic venography, MRV,Duplex : diagnostic Treatment

1. Treatment of the cause 2. Treatment of thrombosis:

o In the acute phase e.g. fibrinolytic therapy followed by anticoagulant o In chronic phase : anticoagulant to prevent further thrombosis 3. Treatment of liver cirrhosis in chronic stage

36

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Post hepatitis cirrhosis

Etiology :

o Post viral hepatitis (hepatitis B,C,D) o Chronic active hepatitis e.g. autoimmune hepatitis ❖ Pathology: o Pathology of cirrhosis o Pathology of chronic active hepatitis o Pathology of the causes e.g. post viral cirrhosis: Ground glass appearance of hepatocytes Clinical picture: 1. Clinical picture of liver cirrhosis 2. Clinical picture of the cause : A. History of hepatitis B. Clinical picture of autoimmune hepatitis ❖ Investigations: 1. 2. A. B.

General investigations of liver cirrhosis Investigations of the cause: Hepatitis markers Autoimmune hepatitis markers

Treatment:

1. General measures for treatment of cirrhosis

2. Treatment of the cause e.g. autoimmune hepatitis

N.B,: causes of enlarged cirrhotic liver:

1. 2. 3. 4. 5. 6.

Alcoholic cirrhosis in early cases Primary biliary cirrhosis Post viral hepatic cirrhosis in early cases Congestive cirrhosis e.g. Budd chiari syndrome Cancer e.g. hepatoma Copper: Wilson disease

7. Fe : hemochromatosis

37

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Manifestations of liver cell failure

1. General manifestations 1.

2.

Generalized fatigue, weight loss, weaimess, muscle wasting (J, muscle protein synthesis) Increase susceptibility to infection due to Kupffer cell dysfunction & J, opsonic activity

3. Fever: A.

Low grade fever in LCF due to :

o

Due to release of pyrogens from the damaged liver cells

o

Failure ofthe liver to clear bacteria from the circulation

B.

High grade fever due to : Spontaneous bacterial peritonitis Chronic viral hepatitis Eye:

o o

4. o

5. 6. o o

"V"

Jaundice of hepatocellular type due to failure of damaged liver to metabolize bilirubin. Endemic parotitis: bilateral painless enlarged parotid Fetor hepaticus: Fruity fecal odour simulating rotten apple

Due to lack of detoxification of putrefactive materials(methyl mercaptan)from intestine due to liver cell failure or bypass due to portosystemic shunts

o

Becomes less intense after: defecation, enema & intestinal antibiotics .

7.

Clubbing due to biliary cirrhosis or large pulmonary AV fistula.

i

2. Cutaneous manifestations

A. Manifestation due to hyperestrogenemia & vasodilator materials: 1. Arterial spiders (Spider navei):

2. Palmer erythema:

3. Paper money skin:

.SHj

o Central dilated arteriole with radiating o

capillaries Compression of central arteriole causes

blanching of radiating capillaries o Present in the distribution of SVC drainage

o Redness of the palm (especially the thenar & hypothenar eminencies and the head of the metacarpal bones) with central pallor.

o

Dilated small vessels

scattered throughout the skin in irregular manner

(head, neck, upper limbs & upper chest).

❖ N.B.: other causes of palmer erythema : 1. P : Polycythemia, Pregnancy 2. A : Alcohol intake. Autoimmune(RA,SLE) 3. L: Liver cell failure ,Leukemia 4. M:

o o

Medications e.g. CCPs, Cortieosteroids Miseellaneous e.g. Thyrotoxicosis, Normal individual

B. Manifestation due to hypoalbuminemia:

1. Leukonychia: true white spots in nails 2. Muehrcke's nails: transverse white bands parallel to lunula 3. Terry's nails: brown distal band with white proximal nail bed without lunula, C. Manifestations related to the cause: e.g.

o Pigmentation in primary biliary cirrhosis & hemochromatosis o Clubbing in primary biliary cirrhosis o Dupuytren's contracture in alcoholic cirrhosis.

38

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

3. CNS manifestations: Hepatic encephalopathyJ Definition :

o Neuropsychiatric manifestations that occur in severe liver cell failure and or extensive portosystemic shunting.

❖ Pathogenesis 1. 2. 3. 4. 5.

1 Ammonia t Amines j' 1" Aromatic AA, J. Branched AA tCABA Alkalosis & hypokalemia

f plasma free cholesterol which is transformed into cholesterol ester as a part of RBCs membrane —> macrocytosis o Folic acid or vitamin B12 deficiency B. Bleeding tendency: due to 1. Defect in clotting factors :

Platelets

o I Fibrinogen, coagulation factor II (prothrombin), VII, IX, X. 2. Defect in platelets :

o Thrombocytopenia due to hypersplenism or megaloblastic anemia

o Thrombocytasthenia due to coating of platelets by abnormal globulins formed by RFS C. Cytopenia (Pancytopenia): o Due to hypersplenism or megaloblastic anemia 6. Endocrinal manifestations

Endocrinal manifestations are due to

t

i

o Estrogen & prolactin. o Sex hormone binding globulin

o

Testosterone

o

Somatomedin

Clinical picture: A. 1. 2.

3. 4.

In females (defeminization) Stunted growth in children Sterility & loss of libido Amenorrhea & galactorrhea Breast atrophy

5. Generalized fall of hair

B.

In males (Feminization)

2.

Impotence & testicular atrophy

3.

Gynecomastia

4.

Feminine distribution of suprapubic hair

42

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

7. Metabolic manifestations

1. Carbohydrate metabolism:

a) Hypoglycemia may occur in massive liver damage as in acute fulminant hepatic failure or end stage liver cell failure. b) Hyperglycemia: Hepatogenous diabetes: DM following liver cirrhosis due to :

■ i hepatic clearance & portosystemic shunting of insulin

a state of hyperinsulinemia —> peripheral insulin

resistance ^ impaired glycogen synthesis —> DM 2. Fat metabolism:

o Defective production of bile will lead to malabsorption offat. 3. Protein:

o Catabolic state will cause excessive protein break down with muscle wasting. 8. Abdominal & renal manifestations A. Abdominal examination B. Ascites

C. Hepato-renal syndrome.

I. Abdominal examination

1. Abdominal wall:

o Ascites & hernia especially umbilical hernia 2. Liver:

o In early cases : enlarged

o In late cases: shrunken,firm in consistency, sharp border with smooth or nodular surface 3. Gall bladder :

o Gall stones due to abnormal bile salts composition 4. Spleen:

o Splenomegaly indicates portal hypertension 5. Pancreas:

o Chronic pancreatitis especially in alcoholic patients 6. Stomach:

o Peptic ulcer (epigastric pain) due to decreased destruction of gastrin & histamine

43

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

II. Ascites

I Splanchnic & systemic vascular resistance Systemic VD

tInterstitial compartment

|,Intravascular compartment

l Albumin

Aldosterone & ADH

9 9

RAAS:—> t Aldosterone || TADH | | |ANP

Primary salt retention

Secondary salt retention

Ascites

Causes:

1. Hypoalbuminemia :

A. Cause : decreased albumin synthesis by diseased liver o N.B.: The threshold for ascites is albumin level < 3 gm/dl B. Pathogenesis :

o I Albumin | ^ osmotic pressure of plasma protein ^fluid shift from intravascular to interstitial compartment ■ ascites & edema ^ underfill of intravascular volume (f, IVV) 2. Salt and water retention :

A. Causes : t aldosterone | & ADH i. ❖ i Albumin ^ i IVV:

ii.

Underfill theory

o

a. Hypovolemia (J, IVV)^+ RAAS —>■ f aldosterone b. Hypovolemia (j IVV) ^ fADH & J, atrial natriuretic peptide (ANP)

o

a & b —> secondary salt & water retention

aggravates ascites

Overfill theory

Primary salt retention due to decrease hepatic metabolism of aldosterone & ADH intravascular overfilling —> f hydrostatic pressure ^ excess fluid spilling into the interstitial ^ starts ascites.

3. Peripheral arterial vasodilatation theory : the most recent theory : o Liver cirrhosis —>■ systemic vasodilatation —> J, splanchnic & systemic vascular resistance —> J, effective arterial blood volume —>• + RAAS (aldosterone) & ADH ^ salt & water retention ascites. 4. Lymphorrhea: A. Causes : occurs with post-sinusoidal obstruction B. Pathogenesis : weeping liver; o Leading to dilatation of lymphatics on the surface of the liver with lymph extravasation into peritoneum 5. Portal hypertension: o This factor alone rarely produce ascites

o

It acts as a localizing factor for transudate in the abdominal cavity in areas drained by portal vein in presence of low albumin.

6. As a complications of malignant ascites, TB peritonitis & spontaneous bacterial peritonitis

❖ Clinical picture, differential diagnosis, investigation, treatment: see before.

44

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

III. Hepato-renal syndrome(HRS) ❖ Definition:

o Functional renal failure with preserved renal parenchyma occurring in patients with pre-existing chronic liver failure and without primary renal disease. ❖ Etiology: renal VC

❖ Pathogenesis: Theories:

^ 2*

Splanchnic VD

VC>VD

1.

Arterial VD theory:

o

Portal hypertension results in systemic/splanchnic VD ^ J. effeetive arterial blood volume ^++ arterial

baroreceptor^ ++ RAAS & sympathetic nervous system ^ VC in renal & systemic circulation o

Early, kidney escape this effect because of local production of VD.

o

Late, renal VC & renal hypoperfusion occur due to maximal activation of VC system that overwhelms the local VD.

2.

Hepatorenal refiex theory :

o

Renal VC in HRS is unrelated to systemic hemodynamics

o

It is due to either a deficiency in synthesis of a VD factor or a hepatorenal refiex that leads to renal VC.

❖

Precipitating factors

A.

i IVV:

o

GIT bleeding

o

Large volume paracentesis without volume replacement

o

Aggressive diuresis & severe diarrhea

B.

t renal vein pressure in tense ascites

C.

Others : SBP, sepsis & major surgery Clinical picture : Acute renal failure with LCF Types: 1. Type 1 HRS

2. Type 2 HRS

o Rapidly progressive

o Slower progressive

o Associated with refractory hypotension

o Associated with refractory ascites

o Initial serum creatinine > 2.5mg/dl

o Initial serum creatinine > I.5mg/dl

o

o

Median survival of2-4 weeks

Median survival of2-6 months

❖ Investigations: as acute renal failure: pre-renal failure.

45

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Criteria for diagnosis :

Creatinine > 1.5mg/dl

1. Absence of primary renal disease. 2. Liver failure evidence with portal hypertension & ascites 3. Renal impairment with creatinine > 1.5mg/dl

4. Absence of sepsis, shock, recent treatment with nephrotoxic drugs

5. No improvement of KFTs/UOP after plasma volume expansion & withdrawal of diuretics. 6. No evidence of renal parenchymal affection e.g. normal renal US & urine analysis Treatment

IGIYPRESSIN* Terlipressin acetate

Ifiidodrine 2.5 mg

; i

forl.V injection FMSOKirTMIEWiM

■txcnoi

JS

1. Treatment of precipitating factors e.g.

o Therapeutic paracentesis of tense ascites with adequate volume expansion 2. Plasma volume expansion by albumin infusion 3. Systemic & splanchnic VC drugs :

o

Assuming that splanchnic VD is the original mechanism initiating HRS;

A. Alpha agonist: midodrine B. Somatostatin analogues : Octreotide C. Vasopressin analogues :

o

Terlipressin (glypressin)

o

Pitressin (vasopressin)

o

Omipressin

4. Renal VD drugs to overcome renal VC : o

Acetylcysteine: anti-oxidant

o

PG analogues : misoprostol

o

Dopamine renal dose

5. Hemodialysis. 6. Hepatic transplantation

46

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Liver function tests: Investigations of liver cell failure I. Laboratory:

A. Test of Proteins, Fats. & carbohydrates: Proteins : 1.

Chemical separation of plasma protein: A. Normal:

o

Total proteins

o

Albumin

o

Globulin

o 6-8 gm/dL o 3.5-5.5 g/dL o 2-3 g/dL

o

Albumin/ Globulin ratio

o

2:1

B. Abnormal: a. Acute liver disease

II.

o

E.g.

o

Albumin

b. Chronic liver disease

o Viral hepatitis o Liver cirrhosis o Normal(long half-life up to 3 weeks) o i

o

Globulin

o

t

o

Albumin/ Globulin ratio

o

Normal

o o

t J, or even reversed

Electrophoresis of plasma protein :

❖ Type

❖ Formed in :

1. Albumin

o

❖ Changes: o 1 Chronic liver disease o J, Chronic liver disease

Liver

2. al globulin e.g. al antitrypsin

o f in a 1 antitrypsin deficiency 3. a2 globulin & (3 globulin

o

4. 7 globulin (immunoglobulin)

& excreted in bile

o RBS( 3 lymphocytes)

o t obstructive jaundice

"t* t in polyclonal & monoclonal gammopathy (see hematology) The predominant antibodies helps in diagnosis e.g. o Iff IgG: in autoimmune hepatitis, o ttl IgA: in alcoholic liver disease, o fit IgM in primary biliary cirrhosis

2. Fats: A. Normal: o

Normal serum cholesterol 150-200mg/dl

o

70 % of this amount is esterified in liver & 30% is not esterified

o Part of cholesterol is excreted with bile. B. Abnormally:

A. Obstructive jaundice o

B. Hepatoceliular jaundice

Increased cholesterol with normal esterification.

o

Normal cholesterol with decreased esterification.

3. Carbohydrates : oral glucose tolerance test(OGTT): A. Impaired glucose tolerance test & DM (for more details see endocrinology) B. Lag storage curve: causes : Liver cell failure, Gastrectomy & thyrotoxicosis A. Normally B. o Gradual rise with gradual decline o Fasting glucose level is normal ( 180 mg/dl At first -ve then -t-ve i.e. +ve in the

peak only

o 2 hour postprandial plasma glucose level (normal < 140mg/dl)

o The normal level is reached by 2 hours

o

The normal level is reached

rapidly

47

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

B. Test of bile pigment & bile salts : 1.

Bile pigments :

Hemolytic jaundice

Obstructive Jaundice

Hepatocellular jaundice

Total bilirubin

t

Direct bilirubin

Normal

T t

Normal

o

0.8-1 mg/dl 0.2 mg/dl 0.8mg/dl Indirect bilirubin Stercobilinogen in stool 50- 200 mg/day 0.5-2 mg/day Urobilinogen in urine

o

Bilirubin in urine

o o

o o

11.

Absent

t t t

Normal

i

t t t i t

Absent

Present

Present

i

Bile salts :

o Normally absent in urine

o Abnormally present in urine in obstructive jaundice —»• J, surface tension of urine —>• frothy urine & +ve Hay's sulfur test

C. Test of liver damage :

1. Aspartate transaminase(AST)or serum glutamic oxaloacetic transaminase(SCOT); o Normally : < 45 lU/L

o Abnormally (Non-specific): ttt in LCF' ^cute kidney injury, myocardial infarction & muscle injury. 2. o o 3.

Alanine transaminase(ALT)or serum glutamic-pyruvic transaminase(SGPT): Normally : < 45 lU/L Abnormally : Specific : ttt only in Uver diseases Alkaline phosphatase(ALP):

o

Formed in liver & bone & Excreted in bile

o Normal level: 3 to 13 King Armstrong unit(K.A.U.) or 30-130 lU/ L. o

Abnormally : A. Liver cell failure o

ALP

o

t but 30 KAU

D. Other causes ofelevated alkaline phosphatase e.g. Leukemoid reaction, Lymphoma,Sarcoidosis, Hyperthyroidism & Hyperparathyroidism 4. 5 nucleotidase (5-NT)& Gamma-Glutamyl Transferase(GGT): A. Liver cell failure B. Obstructive jaundice o

5NT & GGT

o

o

T

ttt

C. Bone disease o

Normal

❖ N.B.: associated increase in 5-NT, GGT & abdominal US finding confirm that increased ALP is due to liver disease not bone disease.

5. Lactic dehydrogcnase(LDH):

o Normally : 150-350 lU/ml

o Abnormally (Non-specific): ttt io LCF, acute kidney injury, myocardial infarction, muscle injury & hemolysis D. Others: I nil II I I I I -f

A. Alpha-fetoprotein (AFP): 1. Normally produced by fetal liver & disappears few weeks after birth o Normal level: very low in serum < 20 ng/ml 2. Abnormally : a. t :20- 500 ng/ml b. t t t > 500 ng/ml o Hepatitis & cirrhosis o Hepatocellular carcinoma o

Pancreatitis

o

N.B.: NORMAL LEVEL OF AFP DON'T EXCLUDE HCC

o Malignancy : GIT, ovary & testis

48

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

3. Clinical importance of AFP: a. Follow up of cirrhotic patients for early detection of HOC

b. Suspected cases of HCC; e.g. local hepatic lesion c. After tumor resection:

o Early: to confirm successful resection, o

Late: to detect recurrence of the tumor

d. Its presence in pregnancy (blood, amniotic fluid) indicates neural tube defects in fetus B. Blood picture : A. Hemolytic jaundice B. Obstructive Jaundice C. Hepatocellular jaundice o Of hemolytic anemia. o Macrocytic normoblastic anemia o Anemia of LCF : 3 types

o Bleeding tendency(thrombocytopenia) o Cytopenia

C. Coagulation profile : 1. Obstructive Jaundice

2. Hepatocellular jaundice o Prolonged PT time & decreased PC concentration that is not corrected by parenteral vitamin K.

o Prolonged FT time & decreased PC concentration that is corrected by parenteral vitamin K Clinical importance of FT & PC: a. To assess the severity & prognosis of liver diseases

b. Before any invasive technique or surgery c. Follow up of oral anticoagulant III. Imaging:

1. Abdominal sonar & CT abdomen show cirrhotic liver & splenomegaly

2. Fibroscan: elastography that maps the elastic properties and stiffness of soft tissue for staging hepatic fibrosis. IV. Liver biopsy:

1. Diagnosis of the cause e.g. iron deposition in hemochromatosis 2. Diagnosis of the complications e.g. hepatocellular carcinoma 3. Follow up the response of the treatment V. Investigations of the cause & complications: 1.

Of the cause e.g. Hepatitis markers for viral hepatitis

2.

Of the complications e.g.

Alpha one antitrypsin level : deficiency can produce primary emphysema(Lung)& Liver cirrhosis Upper GIT Endoscopy may show esophageal varices & congestive gastropathy due to portal hypertension Renal function test for hepato-renal syndrome

Treatment of liver cell failure

1. Treatment of the cause.

2. Treatment of precipitating factors 3. Treatment of manifestations: see before o Treatment of ascites.

o o o o 4. 5.

Treatment of hepatic encephalopathy. Treatment of hepato-renal syndrome, Treatment of portal hypertension. Treatment of bleeding tendency by fresh plasma transfusion Hepatic support using biological or charcoal membrane dialysis Hepatic transplantation: the only definitive treatment.

49

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Portal Hypertension

Inferior Vena Cava

Heart

Hepabc Vein

Inferior vena cava

Hepatic vein

Aorta

Hepatic Artery

Portal Vein

Splenic

Superior

Vein

Portal vein

Mesenterlc Vein

Splenic

Blood supply

Istf^erlor

❖ Blood supply to the liver and venous drainage:

1. Hepatic artery o

■ mesenterlc vein

2. Portal vein

o Formed by the union of superior mesenteric vein & splenic vein

Branch from celiac trunk

o

o It supplies 25% of the total blood flow

Drains most of GIT and spleen

o It supplies 75% of the total blood flow

II. The venous drainage from the liver is by hepatic veins into the inferior vena cava. o The caudate lobe is an autonomous segment, its draining vein drains directly into the inferior vena cava. ❖ Anatomy of portal venous system:

o The portal system includes all veins which carry blood from the abdominal part of the alimentary tract, the spleen, pancreas and gall bladder,

o The portal vein is formed by the union of the superior mesenteric vein and the splenic vein just posterior to the head of the pancreas.

o It extends for a distance of6-8 cm to reach the porta hepatis where is enters the liver in two main branches, one to each lobe.

o The portal vein has a segmental intrahepatic distribution. ❖ Definition of portal hypertension

Normal portal venous pressure less than 5-8 mm Hg. Portal hypertension: portal venous pressure above 10 mm Hg. Causes of portal hypertension: A. Infra-hepatic causes o Obstruction of portal vein before entering the liver ♦♦♦ Pre-sinusoidal: portal vein obstruction

B. Intra-hepatic causes

C. Supra-hepatic causes

o Obstmction of portal vein branches, sinusoids

o

& hepatic venules in the liver

Obstruction of blood flow from liver to RV

1. Pre-sinusoidal:

❖ Post-sinusoidal:

o

1. Right ventricular failure

Sarcoidosis

polycythemia 2. Wall: congenital narrowing of the portal vein.

o Schistosomiasis: Bilharzial periportal fibrosis o Congenital fibrosis o Infiltration of portal tract: Leukemia & Lymphoma

constrictive pericarditis 3. Tricuspid valve disease (TR & TS)

2. Sinusoidal: Liver cirrhosis

4. rVC obstruction

3. Outside: compression by LN &

3. Post Sinusoidal: Veno-occlusive disease

5. Budd-Chiari syndrome

1. Lumen: portal vein thrombosis due to inflammation &

2. Pericardial effusion &

cancer head pancreas

50

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Portosystemic shunts:

❖ When portal hypertension occurs, the body tries to decrease the portal pressure through opening of porto-systemic shunts. Paraumbilical

Obstructions

vein

Body circulation

Esophageal veins

Esophageal

Abdomen

varices

Extrahepatic Shunt Portal

Unfiltered. toxic blood

vein

Intrahepatk shunt

Splenomegaly

Superior

Hltered blood

Normal

mesenteric vein

Inferior mesenteric vein

Hemorrhoidal veins Hemorrhoids

❖ Clinical condition

❖ Portal circulation

1. Esophageal & gastric

o Esophageal branch of 0 Thoracic esophageal left & short gastric veins branch of azygos vein o Superior rectal vein o Middle & inferior rectal

varices

2. Rectal varices

❖ Systemic circulation

❖ Clinical presentation o Mild, moderate, severe bleeding

o Hemorrhoids (piles)

veins

3. Recanalization of the

o

para-umbilical vein:

o

Para-umbilical vein in

the round ligament of

Superior & inferior epigastric veins

o Caput medusa & venous hum

the liver

4. Others: detected by ultrasonography or during operation: ❖ Abdominal viscera:

Abdominal wail or

o

Liver

retro-peritoneal tissues: 0 Diaphragm

o

Spleen

o Diaphragm or Kidney

o

duodenum & colon

o

•

Posterior abdominal wail

Clinical picture:

^ A. Symptoms Bleeding: i. Degree: Mild & asymptomatic.

o It should be searched for in every case of cirrhosis or hepatic bilharziasis in order to take prophylactic measures to prevent their first bleeding

B. Moderated bleeding & repeatedly causing iron deficiency anemia C. Massive bleeding :

o Hematemesis and melena due to rupture esophageal varices, congestive gastropathy or gastric erosions, o Hemorrhoids (Piles) rupture

11. Factors predisposing to bleeding from varices: A. Sudden rise of portal pressure due to exertion or straining B. Ingestion of hardly poor masticated food C. Spontaneous due to peptic ulceration of esophageal mucous membrane 2. Dyspepsia due to gastric congestion.

o N.B.: Portal hypertensive gastropathy: chronic congestive gastropathy with erosion causing bleeding,± varcies, and propranoloi is the best treatment.

3. Distention after meals due to intestinal congestion.

4. Dragging pain in the left hypochondrium due to abdominal enlargement secondary to huge spleen or ascites. 5. Symptoms of cause: liver cell failure manifestations or history of bilharziasis :may be present 6. Symptoms of complications e.g. hypersplenism, hepatopuimonary syndrome & portopulmonary shunt.

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬ 51

1. The Liver:

o In infra hepatic causes: the liver is usually normal & not palpable o In intrahepatic causes(mainly cirrhosis & bilharziasis): the liver is shrunken, firm, with sharp border, o In supra hepatic causes: the liver is enlarged, congested, soft and tender. 2. The Spleen:

o Splenomegaly due to portal hypertension and R.E. hyperplasia. o Splenomegaly may be associated with hypersplenism. 3. Ascites: If portal hypertension is associated with hypoalbuminaemia. 4. Caput medusa : dilated veins radiating from the umbilicus 5. Venous hum:

o Soft systolic murmur auscultated between the umbilicus and xiphistemum o Due to passage of blood in the para-umbilical vein 6. Signs of cause e.g. liver failure: may be present. ❖ Complications :

1. Variceal bleeding & congestive gastropathy leading to hematemesis, melena & anemia 2. Ascites: if there is associated hypoalbuminemia.

3. Hepatic encephalopathy: due to passage of toxins through porto-systemic shunts. 4. Hypersplenism: pancytopenia.

5. Hepatopulmonary syndrome & portopulmonary hypertension Investigations I.

Detection of esophageal & gastric varices:

A. Barium swallow. B.

Endoscopy: Value of endoscopy in varices :

1.

Detect: early esophageal varices, gastric varices, signs of impending rupture, active bleeding and its site

2.

o

Grades of esophageal varices : Grade I: varices can be depressed by endoscope Grade II: varices can not be depressed by endoscope Grade III: confluent varices around the circumference of the esophagus

o

N.B.: Cherry-red spots predicts a high risk of bleeding

o o

3. H

1. 2.

Treat: sclerotherapy or banding of varices. Visualization of the portal system: Ultrasonography & computerized tomography. Percutaneous transsplenic (or trans hepatic) portal venography

o

A radio-opaque material is injected via the spleen into the portal circulation.

3.

Digital subtraction angiography

III

Estimation of portal pressure: Percutaneous intrasplenic pressure:

1. o

o

2. o

The pressure is estimated through a needle introduced into the spleen. It is increased in pre and post sinusoidal causes. Hepatic vein catheterization (wedged pressure): A catheter is introduced through an arm vein into the SVC,IVC, hepatic veins and pushed till it is wedged in hepatic sinusoids.

o

This method measures the sinusoidal pressure.

o

The portal pressure measured by this method is increased in postsinusoidal and decreased in pre-sinusoidal causes.

IV

Evaluation of the liver condition:

1. Liver function tests. 2.

Liver biopsy.

52

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Treatment

I. Preventing the first bleeding (primary Prophylaxis): 1.

Beta-blockers:

o o a. b. c.

Propranolol is the standard method for primary prophylaxis. It significantly decreases the incidence of bleeding variees through lowering the portal pressure by: Decreasing the cardiac output. Blocking the vasodilator receptors on the splanchnic arterioles—»■ splanchnic vasoeonstriction The dose is 80-160 mg /day.

2.

Band ligation:

o

This is done if P- blockers cannot be used due to contraindication e.g. bronchial asthma.

rmm.

II. Management of Bleeding Variees: A. General measures for hematemesis:

Pantoprazoll

1. 2. 3. 4. 0 5. 6.

Sodium for lnjec!io|;

Hospitalization & ABC. l.V line, resuscitation: use fresh blood transfusion to have little ammonia to prevent encephalopathy Wide bore gastric tube & washing. Drugs : IV vitamin K, PPIs (pantoprazole) or H2 blockers Sedatives & narcotics are better avoided if necessary, use oxazepam ( not metabolized in liver) Urgent endoscopy to define site of bleeding Measures to prevent encephalopathy: see liver failure

jjmocfarote cei viji

SlMlli

I

ItrlBiimnoat InluitonOill viBl-Ohci'd

4 poillon

1 B. Drugs: o

1.

This is used till sclerotherapy or banding are available or in combination with them or after their failure. Vasopressin analogues ; iGLYPRESSIN' i. Vasopressin (Pitressin) Action: vasoeonstriction of visceral arterioles will lead to diminished portal pressure Terlipressin acetate and so will decrease hemorrhage.

B. C.

1 ma/5 ml

Administration: 0.2 up to 0.8 U/min infusion Side effects: Blanching, colic, diarrhea & vomiting

for l.V injection

D. Contraindications: o o o

Ischemic heart diseases; as it causes spasm of the eoronaries, so the addition of nitroglycerine to protect the heart Hypertension: as it increases peripheral resistance. Pregnancy: as it cause contraction of the uterus. ii. Terlipressin (glypressin) A synthetic derivative with the same action of vasopressin (pitressin) with less side effects It is given 2 mg/4 hours intravenously till hemorrhage stops then 1 mg/4hours for another 24 hrs. Synthetic Somatostatin : Octreotide (Sandostatin) This is a synthetic growth hormone release inhibiting factor (GH-RIF) It has the same effect of terilpressin but with no side effects. The dose is 50 pg bolus followed by infusion of 50 pg /hr for 48 hrs.

C. Balloon tamponade: Sengstaken-Blakemore tube

o o

This is used if sclerotherapy or banding are not available or after failure of sclerotherapy, banding or pharmacological treatment, The variees are compressed using Sungestaken-Blackemor tube

o

This is a 3 lumen tube:

1. One for gastric aspiration or feeding. 2. The second for inflating gastric balloon (by 100 ml water). 3. The third for aspirating fluids in the oesophagus,

o o a. b.

The tube is put for a maximum of 48 hours. Complications: Esophageal ulceration. Aspiration, pneumonia & lung abscess .

balloon

Gastnc balloon

Gastric

aspiration

Esophageal balloon

Gastnc

balloon

53

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

D.Endoscopy: endotherapy; J

^■■11 'W^l^

1. o o

2.

Injection sclerotherapy : Intra or perivariceal injection of sclerosing material through an endoscope can stop bleeding in 90% of cases. The currently used sclerosant is ethanolamine oleate. Injection of tissue adhesive (Glue):

o This is a material that sticks to the tissues & so prevents bleeding, o It is used for injection of gastric varices & big oesophageal varices. 3.

o The used material is called histoacryl blue. Band ligation: o A special device & rubber bands are used to strangulate the varices. o This stops bleeding & causes variceal necrosis & fibrosis. o It is difficult to use it if there is excess bleeding. D. Catheters: Hepatic vein

1. Transjugular Intrahepatic Portosystemic Shunt (TIPS):

o A special device is introduced through the jugular vein to the liver to put a stent communicating between the inflow portal vein and the outflow hepatic vein, o This decreases the portal pressure & stops bleeding. 2. Transhepatic variceal sclerosis :

o o

Catheter is introduced transhepatic into portal vein Left & short gastric veins are selectively catheterized and injected E. Emergency Surgery (rarely used):

1. Ligation of bleeding varices.

2. Esophageal transection using the staple gun. 3.

Portal-caval shunt.

III. Management of the patient after bleeding: A. B,

Drugs: Propranolol. Endoscopy : Injection sclerotherapy:

Injection is repeated weekly till varices disappear. o

2. 3. C. 1.

Then follow up & re-injection at wider intervals. Injection of tissue adbesives for gastric varices & large esophageal varices. Band ligation of esophageal varices Surgery : To treat varices : Vasoligation

2.

To lower the portal pressure: porto-systemic shunt (shunt operation

o

Portacaval shunt.

Distal splenorenal shunt

54

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Hepatic Bilharziasis (Hepatic Schistosomiasis)

❖ Etiology : 1. The ova :

A. Schistosoma Mansoni: responsible for the majority of the cases because of easy access to the liver. B. Schistosoma Haematobium: responsible for the minority of the cases because of difficult access to the liver through vesicomesenteric anastomosis. 2. Distribution: more common in Delta region where S. mansoni is prevalent. 3. Incidence: more common in males, usually between 10 & 40 years

Pathogenesis

o Bilharzial ova reach liver through portal vein tributaries —> lodged in portal tracts ^ inflammatory reaction (granuloma) —> periportal fibrosis around the portal veins^ pre - sinusoidal portal hypertension, o In pure schistosomiasis: there is ONLY FIBROSIS, no cirrhosis & no liver cell failure. o In mixed pathology: many cases of hepatic schistosomiasis are associated with viral hepatitis, especially HCV, (mixed pathology) resulting in: cirrhosis & liver ceil failure Clinical picture: I.

Symptoms:

o Early cases: asymptomatic or symptoms of intestinal bilharziasis. o

Late cases:

1. 2. A. B.

Symptoms of portal hypertension e.g. bleeding esophageal varices. Symptoms of liver cell failure: Absent in pure hepatic schistosomiasis. Present in mixed pathology.

II. i.

1. o o 2. 3. 4.

Signs : General signs:

Signs of liver cell failure: Absent in pure hepatic schistosomiasis. Present in mixed pathology. Signs of nutritional deficiency. Signs of infantilism. Signs of bilharziasis in other areas: bilharzial cor pulmonale.

ii. Abdominal signs: A. Diseases is classified into 4 stages : ■ Spleen ■ Stage ■ Liver 1. o Hepatomegaly o Splenomegaly (portal 2. hypertension) & may o Shrunken liver 3.

reach a huge size.

4.

■

Others

o

Ascites due to associated hypoalbuminemia.

B. Distended abdomen with signs of chronic increase in the intra-abdominal pressure: o o

Umbilicus is shifted downwards, everted ± umbilical hernia Wide subcostal angle

o

Divarication of recti

C. Dilated veins around umbilicus(Caput medusa)& venous hum in portal hypertension. ❖ Causes of associated hypoalbuminemla: 1. Decreased intake: nutritional deficiency due to poverty.

2. Decreased absorption: malabsorption due to intestinal congestion. 3. Decreased production: due to associated eirrhosis in mixed pathology. 4. Increased loss:

A. Bleeding esophageal varices

B. Protein losing enteropathy: Congestive enteropathy & Colonic polyps.

55

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Investigations: 1. a. b. c. d. 2. o 3.

Investigations for diagnosis of schistosomiasis: Stool & urine analysis: for schistosoma ova. Sigmoidoscopy with rectal & colonic biopsy. Serology & Skin tests: for Schistosoma antibodies. Liver biopsy: shows the typical granuloma & periportal fibrosis. Investigations for diagnosis of portal hypertension: Upper GI endoscopy: for esophageal varices. Investigations for liver function tests: o Normal in pure hepatic schistosomiasis. o Affected in mixed pathology (as chronic liver disease) o Hypoalbuminemia may be present. 4. Investigations for liver imaging: o Abdominal ultrasonography & CT ❖ Treatment :

1. Treatment of active schistosomal infection:

o Anti-bilharzial drugs especially Praziquantel. 2. Treatment of portal hypertension. 3. Treatment of liver ceil failure in cases of mixed pathology e.g. treatment of associated viral hepatitis.

56

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Amebic hepatitis & amebic liver abscess

❖ Etiology:

o Complication of amebic dysentery, due to spread of vegetative forms of entamoeba histolytica from colon to liver via portal tract ❖ Pathology: 1.

Proteolytic enzyme :

o

Produced by entamoeba histolytica causing autolytic necrosis of liver cells, leading to acute amebic hepatitis

2. A.

Amebic liver abscess: occurs when liquefaction & coalescence occurs Number: usually single

B. Site :

Upper anterior part of right lobe (stream line or margination theory, since entamoeba histolytica is present o

C.

mainly in the caecum & right colon —> transported along superior mesenteric vein ^ right branch of portal vein) Rarely left lobe affection Wall: irregular, contains amebic cysts

D. Content:

Pus is chocolate brown in color with necrotic material(anchovy sauce)= hemolysed RBCs & necrotic tissues E. Fate: o o

o o

Natural Cure : if abscess rupture via colon Chronicity Secondary pyogenic infection Spread Clinical picture:

I. Symptoms: 1. History of intestinal amebiasis 2. Toxemia: Toxic facies, pale, fever with rigors , headache, anorexia, maiaise ■ | cancer risk

J,Sex hormone-

Pathology : A. Gross picture: o The tumor may be a single mass or multiple nodules or may be diffusely invasive B. Microscopic picture:

o

Trabeculae of will differentiated malignant cells resembling hepatocytes and invading the BVs.

C. Spread: o Coeliac LNs, peritoneum, lung and bone ❖ N.B.: Fibrolamellar carcinoma of the liver:

o Occurs in young age with no risk factors e.g. cirrhosis o It usually presents by chest pain o Negative a fetoprotein o Better prognosis than hepatoma

Clinical picture:

Symptoms : Asymptomatic. Discovered accidentally during abdominal examination, abdominal US or CT done for unrelated condition. Pain in the hypochondrium or epigastrium with peritoneal invasion Criteria to suspect HCC in patient with liver cirrhosis: Rapid deterioration of cirrhosis patients

I,

1. o

2. 3. o

Refractory ascites & encephalopathy Paramalignant syndrome manifestations e.g. Polycythemia & Hyperthyroidism Signs: II. 1. General: low grade fever, anorexia,jaundice and cachexia

o

4.

2. Abdomen: o o

3.

Enlarged, irregular & tender liver. Malignant ascites Metastasis to brain, bone & lung.

59

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

*t* Differential diagnosis of hepatic nodule : 1. Abscess: amebic or pyogenic 2. Adenoma

3. Hepatoma, Hemangioma, Granulomas 4. Fibrolamellar carcinoma

5. o o o o

Focal nodular hyperplasia (FNH): Small hepatic nodules unassociated by fibrosis. It has been related to connective tissue diseases, blood diseases and steroids, It presents as abdominal mass and diagnosed by biopsy, Hepatocellular carcinoma may complicate the condition.

❖ Investigations : 1. Liver function tests :

2. o o 3.

o t ASL, ALT o t ALP o t Alpha-feto protein > 500 ng/ml o t Des-gamma-carboxy prothrombin Imaging : Abdominal US or abdominal CT: showing hypodense lesion MRI can differentiate benign from malignant tumors Liver biopsy under UC, CT or laparoscopic guidance: the surest. Treatment:

UKrsseund probe on shin

hepatic artery catheter

Radio freciueney eblaUon probe

inserted tluou^ skin into liver and tumor

doxorublcin(DOX) formulation

Surgical resection: If the tumor is confined to one lobe and in the absence of cirrhosis

Trans arterial chemo-embolization of hepatic artery: By gelatin foam with/without injection of chemotherapeutic agent(Chemo-embolization) e.g. Doxorubicin or Mitomycin C. 3. Percutaneous ablation :

A, Percutaneous ethanol injection into the tumor : in tumors less than 2 cm B. Thermal ablation with radiofrequency 4. Liver transplantation:

o In patients with small(< 5 cm)or small multiple(3 nodules each < 3 cm)not amenable for resection or in cirrhotic liver.

60

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Hepatic transplantation

"t* Indications

❖ Patients suffering from irreversible, progressive liver disease for which there is no acceptable alternative therapy e.g.:

1. Acute fulminant liver failure

End stage liver disease e.g.: Alcoholic cirrhosis

Post hepatic cirrhosis

Biliary cirrhosis : Primary biliary cirrhosis & primary sclerosing cholangitis Budd-Chiari syndrome.

Metabolic cirrhosis: Wilson's disease, Hemochromatosis & Alpha one antitrypsin deficiency 3. Congenital biliary atresia 4. Hepatocellular carcinoma.

Portion ofdonor's liver to be

transplanted

Contraindications :

Recipient's liver removed

1. Active sepsis. 2. Active alcohol abuse 3. AIDS.

4. Advanced cardiopulmonary disease. 5. Cholangiocarcinoma. 6. Metastatic malignancy.

Donor's liver

transplanted in recipient ❖ Operations: 1. Cadaveric liver transplantation: liver of recently died donor is used. 2. Split liver grafts transplantation:

o Because of the difficulty in obtaining small donor liver for young children & because of shortage of donors, the donor's liver is split into 2, so can serve 2 patients instead of one. 3. o o 4. o

Living related transplantation: Part of a relative's liver is transplanted to the patient. The results are comparable to whole liver transplant but there is risk for the donor. Xeno-transplantation: Transplantation of animal liver to man has been the subject for research, but no solid results are available till now Immunosuppression :

o

Done by 3 drugs: azathioprine, prednisone & cyclosporin

Complications: 1. Infections.

2. Primary graft non-function. 3. Graft rejection. 4. Drug-related complications. 5. Disease recurrence.

❖ Prognosis :

o 80% long year survival

61

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Drugs induced liver injury 1. Obstructive (cholestatic) Jaundice :

o Chlorpromazine, Contraceptive pills , Chemotherapy o Oral hypoglycemic drugs e.g. Chlorpropamide o

Anabolic steroids 2. Acute liver cell failure

rfj

3..Chronic liver cell failure Chronic hepatitis

❖ Etiology :

❖ latrogenic : drug induced liver injury : A. Alcohol & INH

B. Acetaminophen (Paracetamol)(>10 gm i.e. > 20 tab)

B. Alpha-methyl dopa

C. Anesthetic : Halothane

C. Nitrofurantoin

C. Amiodarone & methotrexate

D. Phosphorus, Carbon tetrachloride, DDT (Dichlorodiphenyl-trichloroethane) 4. Fatty liver :

o Alcohol, Amiodarone, Corticosteroids, Contraceptive Pills, Valproic Acid & Tetracycline 5. Veno-occlusive syndrome : Chemotherapy 6. Budd-Chlari syndrome : Contraceptive pills 7. Neoplasm of liver: B. Hepatoma

A. Hepatic adenoma o

Anabolic steroids

o Contraceptive pills

C. Angiosarcoma

o Androgens & estrogen o Arsenical compound o Pesticide spray o Anabolic steroids o

Aflatoxin

8. Granulomatous drug hepatitis: allopurinol, phenylbutazone, sulfonamides. Causes of palpable liver without hepatomegaly: 1. Down displacement of diaphragm e.g. emphysema 2. Subdiaphragmatic lesion e.g. subphrenic abscess 3. Riedel's lobe

4. Occasionally in normal persons with visceroptosis

Causes of enlarged tender liver :

1. 2. 3. 4.

Malignancy Inflammation : acute fatty liver Infection : amebic hepatitis & abscess , viral hepatitis, pyogenic abscess Congested liver : same causes of cardiac cirrhosis Causes of nodular liver ;

1. 2. 3. 4.

Malignancy Bilharzial with coarse nodularity Post necrotic cirrhosis (post hepatitis) Syphilis Gumma (hepar lobatum)

5. Hydatid disease

Causes of arthropathy with liver disease: 1. Viral hepatitis : arthralgia in HBV & HCV

2. Chronic hepatitis due to autoimmune hepatitis 3. Hemochromatosis ; chondrocalcinosis & pseudo gout 4. Wilson's disease : may be bone fragmentation at elbow & wrists

62

"Mt t i

Liver cirrhosis

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Differential diagnosis

1

Splenomegaly

Hepatosplenomegaly

Hepatomegaly

1. Infections A. Bacterial

o Typhus

o Typhoid

o

o Tuberculosis (Miliary)

o

Anthrax

Subacute bacterial

o

endocarditis

o Leptospirosis o Syphilis o

o Pyogenic cholangitis o Pylephlebitis o Portal pyemia

Brucellosis

Septicemia

1

B. Viral o Viral hepatitis o IMN (EBV) o

HSV,HIV

o

CMV

o

Malaria

o

Bilharziasis

1

C. Others o Amebic hepatitis & abscess

o Hydatid cyst o

Kala azar

o Toxoplasmosis o

Leishmaniasis

o

Fasciolosis

2. Hematological A. Anemia

o

Plummer-Vinson

o Hemolytic anemias especially thalassemia

syndrome

major o Megaloblastic anemia: pernicious anemia

1

o

Sickle cell anemia

B. Malignancy o Primary splenic tumors

o

Essential

thrombocytosis

o

Myelofibrosis

I o Primary hepatic tumors: hepatocellular

o Leukemia & lymphoma o Polycythemia vera o Waldenstrom's macroglobulinemia o

carcinoma

Metastatic tumors

3. Metabolic o

o CHO : glycogen storage disease e.g. Von Gierke disease & galactosemia o Lipid : lipoid storage disease e.g. Gaucher's

Rickets

1 o Fat: causes of fatty liver e.g. DM & obesity o

disease & Niemann-Pick disease

Mineral : Wilson's disease & Flemochromatosis

o Protein : amyloidosis o Porphyria 4. Collagen disease o

Rheumatoid arthritis: Still's disease &

o

SEE, PAN, Sarcoidosis

Eelty's syndrome

5. Circulatory o

All causes of

portal hypertension

o Supra hepatic causes of portal hypertension i.e. same causes of cardiac (congestive) cirrhosis.

| o Supra hepatic causes of portal hypertension i.e. same causes of cardiac (congestive) cirrhosis

6. Congenital o Cysts of spleen

| o

Riedel's lobe

o Polycystic disease

1

7. Others : o Same causes of obstructive jaundice

o Acromegaly o Primary thyrotoxicosis o Primary biliary cirrhosis

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬ 63

Liver affection in systemic diseases

1. Cardiovascular: Hepatic congestion in right sided heart failure 2. Pulmonary:

o o o o 3.

Hepatomegaly in military TB Hepatic displacement in emphysema Alpha one anti-trypsin deficiency Hepatic cysts in cystic fibrosis Renal: Hepatitis with hemodialysis

4. Rheumatological:

o Hepatomegaly with SLE, Filty's and Still's syndromes,

o Primary biliary cirrhosis in Sjogren's syndrome and CREST syndrome 5. Hematological:

o Portal or hepatic veins thrombosis in polycythemia vera, protein C&S deficiency o Hepatomegaly with hemolytic anemia, leukemia and lymphoma 6. Endocrinai:

o

Fatty liver in DM

o Hepatomegaly in acromegaly, primary thyrotoxicosis and myxedema 7. Metabolic:

o Liver cirrhosis in hemochromatosis and Wilson disease

o Hepatomegaly in glycogen storage diseases Systemic affection in liver diseases 1. CNS: o o o

Liver cell failure hepatic encephalopathy Fulminant hepatic failure ^ cerebral edema Wilson disease extrapyramidal manifestations

2. Ocular:

o

Liver cell failure ^jaundice Wilson disease Kayser-Fleischer ring

o

Primary biliary cirrhosis ^ Sicca syndrome

o

3. Cardiovascular:

o Liver cell failure^ hyperdynamic circulation o Obstructive jaundice —>■ sinus bradycardia o Amebic liver abscess—>• amebic pericarditis 4.

Chest:

o o o

Liver cell failure^ cyanosis Autoimmune hepatitis^ interstitial fibrosis Ascites & amebic liver abscess^ right sided pleural effusion

5.

Blood:

o o o

Liver cell failure —> anemia, coagulopathy, thrombocytopenia Autoimmune hepatitis & Wilson disease-^ hemolytic anemia HBV & HCV—> Aplastic aneamia

6.

Renal:

o o o o

Liver cell failure ^ hepatorenal syndrome Viral hepatitis —> glomerulonephritis HBV Membranous glomerulonephritis HCV —> Membranoproliferative glomerulonephritis

7. Rheumatology: o HBV & HCV^ arthropathy &PAN

o

Autoimmune hepatitis & Iry biliary cirrhosis^ arthropathy

8.

Endocrine:

o

Liver cell failure : see before.

o

Autoimmune hepatitis & 1 ry biliary cirrhosis ^ thyroiditis

o

Hemochromatosis —> DM

o

Hepatoma —»■ polycythemia

9.

Skin:

o

Liver cell failure —^ look before

o Hemochromatosis ^ hyperpigmentation o Primary biliary cirrhosis —> itching

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬ 64

Diseases of the gall bladder

Gall bladder stones

Etiology:

I.

Cholesterol stones: 75% caused by:

A. Stasis of bile due to impaired gall bladder emptying: o Pregnancy, total parenterai nutrition o DM & fasting B. Bile salt: cholesterol ratio: 1. Excess cholesterol in bile: o

Obesity, high dietary fat, rapid loss of body weight, pregnancy, female gender and old age.

Decreased bile salts in bile e.g. liver disease Pigment stones: 25% II.

2.

1. Black pigment stones: due to chronic hemolysis. 2. Brown pigment stones: due to:

A. Stagnation of bile in common bile duct e.g. by stricture.

B. Infection: bacterial P- Glucuronidase splits conjugated bilirubin to its free form precipitates as calcium bilirubinate Clinical picture: A. Incidence:

More common in fatty, fertile, fair, females above forty. Asymptomatic(80% of cases), discovered accidentally by abdominal US. C. Pain: recurrent attack of biliary colic : 1. Site : right hypochondrium or in the epigastrium o

B.

2. Radiation : right shoulder 3. Onset: sudden onset

4. Course: increase in severity over 30 minutes 5. Character: colicky pain

6. Duration : < 6 hours, if more than 6 hours this indicates complications 7. 8. 9. D.

Associated symptoms: nausea & vomiting Precipitated by : fatty meals Relieved by : antispasmodics Symptoms of complications

N.B.: Fatty food intolerance, dyspepsia and flatulence which was referred to as gall stone dyspepsia are now not considered to be due to gallbladder stones and referred to as non-ulcer dyspepsia. ❖ Complications: A. Complications in the gall bladder: 1. Obstruction of cystic duct of neck of gall bladder

Biliary

o Mucocele or pyocele of gall bladder ± gangrene & perforation (peritonitis) o Acute calcular cholecystitis 2. Porcelain gall bladder (precancerous) 3. Chronic calcular cholecystitis

4. Carcinoma of gall bladder B. Complication caused by migration of stones :

Chotecysthis Mucocele

1. Migration to common bile duct (Choledocholithiasis): o Obstructive jaundice O Cholangitis

cirrhosis

Obstructive jaundice Cholangitis

Carcinoma Pancreatitis

o Acute pancreatitis (obstruction at lower end of CBD or pancreatic duct) o Biliary cirrhosis

2. Migration to duodenum through fistula :

o Leading to gall stone ileus (impaction at terminal ileum ^ intestinal obstruction) 65

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Gallstone Qeus

❖ Investigations ; 1. Abdominal X-ray:

o Only 10 % of gall bladder stones are radiopaque and the majority is radiolucent o They lie in front of the spine in lateral view 2. Abdominal ultrasonography, CT scan and MRCP: diagnostic Treatment:

A. Asymptomatic gall bladder stones :

o No treatment except if elderly diabetic patient or porcelain gall bladder B. Symptomatic gall bladder stones :

o Cholecystectomy either open or laparoscopic is the standard treatment o Symptomatic treatment e.g. biliary pain; analgesics (pethidine) ❖ N.B.:

o Extracorporeal shock wave lithotripsy & Medical dissolution (ursodeoxycholic acid): nowadays j, due to less efficacy. tfc,..;.

.y nflammation

Distended common

causing

hepatic duct

obstruction

Cholecystitis

bfCBD

Acute ^

Quiescent

Impacted gal^tone

cystic

Distended

gallbladder Stone blocks

Perforation

cystic duct. Chemical and bacterial

inflammation

Mirizzi syndrome Stone drops back into

gallbladder in

7 days or so

Resolution In 2 months or so

Fever & Leukocytosis

Jaundice

Nausea & Vomiting Anorexia Chronic cholecystits

Pain

- Right Upper Quad or Right Shoulder ■ May Radiate To Back

• Increased with Deep BmMlh

Fat Intolerance

Feeling of Fullness Abdominal Distention

Carcinoma

66

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Cholecystitis Acute cholecystitis

Chronic cholecystitis

❖ Etiology

1 I. Acute calcular cholecystitis 90 "/» : o Stones in the cystic duct

1. o o o

2. Acute non-calcular cholecystitis : 10 %

o Bacterial infection (salmonella-cholera-streptococcal) o Part ofsystemic process(IB, sarcoidosis. Syphilis) o

Organism: E. coll (the commonest) Streptococcal faecalis Typhoid

2. Route of infection :

Parenteral nutrition

o Portal, systemic & ascending infection 3. Pathological types : o Chronic calculus (the commonest)

o Severe sepsis & burn o After abdominal surgeries

o

Chronic non-calculus

❖ Symptoms

1 A. Incidence:

o Usually in females,fatty, fertile, fair, above forty

B. General: fever, anorexia, nausea & vomiting

b) Fatty dyspepsia: nausea, abdominal distention & eructation after fatty meals

C. Biliary pain :

c) Recurrent attacks of biliary pain due to stone migration in the eystic duct

1. Site : Right hypochondrium or in the epigastrium 2. Radiation : usually localized but maybe referred to: o Right shoulder o Interscapular

o Retrostemal Chest pain (cholecystic heart) 3. Onset: sudden

4. Character : starts as diffuse colicky pain then it becomes dull aching pain 5. Precipitated by: fatty meals 6. ± relieved by : antispasmodics Mirizzi syndrome:

Gallstones impacted in Hartmann's pouch causing obstruction of the cystic duct & resulting in inflammation, edema & compression of CBD ^ obstructive jaundice ❖ Signs I.

Generally: o Fever, rigors & tachycardia o

II.

± Jaundice

Locally : signs of acute abdomen

1.

Inspection : J, movement Palpation : Tenderness and rigidity

2.

Murphy's sign :

A.

B.

o

Deep inspiration or cough during subcostal palpation of right upper quadrant causes pain and inspiratory arrest

3.

Boa's sign :

o

Area of reflex hyperesthesia between 9-11 rib posteriorly in right scapular line

Palpable mass may be felt: o G.B. may be distend with mucus(mucocele) or pus(empyema) C. Percussion : negative D. Auscultation : hypoactive bowel sounds

4.

E. Others: o

❖ Differential diagnosis: o Other causes of acute dyspepsia (see GIT) o Other causes of acute abdomen (see GIT) ❖ Complications 1) Acute exacerbation in top of chronic cholecystitis 1. Chronic cholecystitis

2. Gallbladder stones complications (see before)

3. Chronic septic focus : Toxic arthritis & myositis

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬ 67

❖ Investigations 1.

1. Blood: LFT: if f direct bilirubin & ALP —♦ stone in

Blood:

CBD —> ERCP needed

o Moderate leukocytosis o AST, ALT, bilirubin & alkaline phosphatase: may be

2. Plain X-ray : 10 % are radiopaque 3. Abdominal US (investigation of choice): thick GB

elevated.

wall & stones

2. Plain X-ray : 10% are radiopaque 3. Abdominal US (investigation of choice): show thick

4. Cholecystography :

o Oral (tetraiodo phenolphthalein) or IV (Biligraphin)

GB wall & stones

o

Radiolucent stones will appear as Filling defects

❖ Treatment

I.

Medical (conservative) treatment:

I.

Medical (conservative) treatment:

❖ Indication :

1. General:

Non-calculus type Contraindication of surgery By: Reduction of weight

o

Rest in bed in modified Fowler's position Stop oral feeding & give IV fluids Nasogastric tube suction

2.

Relief of pain :

1.

o

Pethidine & hyoscine

2.

o

Morphine is contraindicated as it cause spasm of

3.

Avoid fat, heavy metals & alcohol Antispasmodics : hyoscine

sphincter of oddi

4.

Cholagogues e.g. Bile salts, Mg sulfate & Olive oil.

Antibiotics:

5. Medical dissolution of stones:

o o

o

❖

Third generation cephalosporin or a quinolone &

A. Indicated in :

Metronidazole is usually given in combination

o

II. 1.

o

Surgical treatment:

Small non calcified stones in a functioning GB Contraindication of surgery

o

Early(Emergency)cholecystectomy in :

B. Aim :

Empyema Emphysematous case

C.

increase bile salt pool in GB (reduced in gall stones) Drug : Ursodeoxycholic acid Surgical cholecystectomy indicated in : II

o

Perforation

Failure of resolution after medical treatment for 3 days. In complications

1.

Calculus type :

o

Especially when episodes of pain are recurrent

Delayed cholecystectomy after 6 weeks of conservative

2.

Non calculus type :

treatment

o

If medical treatment failed after 6 months

3.

In complications.

Bile duct system

Liver Right hepatic duct Left hepatic duct

Common hepatic duct

Cystic duct Common bile duct

Gall Bladder

Sphincter of Oddi

Ampulla of Vater Pancreatic due Pancreas

Duodenum

68

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Acute pancreatitis

eiuct lfo gradual loss of both

In biliary tract disease, attacks of pancreatitis are caused by: Transient impaction of CBD stone in the ampulla of vater ^ regurge of bile into pancreatic duct with increased intraductal pressure—► t

endocrine & exocrine functions Inflammation & fibrosis of the head of the

intracellular calcium & activation of pancreatic proteases:

Chymotrypsin ^ tissue inflammation, edema Phospholipase A2 & lipase : necrotizing pancreatitis

pancreas —> obstruct lower part of the CBD —> obstructive jaundice

Fat necrosis: split fat in the omentum & peritoneum into glycerol & fatty acids

Fatty acids binds with calcium forming insoluble calcium soap (hypocalcaemia & saponification) ^ white spots of fat necrosis Elastase dissolves elastic fibers of blood vessels ^ hemorrhagic pancreatitis

The proteolytic activity of liberated enzymes produces kallikrein- kinin and other mediators which are responsible for multiple organ dysfunction syndrome (MODs) e.g. hemodynamic and respiratory effects (SIRS)

Mortality rate with hemorrhagic pancreatitis : 10 to 50 %. ❖ Clinical picture 1. Pain :

o Site: severe abdominal pain especially in the epigastrium o

Radiation : to the back

o

Onset: sudden , Course: crescendo

o Relieved by leaning forward = Prayer's position (^compression on sympathetic nerves)

o Associated symptoms: nausea & vomiting, o Differential diagnosis :from acute abdomen

1. Recurrent attacks of abdominal pain as acute pancreatitis but very mild & interrupted 2. Endocrine pancreatic insufficiency (island cell destruction): DM 3. Exocrine pancreatic insufficiency (lipase and protease secretions are < 10% of the o

2. Shock due to :

A. Neurogenic due to pain

B. Vasoplegic : due to kallikrein release causing vasodilation C. Hypovoiemic :intraperitoneal loss & vomiting 3. Abdominal wall ecchymosis e.g.: A. Cullen's sign:

normal): Mal-absorption syndrome : steatorrhea & weight loss

4. SC fat necrosis (effect of released enzymes)

o Bruising around the umbilicus suggests intra-peritoneal bleeding

5. Cholestasis due to compression of CBD as it passes through the head of pancreas

B. Grey Turner's sign:

o Bruising in flanks area, suggests retroperitoneal bleeding. 4. Features of complications

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬ 70

❖ Complications I.

Local :

1. Pancreatic ascites

1. Pancreatic:

2.

Pancreatic pseudocyst.

Ascites, which may be hemorrhagic

3. Pancreatic cancer.

o

Pancreatic abscess

4.

o

Phlegmon (inflammatory mass).

5.

o

Biliary obstruction &jaundice. Obstruction of splenic vein.

Pseudocyst: it's collection of pancreatic secretion & inflammatory exudate within lining of inflammatory tissue rather than epithelium

o

o

(false eyst) Chronic pancreatitis

0

DM

2. Intestinal:

0

Paralytic ileus G.I. hemorrhage : hematemesis & melena : due to stress ulcer

3.

Hepatobiliary: obstructive jaundice & portal vein thrombosis.

o

II.

Systemic : MODs

Cireulatory failure (shock).

o

ARDS , Acute renal failure , DIC Hypocalcaemia (tetany)& hypoglycemia.

o o

❖ Investigations

I.

Laboratory investigations:

A.

bor diagnosis:

1.

1.

Serum amylase (nonspecific):

o

o

0 0

Raised (5 time greater than normal). Returns to normal within 2-3 days Effectively excreted in the kidney & in these cases there is increased urinary amylase : creatinine ratio > 30 %

0 o

I. Laboratory investigations: Serum amylase and lipase:

0

Frequently normal due to loss of pancreatic function.

t only in exacerbation of chronic relapsing pancreatitis

2. Endocrine function assessment:

Persistently elevated amylase indicates pseudocyst It may be elevated in other conditions; intestinal ischemia,

perforated peptic ulcer, ruptured ovarian cyst, renal failure, salivary

0

Oral glucose tolerance test: DM

3. Exocrine function assessment: A.

gland dysfunction and macroamylasemia.

Mal-absorption syndrome: fecal fat excretion > 6gm/day

2.

t serum lipase (specific):

B. Lundh's test::

0

Longer half-life & useful in delayed presentation

o

2.

For complications: CBC: leukocytosis 1 serum Ca^^

3.

LET: 1 bilirubin (due to compression of bile duct by the pancreatic

B. 1.

edema) 4. t Glucose (jinsulin) 5. For MODs e.g. ABO, KPT II. Imaging; 1. Plain X-ray abdomen: o Ileus, calcified gall stones & may be pancreatic calcification o Left sided atelectasis & pleural effusion. 2. Abdominal ultrasound: o

3. o

0 0

Tube positioned in the duodenum & collecting pancreatic secretion which is stimulated by IV secretin alone or with cholecystokinin.

o

Duodenal contents are collected for HC03

0

& enzyme concentrations. i HC03 and J, enzyme concentrations in

chronic pancreatitis II. Imaging: I. Ultrasound & CT: o

Abnormal pancreatic size, duct dilatation & may be calcification.

2. MRCP & ERCP:

Swollen pancreas, fluid collections, gallstones.

0

Contrast enhanced CT(more accurate): Visualization of pancreatic viability The presence of gas among necrotic tissue indicates infection. Involvement of the colon, blood vessels and other adjacent

May show abnormalities in pancreatic ducts

structures.

4. MRI & MRCP:

Can assess the degree of pancreatie damage and obstruction in the biliary tree. III. Diagnostic paracentesis: contains high amylase

0

71

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Treatment

I.

Conservative;

I.

Treatment of the cause

Conservative:

Relief of pain :

. Treatment of the cause e.g. stop drinking

3.

Pethidine (50-1 OOmg /4 hrs) but avoid morphine as it may cause spasm of sphincter of Oddi Replacement of lost fluid :

o

By IV fluids, plasma, blood (in hemorrhagic causes)

Use of narcotics may be associated with

4.

Monitored by vital signs, UOP &. GYP Rest of pancreas &, bowl:

addiction.

o

Nasogastric suction, nothing by mouth & give parenteral nutrition.

o

alcohol. 2.

Enteral nutrition starting by low fat diet should be initiated as soon as possible to avoid bacterial translocation. o

Somatostatin: J, pancreatic secretion

5. Resistance of infection : o

6. 7.

Antibiotic therapy e.g. imipenem in cases with pancreatic necrosis Respiratory care: oxygen mask or mechanical ventilation Reassessment after improvement:

o

ERCP sphincterotomy to remove the bile duct stones Management of complications(MODS)e.g. Platelet activating factor inhibitor e.g. Lexipafant

o

IV calcium infusion

o

8.

4.

II.

Analgesics for pain:

Celiac plexus block Management of diabetes: Cautious use of insulin as hypoglycemia is common in these patients because of the eo-existing deficiency of glucagon. For most patients, serum glucose 200-250 mg% is acceptable and need no treatment Management of steatorrhea: Oral pancreatic enzyme replacement (pancrelipase) H2-blockers: to reduce gastric acid secretion

II.

Surgical(Laparotomy): indications :

release of secretin.

Surgical or endoscopic management:

o Uncertain diagnosis o Infected pancreatic necrosis

o Management of pseudocysts o Common bile duct or pancreatic stricture

o Complications ❖ Prognosis in acute pancreatitis:

❖ Ranson's criteria: Poor prognostic criteria within the 1st 48 hours B. Within the 1st 48 hours

A. On admission

o Ca^"^ < 8mg/dl

o Age >55 years old 0 Blood glucose > 200 mg/dl o Pa02 < 60 mmFIg 0

AST>250 1U/L

o

LDH>350 1U/L

o

Base deficit > 4 mmol/L

o Sequestration fluids(CVP needs)> 6 L

0 TEC > 16,000 mm^

o

HCTfall>10%

o BUN > 50 mg/dl Score & mortality : o

Score

o

mortality

o 0

0 to 2

o

3 to 4

o

5 to 6

o

7 to 8

2%

o

15%

o

40%

o

100%

72

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Pancreatic carcinoma

I.

Exocrine tumors :95 % of cases

II.

A. Arise from the duct epithelium e.g.

B. Arise from the acinar cells

Ductal adenocarcinomas : 90 % of

e.g. Acinar cell carcinoma

o

Endocrine tumors :5 % of cases

Islet cells tumors (neuroendocrine tumors): see endocrine book

cases

i* Predisposing factors: I.

Incidence : more common in old age males

II. Predisposing factors : o Disease: Chronic pancreatitis.

o Drugs & toxins: Smoking & petroleum products on industrial occupations o

Diet:

■

High dietary fat: f risk

■

Fruits and vegetables are probably protective due to their high fiber content and vitamin C

■

N.B. Alcohol probably does not affect the risk.

♦♦♦ Pathoiogy:

❖ Types: A. Cancer head of pancreas :60 %

B. Cancer body & tail: 40 %

o 2/3 in head proper

o 1/3 in periampullary region ; ampulla of vater, duodenal papilla & lower end of CBD

❖ Origin :90"/o of pancreatic tumors are adenocarcinomas and arise from the duct epithelium ❖ o o o o

Spread : Direct to duodenum, CBD, peritoneum, stomach, liver, spleen, aorta & IVC Lymphatic to celiac LN, superior mesenteric LN, porta hepatis LN Blood: liver, lung, bone, brain An elderly man with rapidly Transcoelomic: peritoneal nodules, Krukenberg & malignant ascites

progressive painless jaundice

should be considered as cancer

Clinical picture: I

head of pancreas till proved otherwise.

Type of patient: old age male > 60 years old

1. o 2. ❖

A. Cancer head of pancreas: Malignant obstructive jaundice : Painless, progressive with severe pruritus Distended palpable gallbladder

N.B.: Courvoisier's sign: o Palpable GB with jaundice is highly suspicious of carcinoma of head of pancreas not due to GB stones which associated with chronic inflammation leading to fibrosis of the wall of gall bladder. 3. Malabsorption due to common bile duct obstruction leading to steatorrhoea 4. Pancreatic asthenia due to malignant cachexia &

B. Cancer body or tail: A. Epigastric pain referred to the back B. Asthenia with loss of weight(cachexia)& Anorexia. C. Metastatic lesion :

1. Thrombophlebitis migrans(Trousseau sign) 2. Enlarged Virchow LN: enlarged left supraclavicular lymph node (Troisier's sign) 3. Paraneopiastic syndrome e.g. Gushing syndrome 4. Hard irregular liver due to secondaries,jaundice, malignant ascites 5. DM in 30% of cases

6. Splenomegaly(10% of cases) due to splenic vein thrombosis

steatorrhoea

73

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Investigations : I.

Laboratory :

1. Laboratory evidence of obstructive jaundice & DM

2. Tumor markers as CEA (carcinoembryonic antigen) and CA19-9(carbohydrate antigen). o CA is more specific and more sensitive IT.

Imaging:

1. X-ray with barium meal showing ; o

Wide C curve of the duodenum

o Inverted 3 sign of Frostberg in periampullary carcinoma. 2. Triphasic spiral contrast enhanced CT: diagnostic 3. ERCP: diagnostic III.

Instrumental :

o Fine needle aspirate or tru-cut biopsy if there is difficulty in distinguishing cancer from chronic pancreatitis ❖ Biopsy is not needed if clinical evidence with elevated CA19-9 and hypodense lesion on triphasic CT are all present

Treatment

1. Surgical: Whipple operation : pancreaticoduodenectomy After surgery

Before surgery

Bile duct attached to small intestine

Gaitbladdef Bile duct

Stomach

Panaeas

Remaining pancreas Stomach attached to small intestine

attached to small intestine

Smalt intestine

o Surgical removal of the head of the pancreas also necessitates removal of the duodenum, proximal jejunum, gallbladder, and, occasionally, part of the stomach o

Done in localized tumors of the head.

2. Palliative :

o Stent in CBD to allow drainage o Bypass surgery e.g. choledojejunostomy o

Analgesia

74

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Topic

Page

o Dysphagia

1

o Dyspepsia (indigestion)

2

o Vomiting

4

o Diarrhea

5

o Constipation

7

o Acute abdomen

9

o GIT bleeding

11

o Intestinal polyposis syndrome & Protein Losing Enteropathy

13

o Esophageal Achalasia (cardiospasm)

14

o Gastroesophageal reflux disease(GERD)

16

o Gastritis

19

o Peptic ulcer disease(PUD)

20

o Functional gastrointestinal disorders

26

o Irritable bowel syndrome(IBS)

27

o Inflammatory bowel diseases(IBD)

29

o Malabsorption syndrome

32

o GIT infections : Intestinal Amoebiasis, Shigellosis, Bilharziasis

36

o Familial Mediterranean Fever(FMF)

38

o Intestinal Tuberculosis

40

o Tuberculous Peritonitis

41

o Intestinal ischemia

42

o GIT malignancy :Esophageal carcinoma, Gastric carcinoma, Colorectal

43

polyps & carcinoma o Carcinoid tumor

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

‫‪I‬‬

‫‪/‬‬

‫‪'/ /‬‬

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

JogjJ

Symptomatology Dysphagia ❖ Deflnition :

Oesophams

o Difficulty in swallowing due to impaired progression of matter from pharynx to esophagus. ❖ Etiology : I.

Pre-esophageal causes ;

A. Oral:

1. Painful dysphagia (odynophagia): stomatitis, ulcers, osteomyelitis ofjaw 2. Mechanical factors: ankyloglossia, fracture jaw B. Pharyngeal:

1. 2. o 3.

Painful causes : pharyngitis, tonsillitis Mechanical(more to solids): Abscess, Plummer-Vinson's syndrome, cancers & diverticulum. Nervous(more to fluid):

o True & pseudo-bulbar palsy, motor neuron disease, myasthenia gravis, polymyositis

o Globus hystericus : hysterical dysphagia characterized by a sensation of a painful lump in throat II.

Esophageal causes:

1. In lumen : FB

2. In wall:

Oest^hagus

o Functional disorders of esophagus : Achalasia & diffuse esophageal spasm o

Post corrosive stricture

o

Cancer esophagus

o

Zenker's Diverticulum

o Gastro-Esophageal reflux disease(GERD). o

Scleroderma

3. Compression from outside:

A. In neck : cancer thyroid, enlarged LN

B. In thorax : causes of mediastinal syndrome as goiter, masses (see chest) Approach to patient with dysphagia: A. History: 1. Age: o Post-corrosive in young age

o Cancer in middle and old age 2. Food :

o Dysphagia only to solids in mechanical causes o Dysphagia to both solids and liquids in motor dysphagia. 3. Duration & course:

o Transient & short duration : inflammatory o

Intermittent .• functional disorder

o

Progressive : cancer

4. Association:

o Nasal regurge in pharyngeal paralysis, o Severe loss of weight in cancer o Fleart bum in peptic stricture B. Examination:

o Neurological: for associated neurological disease o Neck: for thyroid enlargement C. Diagnostic procedures: o

Bariums wallow

o Endoscopy: exclude mechanical obstruction o Esophageal manometry studies for functional disorder

N.B.: The commonest causes of dysphagia: Cancer esophagus, Achalasia & Post-corrosive

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Dyspepsia (indigestion) Definition :

o Upper abdominal pain or discomfort related to meals o The discomfort maybe associated with : 1. Abdominal fullness

2. 3. 4. 5. 6.

Bloating (flatulence) Belching (eructation) Early satiety Epigastric pain & heartburn Nausea or vomiting. Etiology

A. Functional(non-ulcer) dyspepsia: o The most common cause for chronic dyspepsia

o GIT symptoms, stress related when no ulcer or structural GIT diseases are found o

The cause may present interaction of:

B.

1. Increased afferent visceral sensitivity 2. Delayed gastric emptying 3. Impaired accommodation to food 4. Psychosocial stressors Organic dyspepsia : almost all GIT & hepatobiliary diseases:

1.

Esophageai: GERD , cancer esophagus

2. Gastric: o o

Peptic ulcer disease, helicobacter gastritis, gastric carcinoma Gastroparesis in DM , hiatus hernia, gastric volvulus

3. Intestinal: o

4. 5. 6.

o o o 7.

Colitis, chronic appendicitis, lactose intolerance, malabsorption, parasites (e.g. giardia) Hepato-biliary: hepatitis & chronic cholecystitis Pancreatic: chronic pancreatitis & pancreatic carcinoma. Systemic: Fevers, pregnancy TB, DM,thyroid disease Heart failure, myocardial ischemia, renal insufficiency Food or drug intolerance: acute, self-limited :

A. Food:

o Overeating, eating too quickly, eating high-fat foods & eating during stress, o Drinking too much alcohol or coffee. B. Drugs: o NSAIDs e.g. Aspirin

o Aminophylline, Antibiotics(Metronidazole, Macrolides) o Corticosteroids, Digoxin, o

Iron & Narcotics

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Clinical picture:

A. History: 1. Functional(non-ulcer) dyspepsia o Psychological : Anxiety, depression e.g. recent changes in employment, social problems

2. Organic dyspepsia o Of the cause e.g. Heart bum in GERD,epigastric pain in peptic ulcer

B. Symptoms: 1. General symptoms: o

Abdominal discomfort

o

Abdominal fullness

o o o o o

Bloating (flatulence) Belching (eructation) Early satiety Epigastric pain & heartburn Nausea or vomiting.

2. WARNING SYMPTOMS: that warrant endoscopy or abdominal imaging: 1) 2) 3) 4) 5)

Persistent vomiting Constant or severe pain Concomitant weight loss Dysphagia Hematemesis or melena

C. Examination:

o To detect signs of serious organic disease e.g. cachexia, organomegaly, abdominal mass ❖ Investigations : 1. o o o

2.

Upper endoscopy: it is indicated in:

All patients > 45 years old with recent onset dyspepsia All patients with recurrent vomiting, weight loss, dysphagia, evidence of bleeding or anemia Failure of response to therapy Upper GIT barium radiography.

3. Abdominal US or CT. 4.

Ambulatory esophageal pH testing

Treatment 1

Treatment of functional dyspepsia:

A. General measures:

o Reassurance, psychotherapy o

Reduction in coffee, alcohol and caffeine

B. Pharmacological agents: b) Anti-secretory therapy a) Anti H.Pyiori

c) Prokinetic agents

d) Low dose of antidepressants

treatment

o Triple therapy

o H2 blockers or proton pump inhibitors

0 Metoclopramide

0 Nortriptyline

0 Improving symptoms in 5-15% of patients

0 Relieve epigastric pain &

0 Enhance gastric emptying 0 Improving symptoms in 60% of patients

0

heart bum

0 Improving symptoms in 10-20 % of patients

Moderate afferent

visceral sensitivity

2. Treatment of the organic dyspepsia: treatment of the cause.

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Vomiting

Systemic causes

Chemoreceptor trigger zone

Definition

o Expulsion of gastric content through the mouth o Vomiting passes by three phases, nausea, retching then vomiting

Vomiting Central

center

Vagal irritation

Etiology 1.

Reflex causes(vaga! irritation):

1. Naso-pharyngeal causes: foreign bodies, inflammation, tumor & induced vomiting. 2. Esophageal causes: achalasia, stricture & carcinoma. 3. Gastric causes: acute & chronic gastritis, peptic ulcer, cancer & pyloric obstruction. 4. Intestinal causes: acute intestinal obstruction, appendicitis.

5. Hepatic & biliary causes: acute viral hepatitis, acute cholecystitis & biliary colic. 6. Pancreatic causes: acute pancreatitis. 7. Ocular causes: acute glaucoma.

8. Cardiac causes: myocardial infarction & digitalis toxicity. 9. Renal causes: renal colic, acute pyelonephritis. 10. Gynecological causes: dysmenorrhea. II. Central causes (stimulation of vomiting center): 1. Medullary & cerebellar lesions. 2. Vestibular lesions: Motion sickness, Meniere's disease 3. Vascular: Migraine. 4. Drugs : Morphine 5. Psychic: visual, olfactory or gustatory. 6. Hysterical.

HI. Systemic causes(++ chemoreceptor trigger zone which in turn ++ vomiting center): 1. Hepatic & renal failure, Hyperparathyroidism , Hyper & Hypokalemia, Hyper & Hypoglycaemia. 2. Addison's disease , Acidosis & Alkalosis.

3. Drugs : Alcohol, Antiarrhythmics, chemotherapy, CCP, Digitalis Complications 1. Dehydration & malnutrition 2. Metabolic alkalosis & hypokalemia 3. Aspiration pneumonitis

4. Mallory - Weiss syndrome: hematemesis from mucosal tear in esophagogastric junction 5. Boerhaave syndrome : esophageal rupture Diagnosis : A. History: 1. Age & sex.

2. 3. 4. 5.

Time of vomiting. Associated nausea & abdominal pain (reflex). Associated headache & blurring of vision (++ I.C.T) Associated vertigo & deafness (vestibular). 6. Of biliary or renal colic & food intake. B. Examination of vomitus:

1. Odor: foul in malignancy & intestinal obstruction. 2. Mucus: chronic gastritis.

3. Bile: persistent vomiting below ampulla of Vater. 4. Blood: ulcer, cancer, or Mallory-Weiss syndrome C. Examination of different systems:

D. Special Investigations: As x-ray, gastroscopy, blood urea ..etc ❖ Treatment: 1. Treatment of the cause.

2. Correct dehydration & electrolyte imbalance. 3. Antiemetic drugs: metoclopramide or ondansetron

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

0

Diarrhea

❖ Definition :

o Change of the normal bowel habits in the form of: 1. Increase in frequency > 3/day

2. Increase in amount: feces > 200 gm/day on low dietary fiber content

3. Decrease in consistency: watery loose stools

I—II 3/day

> 200 gm/day

Watery loose

Pathogenesis & causes of diarrhea: Mechanism: more than one

❖ Causes of acute diarrhea

Causes of chronic diarrhea:

mechanism maybe present at the

diarrhea persisting > 4 weeks.

same time

1. Exudative(Inflammatory) diarrhea:

o

Mucosal destruction: damage to the intestinal mucosa, causing loss of fluid & blood

1) Infection:

a. Bacterial e.g.: o Shigella, E.coli & cholera o Salmonella & staphylococcal food poisoning b. Viral e.g. Rota & Norwalk virus

1. Infection:

o

Amebic & bilharzial colitis

o AIDS due to opportunistic infections o

TB

2. Inflammatory : o Inflammatory bowel diseases

c. Protozoal:

o

Irradiation enteritis

o Entamoeba histolytica

o

Diverticulitis

o

3. latrogenic : drugs : o Antibiotics especially clindamycin which causes pseudomembranous

Giardia lamblia

o

Malignant malaria

o

Balantidium coli.

2. Secretory diarrhea:

d. Helminthic: ascaris, ancylostoma 2) Inflammatory:

4. Enterotoxins: cholera

o

Active intestinal secretions of fluid

o Inflammatory bowel diseases

5. Hormones :

& electrolytes in intestinal lumen

o

Ischemic colitis

■

o

Appendicitis.

■

VIPoma

3) o o o

latrogenic : drugs & toxins Antibiotics & cytotoxic drugs Arsenic, lead, mercury Food allergies.

■

Carcinoid Syndrome.

3. Osmotic diarrhea:

o Presence of high concentration of non-absorbed hypertonic substances

4) Excessive intake of cellulose (fibers)

colitis

o Cytotoxic drugs

Zollinger-Ellison Syndrome

6. Diet:

o Disaccharidase (Lactase) deficiency ^ lactose intolerance in milk ^

bloating & diarrhea. 7. Drugs: laxative (lactulose) abuse,

in intestine which will attract fluid from the blood to intestine —> loose

sorbitol, magnesium antacids.

stools.

4. Hypermotility: o I Transient time —»defective absorption. 5. Hypomotility: o Stasis & bacterial overgrowth 6. Malabsorption : o I Nutrient absorption

7. ], Absorptive surface : o I Functional capacity

5) Acute psychological stress : exaggerated gastro-colic reflex

8. Irritable bowel syndrome. 9. Post-vagotomy

10. Thyrotoxicosis 11. DM,scleroderma

12. Myxedema 13. Causes of mal-absorption syndrome e.g.:

o o o o o

Mucosal e.g. Celiac disease Chronic pancreatitis Bacterial overgrowth Lymphatic obstruction Short bowel syndrome: due to the surgical removal of a large portion of the small intestine (less than 2 m of the normally 6m small intestine

remains)

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Algorithm for diagnosis of chronic diarrhea ❖ Exclude :

1. Causes of acute diarrhea

2. Systemic diseases 3. Previous gastric or ileal surgery 4. Parasitic infestation

5. Drugs 6. Disaccharidase (Lactase) deficiency

50 mOsm/kg

o t fecal fat due to malabsorption syndrome e.g. pancreatic insufficiency or bacterial overgrowth

Normal fecal fat due to

t stool weight e.g. secretory diarrhea

Normal stool

weight e.g. IBS

osmotic

diarrhea e.g. lactose intolerance or laxative abuse

❖ Investigations: ❖ Acute diarrhea

0 Stool analysis and culture o Sigmoidoscopy: in bloody diarrhea not improving in 10 days

❖ Chronic diarrhea

❖ 1. 2. 3. 4. 5. ❖

History and physical examination: Watery stool: secretory diarrhea Greasy stool: fatty diarrhea Sensitivity to milk (lactose intolerance), or to wheat (celiac disease) Neuropathy: DM Arthritis: inflammatory bowel disease. Therapeutic tests:

1. Diet free of milk & dairy products for 3 weeks^ improvement of diarrhea in lactose intolerance.

2. Diet free of wheat for 6 weeks —> improvement of diarrhea in coeliac disease. 3. Metronidazole for giardiasis ❖ Treatment: 1. Treatment of the cause

2. Fluid & electrolytes replacement

3. Loperamide(2 mg after each loose stool) in severe cases as it impairs the clearance of any pathogen in the bowel.

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

pConstipation | r

❖ Deflnition: J

❖ Presence of> 2 of the following:

1/4 times of defecation 3. Straining > 1/4 times of defecation

4. Hard Stools > 1/4 times of defecation resulting in difficult defecation (dyschezia) or painful defecation 5. Decreased volume of stool (normal 35-200gm/day) 6. Manual maneuvers as Digital evacuation and support of pelvic floor > 1/4 times of defecation ❖ Etiology :

A. Diseases

1.

Intestinal:

1. Colon :

o Ischemia, inflammation (IBD), stricture, cancer, volvulus & diverticulosis 2. Anorectal:

o Ignoring urge (rectal hyposensitivity), inflammation, stricture, cancer, fissure, prolapse & rectocele 3. Uncertain pathophysiology: a. Irritable bowel syndrome(IBS)

b. Slow transient constipation: | colon propulsion in absence of muscle disease c. Pelvic floor dysfunction e.g. Spastic floor syndrome (anismus):

o Spastic anal sphincter : Failure of pelvic floor to relax during defecation o It is due to history of child abuse or painful anus o Patient feels the desire to defecate but find difficulty in passage of stools II.

Extra-intestinal:

1. CNS:

o Aganglionic megacolon: Hirschsprung's disease o Autonomic neuropathy o

Parkinsonism

o Prolonged bed rest o

Cerebral stroke

o

Disseminated sclerosis

o Depression & psychosis 2. Connective tissue disease e.g. scleroderma 3. Endocrinal & metabolic:

o o o

Hypokalemia Hypothyroidism, hypopituitarism Hypercalcaemia & hyperglycemia(DM) o Amyloidosis, Pregnancy, Chronic renal failure

1^. Diet: Poor dietary intake offiber & fluids 1^. Drugs: Antacids containing calcium, Anticholinergic, Antispasmodics, diuretics, iron & opioids

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Approach to a case of constipation: 1.

❖ Alarming signs of structural diseases:

History :

o Dietary habits, fluid intake, ignoring urge to defecate o Drugs & symptoms suggestive for systemic disease. II. PR examination: to detect piles, anal fissures

1. Anemia

2. Body weight loss

3. Bleeding in rectum or occult blood in stool 4. New onset Constipation, 5. Family history of Cancer Colon

III. Investigation: 1. Of the cause e.g. thyroid function test 2.

Plain x-ray: for intestinal obstruction & megacolon.

3.

Barium enema: for organic destruction. Colonoscopy:

4. o

5. 6. 7.

V

When alarming signs of structural diseases are present especially in patients over 50 years old Radiologic colonic transit time. Defecography. Manometry: colonic & anorectal. ^

Treatment:

I

1. Treatment of cause 2. If no cause is found:

o Patient education: for proper bowel habits o Diet: wheat bran is one of the best laxatives and plenty of fluids o

Laxatives:

a. b. c. d. 3. 4.

Bulk laxatives e.g. fiber based laxatives Osmotic laxatives e.g. lactulose Stimulant laxatives e.g. senna Softener laxative e.g. mineral oil Biofeedback: to train the sphincter to relax properly in pelvic floor dysfunction Surgical treatment: in Hirschsprung's disease Dysentery Definition :

A disease characterized by diarrhea with blood & mucus in the stools ± tenesmus. Etiology : B. Inflammatory & irritant causes :

A. Infective causes:

1. Amoebic dysentery. 2. Bacillary dysentery. 3. Bilharzial dysentery.

1. Cancer Colon or Cancer rectum.

2. Crohn's disease ofthe colon or ulcerative colitis. 3. Diverticulitis

4. Mercury poisoning. Giardia lamblia, Malignant malaria, Balantidium coli. 5. Uremic dysentery.

4. Protozoa:

o

5. TB enterocolitis Tenesmus

Definition

1.

2.

A disease characterized by: During defecation: painful straining. After defecation: sense of incomplete rectal evacuation + persistent desire to defecate

❖ Etiology:

J

V

4.

Irritable bowel syndrome. Inflammatory bowel disease e.g. Ulcerative Colitis, Crohn's Disease. Infective colitis: e.g. Bacillary Dysentery. Rectal prolapse.

5.

Rectal carcinoma.

6.

All Causes of dysentery.

1. 2. 3.

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Acute abdomen

Hight upper

Myocardial

Quadrant

Infarction

V m \ ^eGallstone

Left Upper

^

Quadrant

Right-sided

^ Perforated

Pneumonia

" Oesophagus

Left-sided Pneumonia

PGptiC UlCGf riit

Gastric

Ruptured Spleen

Ulcer 1-/1S

Duodenal

HUlcer Gallstone ase

Pyelonephritis elonephrttis # * *

Appendicitis '

Right Lower

Perforated *

Aortic

Early I Appendicitis

Colon

Left Lower

Mesenteric

Quadrant

Thrombosis

Renal

Quadrant Renal

Vlu

Colic

9 Ciolic Obstruction Perforated Colon

Perforated

i

Caecum

,

Crohn's

,|Disease

Mesenteric

(Noie:- Visceral

Adenitis

perfoftrion cat» realiy occur anywhere)

Meckel's

i

Divefticulumf rl. }A|.. •

Ulceratlve Co! ColitiSj^ Commonly afteccs

liul Ldn oLCur

Appendicitis

^ Sigmoid

W'

f

Diverticulitis

Tiut notthfffdctomi rumi

Ruptured ectopic

/

Strangulated hernia

pregnancy

/ / Strangulat Strariguli ed

i^ect

hernia hernia

lerrum!

X^

Mittelschmerjuovulaiionfaln)

Ruptured

ectopic

pregnancy

Ruptured Ovarian Cyst

Tubo-ovwjte/abscess, Saipipgltis OvarlartTorsion

I.

1. 2. 3. 4.

Medical causes of acute abdomen :

Acute myocardial infarction, Rheumatic fever Acute pleurisy & pneumonia Acute pyelonephritis Polycythemia vera, PNH, Henoch-Schonlein Ihirpura, Sickle cell disease

5. Collagen diseases : SLE 6. DKA & uremia 7.

II.

1) 2) 3) 4) 5) 6)

Surgical causes of acute abdomen :

Acute appendicitis Acute pancreatitis Perforated viscus e.g. Peptic ulcers Acute cholecystitis Acute intestinal obstruction Ectopic pregnancy, twisted ovarian cyst & acute salpingitis

Embolic & vasculitis

8. Familial Mediterranean fever

9. Food poisoning

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Clinical picture : I.

History:

1. Sudden onset of pain suggests:

Perforation of viscus, rupture aneurysm, torsion of ovarian cyst or acute pancreatitis.

o

2. Back pain suggests:

Pancreatitis, rupture of an aortic aneurysm or renal disease.

o

3. Inflammatory conditions e.g.:

o Appendicitis produce a more gradual onset of pain, o Peritonitis the pain is continuous and may be made worse by movement.

4. Vomiting may occur with any abdominal conditions but if persistent it suggests intestinal obstruction. 5. Ask about other symptoms as change in bowel habit, urinary symptoms and gynecological history. II.

Examination:

1. Absent bowel sounds suggest peritoneal involvement, strangulation, ischemia or ileus 2. Signs of peritonitis: abdominal tenderness, muscle guarding and rigidity 3. Inflammation of pelvic peritoneum may produce tenderness on rectal examination. 4. Search for specific signs & symptoms according to the cause (

1 ❖ Investigations: I.

Blood:

1. Blood picture: TLC in inflammatory conditions. 2. Serum amylase is high in acute pancreatitis. II.

Imaging:

1. X-ray to detect air under diaphragm due to perforated viscus or multiple fluid level in intestinal obstruction. 2. Sonar for cholecystitis, appendicitis.

3. Spiral CT for pancreatitis, appendicitis. III.

Laparoscopy.

10

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

GIT bleeding

Hematemesis

❖ Definition :

o Vomiting of blood, usually coffee ground (acid bematin formation), but in severe cases it's bright red. ❖ Etiology : | 1. Esophageal causes 2. Gastro - duodenal causes 3. Small intestinal causes 1) Rupture esophageal varices 1) Rupture funda! varices 1) Rupture intestinal varices 2) GERD causes esophageal erosions 2) Acute gastritis & gastric ulcer due to 2) Ulcers secondary to drugs e.g. drugs e.g. NSAID NSAlDs 3) Chronic peptic ulcer (gastric ulcer or 3) Typhoid ulcers duodenal ulcer) 4) GERD associated with hiatus hernia. 3) Cancer esophagus 5) Cancer stomach 4) Small intestine cancer (adenocarcinoma) 4) Mallory - Weiss syndrome: 6) Peutz - Jegbers syndrome: 5) Gardner syndrome: o Tear of the esophagogastric o Autosomal dominant disease o A variant of familial junction due to severe vomiting characterized by the 01 polyps & adenomatous polyposis, which especially in alcoholics mucocutaneous pigmentation is autosomal dominant disease characterized by 01 polyps, osteomas of skull, thyroid & desmoid tumors.

5) Rupture of aortic aneurysm into the esophagus

7) Angiodysplasia of the stomach

6) Angiodysplasia of the small intestine.

4. General causes

1. 2. 3. 4.

Hemorrbagic blood diseases: purpura, hemophilia & leukemia. Hemorrbagic fevers: plague Severe Hypertension Systemic diseases e.g. Hepatic failure & renal failure.

5. False bematemesis: vomiting of ingested blood coming from: bleeding nose, mouth or pharynx. i *1* The commonest causes in Egypt: varices, ulcer & acute gastritis. 1 ■

^

..

^

.

..

.

Differential diagnosis

A. B. C. 1. 2. o o o o

Differentiation from hemoptysis (refer to the chest). Differentiation from false hematemesis: by local ENT examination. DD of the cause of hematemesis through: Clinical picture. Investigations: Upper endoscopy & enteroscopy. Barium meal & follow through, Liver function tests & abdominal ultrasonography. Angiography & isotopic studies.

Nasopnaiynx

?'''«■ "sEsoptiagsjs Moniio

U(H)er etidoscope

Management: see esophageal varices.

11

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Melena & Bleeding per rectum Esophagus,stomach & duodenum

Ligament of Treitz Melena

Bleeding per rectum

Jejunum & ileum

1

Ileocecal valve

, ijifltfe. -'.

!_

J

' Colon & anorectum

Melena

Bleeding per rectum

Bleeding per rectum (hematochezia)

Melena •

•

o Passage of black tarry stools due to the presence of o Passage of bright red stools due to the presence of fresh blood in the stools digested blood in the stools. 1. Hematochezia usually indicates 1. Hematemesis or melena usually indicate a gastrointestinal bleeding below gastrointestinal bleeding from a lesion above

Definition

Site of the lesion

ileocecal valve i.e. lower GIT causes

ileocecal valve ;

•

i.e. colon & anorectum A. Above ligament of Treitz: upper GIT causes ; 2. Hematochezia may result from upper esophagus , stomach & duodenum GIT bleeding with rapid transit time B. Below the ligament of Treitz: middle GIT causes : jejunum & ileum due to massive severe brisk bleeding 2. Melena may result from lower GIT bleeding if slowly enough to allow for enzymatic breakdown 1. Inflammatory bowel diseases ❖ Same causes of hematemesis: 1. Esophageal causes 2. Intestinal bilharziasis.

Causes

2. Gastro-duodenal causes

3. Anal fissure.

3. Small intestinal causes

4. Piles: the most common cause.

4. General causes

5. Bacillary dysentery. 6. Colonic polyps: familial polyposis.

5. False causes

7. Cancer rectum or colon: the most serious cause 8. Diverticulitis. 9. TB Enterocolitis •

Amount

o

Amount: > 50- 100 ml blood if less than this it will je occult blood in stool

•

Duration

o > 8-14 hours; time needed for blood to be broken down within the intestinal lumen

•

Differential

diagnosis

o 10,000

1. Jejuna! biopsy: may show villous

2. Malabsorption syndrome

1.

Clinical picture

❖ Intestinal abnormality leading to stagnation of intestinal contents which favors overgrowth of bacteria leading to: 1. Consumption of folic acid & vitamin B12 2. Deconjugates bile salts (release bile acids ^ damage mucosa) 3. Diarrhea & malabsorption

Tropiea! sprue

liliiu! (Slagiiaiit) loop s> ndromc: lineterial overgrovuh ❖ Etiology o Strictures & enterocolic fistula o Occurs in tropical countries due to : A. Persistent intestinal contamination e.g. Crohn's disease by infectious agents with bacterial o Surgery e.g. gastrojejunostomy overgrowth o Diverticulosis B. Nutritional detlciencies. o Diminished motility e.g. DM,

'M

There is flattening of the intestinal villi which are heavily infiltrated by macrophages with obstruction of intestinal lymphatics.

Infectious disease caused by the bacterium Troplieryma whipplei with affection of GIT & other systems.

Penicillin, Sulfonamides, tetracycline Co-trimoxazole for one year Treatment of malabsorption syndrome

General investigations for malabsorption. 1. 2. 3.

PCR.

3.

Electron microscopic reveals the presence of Tropheryma whipplei within macrophages

Acid Schiff stain,

foamy macrophages with positive Periodic

Infiltration of the small intestine mucosa with

Jejuna! biopsy:

Lymphadenopathy Malabsorption syndrome

2.

o

o

1.

7.

6.

|o| 4.

Arthritis

Chest: pleurisy

3. 5.

Eye: oculomasticatory myorhythmia

CVS: endocarditis, pericarditis^

2.

1. CNS: dementia, confusion, convulsion, coma

o

o

M'liipple's disease

Clinical picture:

I. Clinical picture of intestinal affection: mal-absorption: 1

Steatorrhea: Stools are :

a. Pale, bulky, greasy, offensive b. Floating in the toilet witb sometimes oil like bubbles c. Difficult to flush. 2. Abdominal distension

3. Borborygmi : audible intestinal sounds 4. Colics

5. Diarrhea(absent in 15 % of cases) 6. Deceased body weight 7. Eructation 8. Flatulence

II. Clinical picture of nutritional deficiencies: 1) Macro-nutrients Water: dehydration. 2. Carbohydrates: Hypoglycemia 3. Fats: Loss of weight. 1.

4. Proteins: o o

2) Minerals :

3) Fat soluble vitamins o Vitamin A: night

1. Folic acid: 2.

megaloblastic anemia. Iron: microcytic hypochromic anemia.

blindness. o

Muscle wasting Hypoproteinemia with

4.

nutritional edema.

o

cramps & hypotension. Potassium: Myopathy & arrhythmia.

o

o o

Vitamin B2: Glossitis &

o

Vitamin B3: Nicotinic

dermatitis.

o

Vitamin K: bleeding tendency

acid: Pellagra. Vitamin B6: Peripheral neuropathy.

o

Vitamin E:

Vitamin B12:

Megaloblastic anemia &

5. Calcium: Parasthesia

6.

Vitamin Bl: Beri - Beri.

angular stomatitis.

Vitamin D: rickets or osteomalacia.

3. Sodium: Muscle

4) Water soluble vitamins

& tetany. Magnesium: arrhythmia & tetany.

SCO o

Vitamin C: scurvy

III. Clinical picture of the cause e.g. Coeliac disease

J

❖ Investigations:

I. Investigations to diagnose malabsorption syndrome: Fat in the stools:

o Normally total fat in the stools < 6 gm / day. a. Un-split fat: ■ In mal-digestion

b. Split fat:

J

■ In mal-absorption

WV

■

■

E.g. In biliary & pancreatic causes

E.g. In small intestinal diseases.

2. Urinary D -Xylose test: a. Method:

b. Normally:

c. In steatorrhea:

o Pentose sugar not metabolized in the body o Give 25 gm D - Xylose orally on empty

o

o

stomach, then collect urine over the next 5 hours.

Urine collected over 5 hours should contain at

least 5 gm of D Xylose

Urine collected over 5 hours will

contain less than 5 gm of DXylose (provided that renal functions are normal)

3. Barium follow through of the small intestine:

o Loss of the normal feathery appearance of the jejunum, o Moulage sign: Segmentation & flocculation of the barium pattern, o

Dilatation of the intestinal lumen.

4. Jejunal Biopsy:

o Recently: taken through the enteroscope. o Previously: taken by the intestinal biopsy capsule (Crosby capsule)

34

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

11. Investigations to diagnose nutritional deficiencies: 1. 2. 3. 4.

Blood picture: microcytic hypochromic or megaloblastic anemia Plasma proteins: hypoproteinemia. Serum electrolytes: J, iron, Na,K,Ca, Mg. Bone X - ray: osteomalacia. 111. Investigations to diagnose the cause: 250

A. Glucose tolerance test:

^ 200

Glucose DM

tl50 § 100 u

O 50 0

J 30

Flat Insulin curve I 1 I I 60 90 Time in minutes

1

1_ 120

o In pancreatic causes: diabetic curve, o In small intestinal diseases: flat curve. B.

Tests for bacterial overgrowth:

ttt "^C02

Glycocholate breath test:

1.

T\ 14,

C glycine

14,

C giycine-cholate Cholic acid

)J A. Method:

■

Give radioactive measure the

giycine-cholate orally then

B. In bacterial overgrowth: ftt '''CO2 ■ Bacteria will deconjugate '''C giycine-cholate & release

CO2 in the breath

■

of 14C-glycine occurs. The labelled glycine is rapidly absorbed and metabolized to CO2 which is detected in the breath.

2. Culture of the jejunal aspirate: o This is done using a sterile polyethylene tube, o Normally there is 10,000 organisms/ml. Treatment :

1. Treatment of the cause : Gluten free diet in Coeliac disease

2. Replacement of the deficient factors: e.g. o

Parenteral vitamins & minerals,

o Pancreatic enzymes & bile salts.

35

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Intestinal Amoebiasis

intestinal Shigellosis

Intestinal Bilhar/iasis

(Bacillary Dysentery)

(Schistosomlasis)

Etiology

Causative organism: Entamoeba Histolytica

Causative Organism: Gram - ve: Shigella bacilli: S. dysenteriae, S flexneri, S. boydii, S. sonnei.

Source:

Patient or carrier (cyst passer). Mode of infection:

b.

By fecal -oral route through ingestion of the entamoeba histolytica in the cyst form which resists gastric acidity & then it is transformed

It is due to schistosoma mansoni &

japonicum ova which live in the

mesenteric plexus of veins. It is very rarely due to schistosoma

Source:

haematobium which live in the vesical

Transmitted by flies from

plexus of veins due to vesico-

person to person

mesenteric anastomosis.

Mode of infection:

into vegetative form in the intestine & then passes to the colon. d. The incubation period:

Fecal - oral route.

The incubation period: 1-4 days.

From 2 weeks to many years Clinical picture A.

Asymptomatic cyst passers:

1.

They pass cysts in the stools & cause spread

o Fever, toxemia, dehydration 2. Acute bacillary dysentery: o Severe watery diarrhea up to 20 motions per day o Stools: scanty stool with

of infection. B. Acute amoebic colitis :

a) Acute amoebic dysentery: 1.

General condition:

o

Good with no fever, toxemia or dehydration.

2.

General manifestations:

excessive blood, mucus &

Acute diarrhea:

A.

1.

Cercarial dermatitis:

o

Itching occurs after 1-2 days from infection.

2. o

Katayama syndrome : Acute allergic schistosomiasis occurs after 3-9 weeks from infection:

pus.

Frequent motions up to 10 motions per day. Stools: bulky with blood, mucus & may be pus in secondary infection.

3. Associated symptoms:

a.

o

b.

3.

Associated symptoms:

o

o

Abdominal colics & tenesmus

o

Tendemess over the caecum & sigmoid.

o

Asymptomatic: most of the cases.

B. Acute presentation :

Abdominal colics & severe tenesmus

Urticaria, sweating, cough Fever, headache, anorexia, malaise, myalgia

Pneumonitis, abdominal pain & splenomegaly Chronic presentation :

Tenderness over the caecum

& sigmoid.

4.

Course:

Occurs after 2 months from infection,

o

The condition subsides in few days or turns

adult worms can live for > 20 years

into chronic form

Schistosoma mansoni:

Dysentery: diarrhea, tenesmus, passage of blood & mucus in the

b) Acute amoebic diarrhea: o

As before but without tenesmus(no rectal affection)

stools

Portal hypertension with portosystemic shunts leading to hepatosplenomegaly, ascites & hematemesis from ruptured esophageal

C. Chronic amoebic colitis:

1.

Chronic amoebic dysentery: Recurrent short attacks of diarrhea &

tenesmus alternating with constipation or normal bowel habits

varices.

2.

Chronic amoebic diarrhea.

3.

Atypical presentations: Abdominal pain: over the caecum or sigmoid

Bilharzial cor pulmonale. Bilharzial pericolic mass in the left iliac fossa: bilharzioma

colon

Bilharzial polyps & bleeding per rectum

o

Constipation Dyspepsia

o

Flatulence.

o

Bilharzial myelopathy Schistosoma japonicum: As schistosoma mansoni with CNS

❖ Complications A. Intestinal :

Bleeding, perforation &

1.

Amoehoma:

fibrosis

o

Mass in the right iliac fossa —»• intestinal

Bacteremia.

obstruction

Chronicity Dehydration

2. Amoebic ulcers: which may rarely perforate. 3. GIT bleeding 4. Chronicity

Schistosoma haematobium:

Urinary schistosomiasis: Painless terminal hematuria

Pain in lion radiating to groin Pyelonephritis, pyonephrosis or hydronephrosis I incidence of urinary bladder squamous cell carcinoma

Dissemination: Reiter's

syndrome: conjunctivitis,

B. Extra-intestinal:

1. Amoebic hepatitis & amoebic liver abscess. 2. Pulmonary amoebiasis with lung abscess 3. Systemic e.g., brain abscess

manifestations e.g. epilepsy, blindness, hemiplegia & paraplegia

arthritis & urethritis. 6.

Hemolytic uremic syndrome

Complications: as before + 1.

Anemia of chronic disease.

2. Ascites & edema due to chronic protein loss

3. Rectal prolapse 4. Clubbing.

36

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

0

From other causes of acute diarrhea.

o

From other causes of chronic diarrhea.

0

From other causes of dysentery From other causes of mass in right iliac fossa

❖ Differential diagnosis From other causes of acute

0

From other causes of chronic diarrhea.

diarrhea.

o

From other causes of dysentery

From other causes of

0

0 0

1. Serology:

dysentery ❖ Investigations 1. Serology:

o

o

0

Amoebic antibodies may be detected in the serum of the patient.

2. Stool analysis: o May show entamoeba histolytica: ■ Vegetative form in acute cases

■ Cyst form in chronic cases 3. Sigmoidoscopy: o Amoebic ulcers : flask - shaped ulcers with healthy mucosa in between o

Positive swab for amoeba.

For shigella (agglutination test) 2. Stool analysis: o

Excessive WBCs & RBCs.

o

Culture may demonstrate the organism. 3. Sigmoidoscopy: o

Generalized inflammation of the colon.

o

Dirty yellowish pseudomembrane which bleeds when removed,

leaving superficial ulcers

From other causes of mass in left iliac fossa

1. Serology & skin tests: o

For schistosoma antibodies.

2. Stool & nrine analysis: o

For schistosoma ova.

3. Sigmoidoscopy with rectal & colonic biopsy 4. Barium enema:

o 5. o 6.

For schistosoma polyps in the colon. Blood picture: For anemia & eosinophilia. Investigations for diagnosis of complications: o E.g. liver imaging for hepatic schistosomiasis.

with inflamed mucosa in between. Treatment

A. Symptomatic treatment:

o o

Correction of dehydration: fluids & electrolytes replacement wither orally or IV o Antidiarrheal drugs: Antidiarrheal drugs. should not be given because they may decrease the intestinal motility and thus

Antidiarrheal drugs.

decrease the clearance of

bacteria, leading to more deterioration.

B. Specific treatment: Tissue amebicides:

Indication: for acute amoebiasis (vegetative form)& extra- intestinal amoebiasis e.g. hepatic form Drugs: Metronidazole: 750 mg/8hours orally for 510 days. Tinidazole: 2 gm daily orally for 3 days. Secnidazole: 2 gm single dose once Chloroquine: effective only in amoebic liver

1.

3.

Ceftriaxone in children: 50

mg/kg rV or IM once for 5 days. Ciprofloxacin 500 mg/12hr orally for 5 days. Cotrimoxazole (400/80 mg): 2 tablets/12 hours for 5 days.

Treatment of Katayama syndrome: steroids first then praziquantel B. Treatment of active schistosoma!

infection: anti-bilharzial drugs : Praziquantel: Effective against all forms Dose : 40mg/kg single oral dose Side effects: rarely GIT disturbances e.g. abdominal pain, colics, nausea N.B.:

Oxamniquine(S mansoni & japonicum)& Metrifonate(S haematobium): not broad spectrum anti-bilharzial drugs Niridazole (ambilhar)& Tartar emetic: not commonly used for many side

abscess. Luminal amebicides:

Indication: for chronic amoebiasis(cyst form) Drugs: Diloxanide furoate or Paromomycin : 500 mg/8hours orally for 10 days.

effects

Treatment of polyps by endoscopic polypectomy.

37

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Familial Mediterranean Fever(FMF) Familial paroxysmal polyserositis

❖ Definition :

o Inherited disorder characterized by recurrent attacks of fever, serositis & arthritis ❖ Epidemiology :

o Eastern Mediterranean persons : Armenians, Arabs , Turks & Sephardic Jews ❖ Etiology : ❖ Genetic : o

Autosomal recessive

o Genetic defect in gene MEFV (Mediterranean fever) on chromosome 16, which encodes pyrin; a 781- amino acid protein associated with cytoskeleton in neutrophils & activated monocytes ❖ Clinical Picture:

■ ■iulTTaroiiuijR

Type of patient: starts in early childhood : 5-15 years old II.

Recurrent attacks of:

1.

Fever: 38° - 40° C, the cardinal manifestation

2.

Polyserositis: may last for 12 - 72 hours

A. Peritonitis :

o

Acute abdominal pain, rigidity, vomiting. Patient is advised to do an elective appendectomy to avoid misdiagnosis

B.

Pleurisy :

o

Acute chest pain, cough, friction rub & transient pleural effusion

o

C. Pericarditis : the least common

3. Polyarthritis: may last for several weeks Acute, rarely chronic with effusion

o

o

Mono, oligo or polyarticular, affecting mainly large joints Arthralgia or MYALGIA may replace arthritis

4.

Erysipelas like rash :

o

o

5. III. IV. o

o o

Painful erythematous edematous rash over lower limb. Scrotal edema due to inflammation of the tunica vaginalis Attacks precipitated by stress, menses, exercise Attacks characterized by periodicity (disease free intervals) : Attacks from hours to days Attacks from twice / week up to once / year Remissions may remain for years

38

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Complications:

1. Amyioidosis: The most serious : o

Proteinuria & renal failure

o Intestinal malabsorption 2. Depression 3. Drug addiction (abuse of analgesics)

Differential diagnosis: A. Acute appendicitis & pelvic inflammatory disease B. Porphyria C. Hereditary angioedema D. Rheumatic fever E. Other causes of fever

F. Other causes of arthritis e.g. septic arthritis & Still's disease Investigations:

1. Genetic test for MEFV

2. High acute phase reactants:

o o 3. o o

|ESR,C-reactive proteins, fibrinogen t Neutrophils during attack In renal amyioidosis : t glycoproteins & serum amyloid A protein Positive investigations of nephrotic syndrome ❖ Treatment :

Colchicine : the drug of choice o Dose : 0.6 mg,2-3 time/day

1.

o

Benefits:

A. Reduce frequency of attacks B. Protect against amyioidosis C. Lessens the proteinuria Narcotic analgesic : Given only in extreme pain uncontrolled by colchicine

iiOcn«34C18«

wLCHlClNfc CAPSULES

VVIiST-WAfV

In resistant cases :

Interferon a

Etanercept(tumor necrosis factor blocker) Anakinra(IL-1 antagonist) Canakinumab (monoclonal IL-ip antibody) ❖ N.B.: Corticosteroids are ineffective

39

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Intestinal Tuberculosis

❖ Etiology :

o Primary: ingestion of infected milk(Bovine bacilli), o Secondary: to pulmonary TB(Human bacilli). ❖ Pathology :

o The most common affected site is the ileo-cecal region

ABDOMINAL

TUBERCULOSIS

■** Clinical picture:

ttrmM ■ Mlouivd nu 27 mg/day is diagnostic. ❖ Treatment:

1. Diet: rich in proteins, niacin, vitamins 2. Drugs:

o o o 3.

Symptomatic e.g. Anti serotonin: Methysergide reduces diarrhea Somatostatin analogues e.g. Octreotide, inhibit release of vasoactive substances Interferon alpha Surgical removal of tumor

GIT Affection In Systemic Diseases

1. CNS:

o Abdominal colics in autonomic epilepsy 2. CVS:

o Superior mesenteric vascular occlusion with AF 3. Respiratory: o

Terminal ileitis with TB

4. Endocrinal:

o o o o

Thyrotoxicosis Diarrhea Myxedema —> constipation Addison ^ nausea, vomiting and diarrhea DM —> Gastroparesis, constipation or diarrhea (autonomic neuropathy)

5. Rheumatology:

o Rheumatoid arthritis peptic ulcer(NSAID). o Scleroderma —> Dysphagia, constipation, o

Vasculitis ^ mesenteric vascular occlusion.

6. Renal: gastroparesis, peptic ulcer, constipation. 7. Autoimmune:

o Autoimmune gastritis, o

Coeliac disease,

o Inflammatory bowel disease, o Food allergy Multisystem Manifestations Of GIT Disorders A. Stomach:

o Chronic atrophic gastritis —> pernicious anemia o Pyloric obstruction —+ electrolyte disturbances o Peptic ulcer —> Liver cell failure B. Intestine:

o Whipple's disease —^ dementia, confusion, convulsion, coma, oculomasticatory myorhythmia, endocarditis & arthropathy o Malabsorption syndrome —> see nutritional deficiency manifestations o Inflammatory bowel disease —+ see extra-intestinal manifestations o Carcinoid tumor —> carcinoid syndrome C. Pancreas:

o Acute pancreatitis look complications o Chronic pancreatitis —> malabsorption, DM o

Pancreatic island tumors ^ look endocrine

46

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Endocrinology Topic o The pancreas o Diabetes Mellitus(DM) o Pancreatic Endocrine Tumors

o o o o o o o o o o o o o o o o o o o o o o o

Page 1 3 31

The pituitary gland 33 Hyperpituitarism 35 Gigantism 35 Acromegaly 36 Hyperprolactinemia 38 Syndrome OfInappropriate ADH Secretion(SIADH) 40 Hypopituitarism 41 Levi-Lorain, Froelich's & Laurence Moon Biedl Syndrome 41-42 Simmond's disease & Sheehan Syndrome 43 Diabetes Insipidus 47 The thyroid gland 49 Thyrotoxicosis & Myxedema 52 The Parathyroid gland 60 Hyperparathyroidism 62 Hypoparathyroidism, Hypocalcemia, Tetany 65 The suprarenal glands(The adrenal glands) 68 Hyperaldosteronism 69 Gushing syndrome 74 Congenital adrenal hyperplasia (adrenogenital syndrome) 79 Pheochromocytoma 80 Adrenocortical insufficiency (adrenal failure) 82 Multiple endocrine neoplasm(MEN) 89 Autoimmune polyendocrine (polyglandular)syndromes(APSs)

o Disorders :

o Disorders of growth o Disorders of puberty o Disorders of weight: Obesity & metabolic syndrome

90 92 94

o Hirsutism

98

o Polycystic ovary syndrome(PCOS) o Gynecomastia

100 101

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Endocrine

The pancreas

❖ Anatomy of pancreas: 1. Description : retroperitoneal structure formed of head, body & tail 2. Relations: A. Anterior:

o Stomach, transverse colon, it lies in concavity of duodenum. B. Posterior:

o IVC, aorta, CBD,left sympathetic chain, left psoas major, left suprarenal, hilum of left kidney, hilum of spleen C. Ducts;

o Pancreatic & CBD join each other to open in ampulla of Vater in second part of duodenum *1* Function of pancreas:

I.

❖ 1. o 2.

Endocrinal:

Islets of Langerhans are the regions of the pancreas that contain its endocrine(hormone-producing) cells: Alpha cells (a): Glucagon (fglucose - antinsulin), proglucagon, glucagon like peptides(GLP1,2) Beta cells (p):

o Insulin (J,glucose), C peptide, proinsulin, amylin, gamma aminobutyric acid(GABA)( Red Blood

3. Delta cells (8): somatostatin 4. Gamma cells (y)(F cells or Pancreatic polypeptide cells): pancreatic polypeptide 5. Epsilon cells (s): ghrelin 11.

1. 2. 3. ❖

Exocrinal:

Amylase: split glycogen into disaccharide Trypsin & chymotrypsin: split proteins into dipeptides and monopeptides Lipase & coiipase : split fat into glycerol & fatty acids N.B.: The bicarbonate of pancreatic juice neutralizes acidic gastric juice in duodenum. ❖ Physiology of insulin: C-peptide

Insulin

Insulin receptor GLUT-4

A-chaUi

Glucose

B«tialo

❖ Hormone:

o o o ❖

Insulin is a polypeptide hormone containing 2 polypeptide chains(a & |3) linked by disulfide bridges(S-S) It's synthesized as pre-pro-insulin which is then converted into pro-insulin The pro-insulin is hydrolyzed into insulin & C peptide which are secreted in equimolar amounts Gland: Insulin is secreted from p cells of islands of Langerhans in the pancreas.

❖ Mechanism of action:

o The binding of insulin to its receptor in cell membrane -> activation of a tyrosine kinase —> phosphorylation intracellular protein ^ insulin action

o Insulin -> t phosphodiesterase & j. adenyl cyclase —>• j c.AMP induced by counter regulating hormones

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Action:

High

Rdlsei

Insulin

Blood*''

Blood

Skeletal muscle

Liver

Adipose tissue

T glycogenesis T protein synthesis

T glycogenesis

T adipogenesis

i. gluconeogenesis

1 lipolysis

formaV^o*^ g^ycogen Insulin

Tissue metabolic spectrum

INSULIN

Stimulates

glucose uptake

Cata holism

^om blood

Tissue buildup Glycogen, protein,

Tissue breakdown

Tissue Ceils

(ffluscie, kldfvey, fat)

Glycogenolysis, gluconeogenesis, protein catabolism, lipolysis

Low Blood

flowers

Anabolism

fat synthesis

Sugar

Blood

Sugar A.

CHO: I glucose in blood (hypoglycemia):

1.

1 Glucose uptake in skeletal muscles and adipose tissue by increasing the level of glucose transporter(GLUT 4). N.B.: glucose uptake into brain is obligatory & not dependent on insulin

o

B.

t glucose utilization(|oxidation, giycoiysis, glycogenesis & iipogenesis) I glucose production(|gluconeogenesis & glycogenolysis) Lipids: J, FFA in plasma

1.

Increase Iipogenesis:

2. 3.

o

In the liver excess glucose in converted into FFA which is carried as TGs in VLDL to adipose tissue.

2.

Inhibits lipolysis:

o

By inhibiting the activity of the hormone sensitive iipase enzyme in adipose tissue.

C. Protein: anabolic effect 1. 2.

Inhibits proteolysis and by preventing gluconeogenesis, it perseveres aminoacids for protein anabolism It increases the transport of AAs inside the cells.

D. Minerals: o

Insulin fNa/K ATPase activity Regulation:

f K. shift intraceiiuiar

A. Secretion is increased by:

B. Secretion is decreased by:

o

o

Cortisoi & Catechoiamines

o

Growth hormones

Glucose

o Giycine & arginine amino acids o Glucagon o GIT hormones e.g. Gastrin, Secretin & Choiecystokinin

o Thyroxin o

Estrogen-progesterone

Physiology of glucagon: 1. 2. 3.

Single chain peptide hormone secreted from pancreatic alpha ceils Given parentally & metabolized in liver, kidney & plasma Mechanism of action: G protein linked receptor^ f adenyi cyciase •

t c.AMP

4. Actions : A. Metabolism :

a) CHO metabolism :

I glucose utilization : J, giycoiysis, glycogenesis t glucose production f gluconeogenesis & glycogenolysis Lipid metabolism: f lipolysis & i TG synthesis ^ fFFA —» ketogenesis b) Protein metabolism : proteolysis —> transport of AAs to liver —> gluconeogenesis c) B. Endocrine: f secretion of insulin, catechoiamines & caicitonin C. Heart: positive inotropic & chronotropic o o

D. Smooth muscle relaxation

E. BM : suppressive effect on BM

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Diabetes Mellitus(DM)

Definition :

o It is a metabolic disorder of carbohydrate metabolism due to absolute or relative insulin deficiency leading to

hyperglycemia & glucosuria with secondary disturbance of lipid and protein metabolism.

❖ Etiology :

1. Primary DM(95% of cases): o Type 1 DM o Type II DM o Mature onset diabetes in the young(MODY). 2. Secondary DM(5% of cases) 3. Gestational DM

❖ Pathogenesis:

1. Primary DM:

Healthy

Insulin

Glucose

receptor

Insulin '

Typel Glucose

W'%

■ i|.' '"tfi

Pancreas failure to

produce Insulin

Type 2

Insulin

Glucose

Insulin

receptor

?

Cells fall to

respond to

insulin properly

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

I.

Type I DM

1. synonym

o

Juvenile onset DM

o

Insulin dependent DM

o o

2. Incidence

o

10%

o

3. Pathogenesis

❖ Absolute insulin deficiency : o In genetically predisposed patients(HLA-DR3,DR4, DQ),infection hy certain viruses(Coxsackie B4 Virus, mumps or retroviruses)^ triggering autoimmune response leading to antibodies against beta cells (e.g. islet cell cytoplasmic autoantibodies, insulin autoantibodies, glutamic acid decarboxylase autoantibodies) —>■

Insulin resistance (IR):

❖ Definition: decreased ability of target tissues e.g. muscle, liver, adipose tissue to respond properly to normal circulating insulin i.e. lose of sensitivity to insulin ❖ Causes: 1. Genetic factors:

A. Receptor level:

o Due to reduced number of insulin receptor B. Post receptor level:

o Defective in cellular transduction of insulin signal o Reduced capacity for translocation of GLUT4 to the cell surface in muscle cell

exogenous insulin needs and help blood glucose control. 50%

o

100%

Chromosome 11 - multifactorial

destruction of beta cells with

production. ❖ N.B.: the honeymoon phase of DM 1:

o A temporary period (1-2 years) shortly following diabetes diagnosis when the pancreas is still able to produce a moderate amount of insulin to reduce

o

90%

1.

2. Acquired factors: obesity (insulin resistance syndrome): Adipocytes secrete leptin, resistin, free fatty acid, tumor necrosis factor alpha blocking insulin receptors causing IR. ❖ IR leading to : 1. IR —> insulin can no longer inhibit gluconeogenesis —> excessive hepatic glucose production —» hyperglycemia 2. Early there is f insulin secretion due to compensatory beta cell hyperplasia to maintain normoglycmia. 3. Later there is J, insulin secretion due to exhaustion of p cells with hyperglycemia(Type II DM) 11. Relative insulin deficiency : beta cell dysfunction leading to defect in insulin secretion

very low or absent insulin

4. Inheritance in

II. Type II DM Maturity onset DM Non-Insulin dependent DM

identical twins 5. Genetic locus

o

Chromosome 6-recessive

o

6. Pathology

o

Insulitis: the islet cells are

o The islet cells show deposition of amyloid material (amylin) which is co-secreted with insulin

infiltrated by lymphocytes, o After destruction of the cells,

the inflammatory process ceases. This explains the presence of antibodies even before the onset of DM

7. Subtypes

8. Age of onset & onset

A. Type lA: transient antibodies (80%) B. Type IB; persistent antibodies(20%) o 5-15 years with sudden onset o 15-40 years with slower

A. Type II Obese (mainly central obesity): 80%: B. Type II Non-Obese: 20% .

o >40 years, gradual onset

insulin deficiency: latent autoimmune diabetes of

adults(LADA)

9. Body weight

o

10. Autoimmune

o

Thin

o

Obese 80 %,non obese 20%

Associated with autoimmune

o

Not associated with autoimmune diseases

diseases e.g. hypothyroidism,

diseases

Addison's disease.

11. Complications

o Ketoresistant, need precipitating factors to occur .

o

Ketolabile

12. Insulin level

o

Low or absent

13. C peptide

o Disappearance of C peptide

o

14. Treatment

o

o 1 body weight, oral anti diabetic drugs,± insulin

: ketoacidosis

Insulin is a must

o Early: increased Later: decreased

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

III. Mature onset diabetes in the young(MODY): A. Inheritance: Autosomal dominant B. Incidence :

o

15% of cases

o Young obese patients o Intermediate between type I & type II ❖ Type I. MODYl

❖ Characters

o Mutation in hepatocyte nuclear transcription factor.

o o 4. MODY 4 o 2. MODY 2

3. MODY 3

5. MODY 5

Mutation in glucokinase Mutation in hepatic nuclear factor 1 a Mutation in insulin promoter factor

o Mutation in hepatic nuclear factor p o Associated with renal cysts, proteinuria and renal failure

D. Associated by: Cblorpropamide alcohol flush phenomenon: o Due to release of VD material as prostaglandins or encephalins E. Treated by oral antidiabetic drugs

2. Secondary DM:

I. Pancreatic causes: J 1. Cystic fibrosis, Chronic pancreatitis, Cancer body of pancreas 2. Hemochromatosis

3. Pancreatectomy

4. Fibrocalculous Pancreatopathy(Chronic malnutrition)

II. Endocrinal causes: f anti-insulin hormones: t Anti-insulin hormones

1. 2. 3. 4. 5. 6.

Acromegaly(t growth hormone) Pheochromocytoma(|adrenaline) Cushing syndrome (fcortisol ) Conn's syndrome (f Aldosterone - hypokalemia ^ insulin resistance) Glucagonoma(f glucagon) Thyrotoxicosis(f T4)

3:4

III. Others

9^* 1. Chronic liver & renal failure

2. Drugs: o Beta blockers, Corticosteroids , Contraceptive pills, Diuretics (thiazides & flirosemide), Diazoxide

3. Receptor Defect: A. Down's, Klinefelter and Turner's syndromes B. DIDMOAD syndrome C. Friedreich's ataxia, myotonia congenital, Huntington's chorea

3. Gestational DM:see lat( r

tdJ

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

I Insulin

Clinical picture:

o t•e MOI N W 4 •f a 4. c »#•#«

Asymptomatic in 1/3 of cases and accidentally discovered during blood glucose testing for unrelated condition Polyuria: osmotic diuresis due to hyperglycemia (nocturnal enuresis in children) Polyphagia

N.B.: Loss of body weight in type I DM (Igm glucose loss in urine = 4 calories) Polydipsia

Premature loosening of teeth due to peri-alveolar resorption of bone Blurred vision: due to osmotic swelling of lens. Pruritus especially of vulva & anal region due to monilial infection Pain and paresthesia secondary to peripheral neuritis Symptoms of the Cause in secondary DM

❖ Differential diagnosis: A. Other causes of mellituria (sugar in urine):

1. DM 2.

Renal glycosuria due to : Hereditary low renal threshold Fanconi syndrome Pregnancy

3.

Aiimentary glycosuria: lag storage curve in:

o

Liver cirrhosis

o o

'eooius

plasma mM

Thyrotoxicosis Gastrectomy (late dumping syndrome)

4. Inborn error of metabolism: o

5. o o

B. o

C.

Fructosuria, galactosuria, pentosuria

- .. io^anc«

Reducing substances in urine: Acetylsalicylic acid, Amino acids Vitamin C, Chloral hydrate

Other causes of increased appetite with loss of weight Malabsorption, parasitic infestation & thyrotoxicosis. Primary from secondary DM e.g. Gushing syndrome. ❖ N.B.: Terms used in DM:

1. Potential DM:

o Normal OGTT with increased risk of DM e.g.P' degree relative with DM 2. Latent DM:

o Tendency to develop transient DM after stress e.g. infection, stroke o Later on DM may establish o The patient has positive corticosteroid-glucose tolerance test 3. Chemical DM:

o Laboratory DM with no clinical symptoms of DM. 4. Clinical or overt DM:

o Laboratory DM with clinical symptoms of DM

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Investigations:

1. Blood glucose test:

1. Fasting plasma glucose level: fasting at least 8 hours

llOmgdl

100

\ Pre-diabetes From 100-125

Normal

Diabetes

❖ Pre-diahetic state (borderline DM) o > 100- 125 mg/dl i.e. IMPAIRED FASTING GLUCOSE o 126 mg/dl

2. Oral glucose tolerance test(OGTT):

|40mgdl

lOOmgdl

\Pre 200 mg/dl 3. Random (casual) blood glucose: ❖ Normal

❖ Pre-diabetic state (borderline DM) ❖ Diabetes mellitus

o 140- 199 mg/dl

o > 200 mg/dl PLUS classic symptoms ofDM e.g. polyuria, polydipsia, ...

❖ N.B.: Corticosteroid-glucose tolerance test: o Dexamethasone 3 mg is given before GTT. o Patients with latent DM give a diabetic curve 2. Urine analysis a. Glucosuria:

o Occurs when glucose serum level exceeds 180 mg/dl o It is not a good indicator for DM diagnosis or assessment of treatment h. Ketonuria: for diagnosis of diabetic ketoacidosis

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

3. Investigations for detection the type of DM : A. Type I DM

1. Insulin level(Normal fasting level 2-20 mlU/L) 2. C-peptide level(Normal fasting level 0.5-2.5ng/ml)

B. Type II DM

o Early normal or increased o

Decreased

o

Latter on decreased

o

Absent

o Islet cell cytoplasmic autoantibodies

3. Autoantibodies

o

Insulin autoantibodies

o Glutamic acid decarboxylase autoantibodies

4. Investigations for monitoring the efficacy of the treatment

1. Self-monitoring of blood glucose: capillary blood glucose is measured by the patients 2. Glycosylated hemoglobin (HbAlC): Glucose Glucose

V

Hemoglobin

Hemoglobin

Glycatecl Hemogioblrii (HbA1c)

C'ilyc4led hemoglobin

Red Blood Cell

Formed by non-enzymatic glycosylation of hemoglobin in a two-step process.

HbAlc is synthesized over the life of RBCs in proportion to the degree of glycaemia prevailing, and thus gives an index of the average blood glucose over the life of Hb molecule i.e. glycemic control in the past 2-3 months. ❖ Normal

♦> Pre-diabetic state (borderline DM)

❖ Diabetes mellitus:

o

0

o

6.5

3. Glycosylated albumin : o Detected by the fructosamine reaction

o Assess glycemic control in the past 2-3 weeks as albumin has more rapid turnover than Hb. 5. Investigations for the cause & complications :

A. Investigaiiuiis of the cause m secondary DM: e.g. Hormones level, liver function tests B. Investigations for complications e.g. blood ketone level, renal function tests, ECG

Diagnostic criteria for DM :

❖ Investigation :

❖ Diabetes mellitus:

a. Fasting plasma glucose level

o > 126 mg/dl

b. 2 hour post prandial plasma glucose

o > 200 mg/dl

level during an OGTT

c. Random blood glucose

o > 200 mg/dl PLUS classic symptoms of DM

d. HbAlc

o

e.g. polyuria, polydipsia,... >6.5%

Management: 1. 2. 3. 4.

Life style modification. Oral antidiabetic drugs. Insulin therapy. New trends in treatment ofDM:Pancreatic transplantation Pancreatic islet cell transplantation

5. Treatment of the cause

6. Treatment of the complications

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Goals of management:

1. Reduce acute & chronic complications & improve the quality of life. 2. Pre-prandial capillary glucose level : 70 -130 mg/dl 3. Peak postprandial(2 hours after the beginning of the meal) capillary glucose level 18 mEq/L

❖

Potassium: check K ievel

o o o

< 3.5:40 mEq 3.5-5.5: 20 mEq > 5.5: don't give & check every 2 hours

3'''' iiter over 2 hour 4"" iiter over 4 hour 1.

V. Hospitalization & care of comatose

Treatment of the cause & precipitating factors. 3. Fluid replacement guided by CVP & UOP: resuscitation of hypovolemic shock: A. Normal saline (0.9%): Average fluid deficit 4-6 L f liter over 30 minutes^ 2"'* liter over 1 hour- 3'''* liter over 2 hour —> 4* liter over 4 hour until correction of dehydration & t UOP. 2.

N.B.: 1. 2. o o

Correction should be slowly to avoid cerebral edema. When the patient becomes euvolemic, check corrected Na level: If there is low Na level —> continue use of normal saline (0.9%). If there is normal Na level or hypernatremia use half normal saline (0.45%).

B. Glucose 5 % infusion if blood glucose level < 250 mg/dl to avoid hypoglycemia 4. Regular insulin:

o o o o o

Bolus dose O.lU/kg IV(SC is ineffective, hypotension ^ fskin blood flow—>1absorption of insulin) Maintenance dose: O.lU/kg/hour IV infusion Continue IV insulin infusion till pH > 7.3 & plasma HC03 > 18 mEq/L then give SC regular insulin before meals, Gradual reduction of glucose (50-100mg/dl/hr) is important to prevent cerebral edema Follow up by blood glucose every hour & give further insulin accordingly.

5. Correct plasma K level (if no oliguria):

o Hypokalemia occurs with insulin treatment due to intracellular shift o Potassium infusion according to the potassium level: c. > 5.5 mEq/L a. one of spinal nerve roots affection —> asymmetric lesion in well defined dermatome

2. A. B.

3. o o o

Mononeuropathy or mononeuropathy multiplex (mononeuritis multiplex): Peripheral nerves : ulnar, median, radial, femoral, lateral popliteal nerves & sciatic nerve Cranial nerves: optic neuritis, 3,4,6 palsy, facial palsy, Argyll-Robertson pupil Proximal motor neuropathy : diabetic amyotrophy or femoral neuropathy: Wasting & weakness of proximal muscles of lower limb Sensory loss in femoral nerve distribution Associations : weight loss & depression

II.

Generalized symmetric polyneuropathy :

/ Acute sensory neuropathy:

Small nerve fiber injury leading to severe pain & hyperesthesia especially at night following an attack of OKA. Chronic distal sensorimotor polyneuropathy: Incidence : The most common type Etiology :

It is due to axonal loss & involves all somatic nerves especially distal sensorimotor nerves of the feet & hands It affects both small(pain & temperature) and large (position & touch) sensory fibers Clinical picture :

Loss of superficial sensation e.g. neuropathic foot ulcers & stock & glove hyposthesia Loss of deep sensation leading to sensory ataxia e.g. loss ofjoint sense, muscle sense(early tender calf muscle • late lost sensation ) Lost ankle reflex with preserved knee reflex Wasting & weakness of small muscles of hands & feet Associations: weight loss & depression

22

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

3. Autonomic neuropathy: A. CVS :

o Painless (silent) myocardial ischemia & infarction o Postural hypotension (orthostatic syncope) due to sympathetic dysfunction

o Resting tachycardia & fixed H.R. i.e. absent variation of HR with deep breathing due to cardiac vagal denervation B. Chest: respiratory arrest(unknown cause) C. GIT:

o Gastroparesis diaheticorum : delayed gastric emptying, nausea & vomiting o Early nocturnal diarrhea, stagnant loop syndrome o Later on constipation D. Genitourinary:

o Impotence: neurogenic, vasogenic, psychogenic, iatrogenic o Neurogenic bladder: sensory atonic bladder, motor atonic bladder & autonomic bladder E. Skin: anhidrosis or hyperhidrosis F. Trophic changes:

o Fall of hair, brittle nails, trophic ulcers, thin skin, loss of SC fat o Charcot's neuropathic joint: painless deformity ❖ Treatment:

A. Strict control of DM: diet, oral hypoglycemic, better insulin B. Physiotherapy for muscle weakness C. Drugs: 1. Aldose reductase inhibitor : Sorbinil

2. Analgesics : NSAlDs, carbamazepine & gabapentin 3. Orthostatic hypotension : o Stock support

o 9 a fluorohydrocortisone, Pindolol(PB with VD), Clonidine o

Midodrine, Octreotide in severe cases

4. Gastroparesis : Metoclopramide, Erythromycin (stimulate gastric emptying) 5. Bladder emptying: Bethanechol 6. Impotence e.g. sildenafil, vacuum erection aids Ocular complications & diabetic retinopathy

HEMORRHAGES

1. Lid:

o 2. 3. 4. 5.

Blepharitis, stye , xanthelasma from hypercholesterolemia Conjunctiva: conjunctivitis Pupil: Argyll Robertson pupil & Homer's syndrome Ocular muscles: extemal ophthalmoplegia (3,4,6 palsy) Iris: Rubeosis iridis (Neovascularization ending in glaucoma)

ABNORMAL QROWTtOF BLOOO VESSELS

HARD EXUDATES

'COTTON WOOL"SPOTS

6. Lens: errors of refraction & diabetic cataract

7. Macula: maculopathy, macular edema which may end in loss of vision 8. Optic nerve: retrobulbar neuritis ending in optic atrophy 9. RETINA : DIABETIC RETINOPATHY:

❖ Incidence : More common in type I DM of long duration than type II DM ❖ Types: A. Non-proliferative: o Microaneurysm, retinal blot hemorrhages

o Exudates : hard exudates (lipid extravasation)& soft exudates (cotton wool spots represents retinal nerve fiber infarction) B. Proliferative:

o Neovascularization & fibrovascular proliferation : this will lead to vitrous hemorrhage, retinal detachment & blindness

❖ Treatment of diabetic retinopathy: 1. Early detection : annual ophthahnologic examination 2. Strict diabetic control

3. Photocoagulation by laser to destroy new vessels 4. Calcium dobesilate (Doxium): regulates capillary permeability & J, neovascularization 5. Vitreoretinal surgery: remove vitreous hemorrhage & repair detached retina

23

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Diabetic nephropathy I. I. Glomerular Injury: Diabetic glomerulosclerosis: Etiology:

Long standing DM (type I, type II) especially poor controlled. Onset within 10- 20 years.

High correlation occur with diabetic retinopathy & diabetic neuropathy Pathogenesis :

Damaged endothehum

c

Protemur a

Sclerosis^— \ Increased mesangiai Exiracetlular matrix

Mesangiai cell hypertrophy

tbickoning

❖ Irreversible loss of nephrons due to glucose toxicity, AGEs,ROS

t cytokines leading to :

1. Compensatory hypertrophy of remaining nephrons with afferent arteriolar dilation 2. Activation of RAAS ^ efferent arteriolar constriction & systemic HTN

❖ I & 2 leading to glomerular hyperfiltration —> glomerular HTN (f intraglomerular pressure) with proteinuria ^ ttt glomerular damage —> glomerular fibrosis & sclerosis —> complete destruction of all nephrons ^ progressive UJ, of renal function ^ CKD

❖ Pathology: The AGEs accumulate in renal glomeruli leading to : 1. Mesangiai expansion associated with increased matrix production (hyalinosis) 2. Thickening of glomerular basement membrane 3. Glomerulosclerosis:

A. Diffuse glomerulosclerosis

B. Nodular glomerulosclerosis : Kimmelstiel-Wilson lesion

/A"* f

#

/ »S •c* I t

[i

■

*

'■«, 'SI-

/a \ •i

A f' ".> ■ T'fli ij

V

o

75% of cases

o

25% of cases

0

Diffuse increase in mesengial matrix

o

Nodular deposition of hyaline material in the periphery of glomeruli

❖ Clinical Picture

1. Nephropathy: A. Early: o Asymptomatic with microalbuminuria. B. Later:

o Heavy proteinuria, which may extend to the classic nephrotic syndrome(> 3.5gm/1.73m^/day.). C. Latest:

o

Chronic renal failure.

2. Hypertension (due to activation of RAAS) 3. Diabetic retinopathy usually precedes diabetic nephropathy

24

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Histological

o

BP

Chronological in years

o

o

1.

3500mg/day)

o > 300 mg/day

glomemlosclerosis

Diffuse or nodular

5.

End stage

Renal function test: late rise in urea, creatinine & creatinine clearance, Renal imaging(US)to exclude obstructive nephropathy. Fundus examination for diabetic retinopathy

A. Symptomatic control B. End stage: hemodialysis or peritoneal dialysis C. Recently: simultaneous renal & pancreatic transplantation

3. Treatment of renal failure:

3.

25

Preventing or delaying macroalbuminuria 4. Efferent arteriolar vasodilation -^j, intraglomerular pressure & proteinuria 5. Modulating some growth factors & cytokines

2. Reverse microalbuminuria

Value of ACEI in DM nephropathy: Control of hypertension

ACE inhibitors e.g. captopril & enalapril or angiotensin II receptor blockers e.g. losartan

2.

1.

By multiple SC insulin injection, but with j, in insulin dose (insulin being metabolized in kidney).

o

1. Strict control of DM:

❖ Treatment:

4.

3.

o

o

details see nephrology book.

albumin/creatinine ratio(ACR),for more

** N.B.: To compensate for variations in urine coneentration in spot-check samples, comparing the amount of albumin in the sample against its concentration of creatinine is helpful. This is termed the

exercise)

involvement. Also screening assay should be done in absence of UTI,DKA & vigorous

results can be considered indicative of renal

10-15

Normal or f

o o

Normal or J,

o

o 30-300 mg/day

o

macroalbuminuria

o

Late: macroalbuminuria(>300 mg/day) with hyaline & granular casts.

5-10

o

Thickening of GBM & mesangial expansion

Mild

4.

Overt nephropathy:

be repeated on two or three occasions over a two to three month period before the

o

o

o

o

o

Screening assays for microalbuminuria(30- 300 mg/day) can be diagnosed from a 24-hour urine collection or spot urine sample.

Normal

o

normoalbuminuria

Silent nephropathy:

3.

o Incipient nephropathy:

albumin excretion, screening assays must

T

Ln

1

0

o

2.

Good metabolic control CAN REVERT renal insult

Glomerular hypertrophy

o

Pre-nephropathy: Hyperfunction, Hyperfiltration

o

o

0

o

o

2. Urine albumin excretion :

Investigations:

GFR

excretion

albumin

Urinary

o

o

Clinical term

o

feature

Clinical Stages Stage

o

1. Of DM

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

II. Interstitial Injury: diabetic

interstitial nephropathy:

jjUherosclerosis 1.

Ischemic injury: Pathogenesis :

Renal hypoperfusion: ischemic injury induced by hyaiine narrowing (atheroscierosis) of the vessels supply the kidney —> f cytokines

fibroblasts activation —♦ tubulointerstitial fibrosis

GRF ^ progressive of renal function ^ CKD Interstitial injury leads to: A.

i GRF

B.

Renovascular hypertension (renal artery stenosis due to accelerated atherosclerosis)

CKD "

C.

RTA type IV (hyporeninemic hypoaldosteronism) with hyperkalemia, hyperchloremic acidosis & hypertension.

2. Acute renal failure:

May occur in the presence of predisposing factors e.g. aminoglycosides, NSAIDs & radiocontrast agents

o

Acute pyelonephritis Acute necrotising papiliitis

3. 4.

Macro-vascular complications (Macroangiopathy) Pathogenesis of atherosclerosis in DM:

Hypergiycemia Hypertension Hyperlipidemia

Hypercoagulabiiity: I Fibrinolysis t Clotting Factors t Fibrinogen t Platelets Aggregation

Endothelial damage

Accelerated

(premature) atherosclerosis

❖ Macro-vascular complications(Macroangiopathy): A. Cerebral: thrombosis, ischemia, infarction B. Cardiovascular :

1. Coronary: angina, MI, arrhythmia. 2. Hypertension :

❖ Definition of metabolic syndrome

❖ Etiology:

according to IDF:

❖ Etiology of HTN in diabetic patient : 1. Part of metabolic syndrome (insuiin resistance —> "f

*1* Central obesity plus 2 of the following: 1. I HDL cholesterol 2. 1 Triglycerides

sympathetic activity & sodium retention) 2. Endotheliai cell dysfunction 3. Diabetic nephropathy 4. Secondary DM e.g. Cushing syndrome

3. HTN

4. Impaired fasting glucose or DM type H ^ For more details: see obesity

❖ Treatment

1. Treatment of hypertension o Target BP: o

Age < 65 years

o

Age > 65 years

120 - 130

130-140

70-80

70 - 80

o o o 2. o o o C.

Avoid thiazides : they are hyperglycemic Avoid non selective B-Blocker : mask warning symptoms of hypoglycemia Best drugs: ACEI, Angiotensin II blockers. Calcium channel blockers I cardiovascular risk: Low dose aspirin (75-150mg/day) Stop smoking Treatment of dyslipidemia Peripheral:

o

Ischemic foot ulcers

o Intermittent claudication & gangrene

26

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Diabetic foot complications: Diabetic foot ulcers SiiVii.iii I 'll"ill -

■ •

I ■ I ■, I.iii--ilitiiiii)iii}nifiti«ri

B. Neuropathic foot ulcer

A. Ischemic foot ulcer

A C. Inspection

o Impaired peripheral circulation o Chronic distal sensorimotor polyneuropathy o Claudication & rest pain o Usually painless, but neuropathic pain may occur. o Trophic changes o High arch o Clawing of toes o Thick callus at pressure points

D. Palpation

o

Cold

o

o

Pulseless

o Palpable pulse

o

Painful ulcers

o

o

Foot sides & distal end of toes

o At the pressure areas e.g. metatarsal heads & heals

A. Etiology B. Symptoms

E. Ulceration

Warm

Painless ulcers

F. Complication o Infections: fungal & bacterial in bctions o Gangrene & amputation o Charcot's joint: painless, deformed & hypermobile Treatment: 1. Control of diabetes 2.

Foot care & bygiene: repeated wash, drying, powdering, cutting toe nail straight to avoid in growing toe nails

3.

For infection: antibiotics, drainage of pus, excision of infected tissue & bone For ischemia: revascularization or amputation in gangrene

4.

Pulmonary complications

o

Pulmonary infection especially: TB(TB follows DM as its shadow)

o

Pneumonia

2. o

During ketosis : Dyspnea

o

Kussmaul breathing (air hunger): deep rapid respiration

o

Acetone odor of breath

1.

GIT complications 1.

Mouth: inflamed gums, dental caries, loose teeth, red glazed tongue

2. Stomach: o o

3.

Dyspepsia due to hypochlorhydria, and gastroparesis diabeticorum In ketosis : pain, nausea, vomiting, hematemesis Intestine: autonomic neuropathy leads to nocturnal diarrhea & stagnant loop syndrome

4. Liver: o o

5.

Fatty infiltration

Tender during ketosis due to glycogen depletion Gall bladder: emphysematous cholecystitis

27

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Genitourinary complications I.

I

Genital:

1. Males: impotence 2. Females:

o

Menorrhagia

o

Moniliasis

o

Pruritus vulvae

II. Urinary: 1. Infections: cystitis, pyelonephritis especially necrotising papillitis 2. Neurogenic bladder. 3. Stones: from stasis & recurrent infection

4. Diabetic nephropathy Joint complications 1. Neuropathic joint: Charcot's Joint (painless, deformed & hypermobile)

2. Stiffjoints e.g. temporomandibular & atlanto-occipital joints 3. Osteoarthritis

Cutaneous complications

m-

it Granuloma Annulare Bullosis diabeticorum

1. Infections:

o

Carbuncle, furuncle , abscesses , cellulitis.

o Rhinocerebral mucormycosis : opportunistic fungal infection of the sinuses, nasal passages, oral cavity, and brain 2. Granuloma Annulare: o

Papules arranged in ring, with depressed center, over extensor surface of fingers

3. Pruritus: Pruritus vulvae 4. Bullosis diabeticorum :

o Superficial bullae, with clear serum which may be hemorrhagic. 5. Carotenemia : o

I Conversion of carotene to vitamin A in liver

o

Excess vegetable intake

6.

Complications of insulin treatment: lipoatrophy & lipohypertrophy

7. Delayed healing of wound 8. Xanthomata & Xanthelasma: hyperlipidemia

9. Necrobiosis lipoidica diabeticorum

10. Diabetic dermopathy (spotted

iPH

o Red painless papules ending by o Red painless plaques with atrophic hyperpigmented skin yellowish center (fat deposition) & brownish border

o

11. Acanthosis nigricans

leg syndrome)

% k

o Hyperpigmentation (brown to black) velvety patches of the skin

lesions

o

Over chin of tibia & may ulcerate

o Due to microangipathy ^ cutaneous blood vessels occlusion

o

Over the neck, axilla & anogential region Insulin resistance —^ f insulin —>

epidermal cell proliferations

28

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Gestational DM(GDM)

❖ Definition:

o Any degree of glucose intolerance first detected during pregnancy

o It develops in 3% of pregnancies especially in 2"'' or 3'''' trimester, o The insulin reserve is not sufficient overcome the antagonists released in pregnancy o

Glucose level retum to normal few weeks after labor,

o 30-50% develop DM after 5-15 years ❖ Effect:

I. 1. 2. 3. II. A.

Effects of pregnancy on DM: t Needs for insulin due to f anti-insulins: estrogen, progesterone, lactogenic hormones & steroids I Renal threshold for glucose (lost in urine). t Incidence of complications e.g. nephropathy. Effects of DM on pregnancy: Maternal complications: t incidence of

1. Abortion

2. Premature labor

3. 4. 5. B. 1.

Pre-eclampsia Post partum hemorrhage Puerperal sepsis Fetal complications: | incidence of High birth weight(macrosomia)

2. Hypoglycemic baby (overactive pancreas in response to maternal hypoglycemia) |

❖ 1. 2. a) o

o

3. Congenital anomalies e.g. anencephaly 4. Hyaline membrane disease (jsurfactant)(respiratory distress syndrome) 5. t Incidence of neonatal death Investigations: Fasting blood sugar > 126 mg/dl Screening glucose challenge test(O'Sullivan test): at 25th week of pregnancy Technique: No previous fasting is required for this screening test. The O'Sullivan test involves drinking a solution containing 50 grams of glucose, and measuring blood levels 1 hour later.

b) Results:

o Gestational DM is suggested by blood glucose > 130-140 mg/dl one hour after 50 gm oral glucose 3. Oral glucose tolerance test(OGTT): a) Technique: o Done in the morning after an overnight fast of between 8 and 14 hours.

o During the three previous days the patient must have an unrestricted diet and unlimited physical activity, o The test involves drinking a solution containing a 100 gm glucose o Drawing blood samples to measure glucose levels at zero time (baseline), P', 2"'' & 3'"'' hour,

h) Results: the diagnosis of GDM is made when any of the following values are exceeded : o o o o ♦♦♦

Fasting blood glucose level > 95 mg/dl 1 hour blood glucose level >180 mg/dl 2 hour blood glucose level > 155 mg/dl 3 hour blood glucose level > 140 mg/dl Management of DM during pregnancy:

1. Monitor DM by blood glucose not urine (renal threshold falls in pregnancy) 2. Lifestyle modification with weight loss

3. Insulin is the preferred medication for treating hyperglycemia in gestational diabetes mellitus as it does not cross the placenta to a measurable extent. 4. Oral hypoglycemic drugs

o Metformin and glyhuride may be used, but both cross the placenta to the fetus, o

ALL OTHER ORAL AGENTS ARE TERATOGENIC.

5. Hospitalization at 36-38 weeks

6. Discontinue insulin after labor & shift to oral drugs 7. Repeated glucose administration to the baby

29

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Brittle DM

❖ Definition:

o Unpredictable fluctuations of blood glucose with recurrent attack of hyperglycemia and/or hypoglycemia ❖ Etiology: A. Causes of recurrent hypoglycemia:

1.

Over treatment by insulin

2. Renal failure

3. Low renal threshold 4. 5. o

6.

Other hidden endocrinal problems e.g. pituitary or adrenal insufficiency. Gastroparesis (due to autonomic insufficiency): It may lead to difficulty in matching the time offood absorption to that of insulin peak. Uncooperative patient.

B. Causes of recurrent hyperglycemia: 1. Intercurrent illness e.g. infection 2. Inappropriate insulin dose ❖ Treatment:

1. Revision of treatment schedule 2. Patient education

3. Insulin pump.

Management of DM during Surgery

1. Stop oral drugs or moderate & long acting Insulin two days before operation to be replaced by short acting insulin 2. Glucose/insulin + potassium solution should be infused during surgery 3. Post operatively maintain infusion till patient is able to eat then restart the preoperative regimen of the patient.

30

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Pancreatic Endocrine Tumors

o o

Endocrine tumors of the pancreas arise from the APUD (Amine precursor uptake and decarboxylation) cells. They may occur with other endocrine tumors as a part of MEN. Gastrinoma (Zollinger-EUison syndrome)

o o o

Pathology : They arise from G ceils of the pancreas

They may arise also from the duodenum, stomach, LNs or spleen 90% of the tumors arise within the gastrinoma triangle bounded by the porta hepatis, neck of the pancreas and the third portion of the duodenum.

o o

»:» 1. o o o

25% of the patients have mulicentric tumors associated with MEN I syndrome The tumor secretes large amount of gastrin that stimulates acid secretion by the stomach Clinical picture: Peptic ulcer:

It's usually occurs in the stomach or the duodenum It's unusual to occur in the esophagus and the jejunum. The ulcers tend to be large, difficult to treat and recur rapidly.

nil!

2. Malabsorbtion and diarrhea : o

Due to high pH in the upper intestine that inactivates pancreatic enzymes and injuries the intestinal mucosa

❖

Investigations:

1.

Multiple peptic ulcers in unusual sites as detected by endoscopy High fasting serum gastrin level(> 200 pg/ml) High basal gastric acid output(>15 meq/hr) Secretin stimulation test: IV secretin (2u/Kg) produces rise in serum gastrin > 200 pg/ml

2.

3. 4.

5. To localize the tumor. o

CT, MRI, 111-Indium-labeled octreotide scintigraphy, angiography and portal venous sampling Treatment:

1. Surgical removal of the tumor 2. Metastatic tumors are treated by omeprazole or chemotherapy Somatostatinoma

(Gastnn)

o

These are tumors of the delta cells and secrete Somatostatin.

o They present by DM,steatorrhoea, weight loss, achlorhydria & gallbladder stones. VIPomas(pancreatic cholera)

o These tumors secrete vasoactive intestinal polypeptide(VIP) which is a neurotransmitter that stimulates adenyl cyclase leading to :

a. WDHA syndrome: chronic Watery Diarrhea (pancreatic cholera) and resultant dehydration, Hypokalemia, Achlorhydria

j

b. Flushing and hypotension (from vasodilation), hyperglycemia & hypercalcemia o Diagnosis : very high level of VIP o

Treatment:

a. Octereotride & metoclopramide b. Tumor resection if possible

31

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Glucagonoma

1. 2. 3. 4.

Pathology: These arise from a-cells and secrete glucagon. Clinical picture: 70 % malignant DM : hyperglycemia & glycosuria Skin : necrolytic migratory erythema GIT: glossitis & diarrhea Genital: vaginitis, urethritis

5. Blood: anemia ❖

Investigations:

1.

Biochemical: | Glucagon | , neuroendocrine markers e.g. pancreatic polypeptide & glucose

2.

Tumor localization : Abdominal US, CT & Octreotide scan : best for evaluation of metastases

❖ Treatment: 1. 2.

3.

Surgery: only curative method Palliative chemotherapy Somatostatin analogues e.g. Octreotide: of choice in necrolytic migratory erythema

Insulinoma: insulin secreting tumor Pathology: These are tumors of the beta cells

The tumor is benign in 95% of cases Most cases are sporadic but some are multicentric as in cases with MEN I. Clinical Pictures:

%

Diagnosing ' cemia

Relief of symptoms with increased plasma glucose 1. 2.

3. ❖

The main presentation is fasting hypoglycemia Patients may present by psychiatric manifestation e.g. amnesia, automatism & bizarre behavior. Focal neurological manifestations may occur. Diagnosis is based on fulfilling the Whipple triad:

1) Symptoms caused by hypoglycemia especially after fasting or heavy exercise. 2) A low plasma glucose measured at the time of the symptoms 3) Relief of symptoms when the glucose is administrated

Differential diagnosis : from other causes of hypoglycemia (see before) Investigations 1.

2. 3.

4.

Fasting blood glucose : low Plasma insulin : high during hypoglycemia High proinsulin serum level due to defective proinsulin metabolism in tumor cells High level of C-peptide

5. To localize of the tumor : o

CT, MRI, 111-Indium-labeled octreotide scintigraphy, angiography and portal venous sampling Treatment

1. Treatment of hypoglycemia

2. Medical treatment: diazoxide or octreotide may suppress insulin secretion 3. Surgical removal of the tumor.

32

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

The pituitary giand %1lliliiU'Miii I 111

11 li •

iiiiiiKj/

3rd ventricle

diencephalon

Embryology:

I optic chiasm neurohypophysis

Mm

Rathke's pouch

adenohypophysis

W

o Anterior lobe: develops from Rathke's pouch, a diverticulum of the roof of primitive buccal wall, o Posterior lobe: developed from floor of diencephalons. *1* N.B.: Remnant ofRathke 's pouch can turn malignant tumor named craniopharyngioma or suprasellar tumor. Anatomy:

1. Pituitary gland: is formed of2 lobes (anterior & posterior) separated by a pituitary cleft. 2. Site:

o

Inside the sella turcica in the middle cranial fossa, and is covered by diaphragma sellae which is pierced by the pituitary stalk that connects posterior lobe with the hypothalamus. internal MKflOr

3.

hypophyseal

carotid

Relations:

arteries

o Anterior: optic nerve o Posterior: posterior clenoid process, dorsum sellae, mid brain & pons.

external plexus

long portal

o Superior: optic chiasma, hypothalamus, and 3"''' ventricle,

veins

capsular arteries

o Inferior : sphenoid air sinus o Lateral: cavernous sinus & temporal lobes. 4. Blood supply:

middle

hypoph yseal

A. Arterial: superior & inferior hypophyseal artery (from internal carotid artery)

short portal

B. Venous: hypothalamo-hypophyseal portal circulation. It consists of: o Primary capillary plexus in the hypothalamus. o Connected along the pituitary stalk to a secondary plexus in anterior lobe. l^^physeal

inrenor hypophyseal arteries

Hypothalamic Hypophyseal Control:

Hypothalamus «"

GnRH

^

1

CRH

^

^

PRH

TRH

M 1

GHRH

^

^

Adenohypophysis FSH/LH

ACTH

ADH

Oxytocin

I

Neurohypophysis

TSH

^PROLACTIN

^

I

]

GH

i

Target organ Adrenal Gonads Cortex

Thyroid

1 Mammary| giand

33

Mammary

(and all hadyL—'

Kidney

gland

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ The hormones of hypothalamus reach pituitary gland through: A. Anterior pituitary: adeno-hypophysis

B. Posterior pituitary: neuro-hypophysis Paravertnni* ^

■I)

'"W ff vk

PpiUderpMliiy

H BBSea

^ WWHI rtw vtnousouflkxt

o

By vascular connection: hypothalamic hormones —> hypophyseal portal veins —> anterior pituitary.

o By neural connection: hypothalamic hormones supraoptic and paraventricular nuclei of the hypothalamus —> pituitary stalk —> posterior pituitary.

❖ These hormones are:

A. 1. 2. 3. 4. B. 1. 2, ❖

Releasing hormones or factors : Corticotropin-releasing hormone(CRH)—> stimulate release of ACTH Thyrotropine releasing hormone(TRH) —> stimulate release of TSH & prolactin hormone Growth hormone releasing hormone(GHRH)—> stimulate release of growth hormone Gonadotrophin releasing hormones(GnRH) stimulate release of LH & FSH Inhibitory hormones or factors :

Growth hormone releasing inhibiting hormone (somatostatin) —> inhibit release of growth hormone Prolactin inhibiting factor(dopamine) —>■ inhibit release of prolactiri The control of these factors is regulated by:

1. CNS control: Stress, emotion.

2. Negative feed back: o Long feedback: from target organ to pituitary or hypothalamus. o Short feedback: from pituitary to hypothalamus.

i Short-loop negative

1 Long-loop negative

Structure & Functions Of Pituitary Gland:

Anterior

pituitary

feedback

I. Anterior pituitary (pars distalis) hormones: A. Chromophobe cells: the function of these cells is obscure till now B. Chromophil cells: i. Acidophil cells: these cells secrete:

1. 2. ii. 1. o

I ■

Endocrine

gland ;

Growth hormone(GH) (somatotrophin) T Prolactin hormone(mamotrophin) Basophil cells: these cells secrete: Gonadotrophin hormones: FSH & LH Follicle-stimulating hormone (FSH): stimulates graafian follicles in $ and spermatogenesis in

■ ;r.T.-,-.T.riT3

o Luteinizing hormone(LH): stimulates ovulation in $ and secretion oftestosterone in activate liver & other tissues to control the secretion of an insulin-like growth factor - 1 (IGF - 1) previously known as Somatomedin C. o This compound functions as hormone controlling the growth of cartilage & soft tissues. 2. Gland: secreted by acidophil cells of the anterior pituitary 3. Action:

a. Carbohydrate:

o Diabetogenic: fgluconeogenesis in liver & J. uptake of glucose in muscles & fat {insulin antagonism} b.

Fat:

o Ketogenic: stimulate lipolysis, leading to }free fatty acids. c. Protein:

o Anabolic: | chondrogenesis, osteogenesis, growth of muscles and viscera. d. Electrolytes: o fNa (Aldosterone like)

o t Ca (t intestinal absorption) o t K & P04(secondary to f protein synthesis) e. Prolactin like activity

❖ N.B. It's similar structurally to prolactin & human placental somatomamotropin 4. Regulation: A. Blood glucose: {glucose ^ f GH. B. Amino - acid: arginine —GH.

C. Hypothalamic control: stress, exercise } GH. D. Estrogen, a — receptors, cortisol, dopamine, GABA,Serotonin —>{ GH. Gigantism

S HypothalMiMit

❖ Definition: Increased GH secretion BEFORE fusion of epiphysis.

W

❖ Etiology: 1. o o o 2. 3.

Pituitary : Acidophil hyperplasia (more common), adenoma, carcinoma May secrete GH only or co-secrete GH & prolactin Either alone or associated with hyperparathyroidism & pancreatic tumor(MENI). Hypothalamic hamartoma :}GHRF or{ GH-RIF Extra-pituitary: Pancreatic islet cell tumor or bronchial carcinoma. Clinical picture:

1. Generalized overgrowth of metaphysis of long bones leading to disproportionate gigantism (span > height and lower segment > upper segment) 2. Later on features of acromegaly develops 3. End (decline) stage : weakness, fatigue due to pituitary insufficiency Differential diagnosis of tali stature: see later.

❖ Investigations & treatment as acromegaly N.B.: Pituitary adenomas:

❖ The most common hormone-producing adenomas are named in conjunction with the hormone they stimulate: o Growth hormone-secreting pituitary adenomas, Prolactin-secreting pituitary adenomas (prolactinomas). Thyroid stimulating hormone secreting pituitary adenomas or ACTH-secreting pituitary adenomas.

35

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Acromegaly

*«* Definition: Increased GH secretion AFTER fusion of epiphysis. | ❖ Etiology: as gigantism, but pituitary Adenoma is more common

❖ Clinical picture: gradual onset with slowly progressive course ' .

I.

_ .

.

I

■

. .

_ .

General overview :

A. Head: Acromegalic fades(Ape like): 1. Big elongated skull

2. Prominent bony proeess : frontal bossing & maxillary overgrowth 3. Prominent supraorbital ridges , infraorbital puffmess 4. Big nose, lips & ears

5. Prognathism (prominent lower jaw) with widely separated teeth

6. Big tongue: true (hypertrophy) macroglossia ^traumatic ulcers, difficult talking, deglutition & obstructive sleep apnea.

7. Husky voice (thickened vocal cords)

8. Effect of DM on teeth, eye, skin, ... (see DM): 30 % ofcases have DM(GH is diabetogenic) B. Upper & lower limbs changes :frequent change of rings & shoes due to:

o Big hands (spade shaped) with broad fingers & blunted tips (sausage shaped) o Big feet with prominent heel (calcaneal bone C. Skin changes :

o Skin tags in neck , may be associated with polyposis coli (precancerous) o Skin is thickened, thrown into folds & wrinkled (lipolysis of subcutaneous fat) o Greasy oily skin (seborrhea)± sebaceous cyst o Excessive sweating ± malodorous D. Thyroid exam : goiter (euthyroidism) H. Systemic examination : A. CNS:

1. 2. o o 3. o o

Pressure manifestation e.g. bitemporal hemianopia in case of pituitary macroadenoma Motor power : Early increased muscle power, Later on decreased muscle power (pseudohypertrophic myopathy) Sensation : peripheral neuritis (paresthesia of hands & feet) due to: Interstitial neuropathy Entrapment neuropathy : carpal tunnel syndrome & tarsal tunnel syndrome

o Diabetic neuropathy

4. Joint: Osteoarthritis & kyphosis B. CVS:

1. Hypertension (salt & water retention + hypertrophy of the wall of the BV) 2. Cardiomegaly 3. HE due to HTN & Cardiomyopathy C. Abdominal:

1. Umbilical hernia , divarication of recti

2. Visceromegaly e.g. hepatosplenomegaly 3. Colonic polyps

risk of colonic cancer

4. Genital examination:

a. In females : menstmal irregularities & Galactorrhea b. In males : o o

Gyneeomastia & Galactorrhea Sexually: 2 stage Early : increase desire & potency due to effect of GH Later: impotence due to : Prolactin like action of GH

t Prolactin in 30 % of cases(damage of pituitary stalk or presence of mixed GH & prolactin secreting tumor) Tumor destroys cells of gonadotropin DM

36

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Investigations: I.

Laboratory:

A. Blood chemistry :

o o B. 1. 2.

t Glucose & 1 free fatty acids Hypercalcemia & hyperphosphatemia Hormonal profile: GH level: increased (Normally < 5 ng/ml in adult) IGF-I level or Somatomedin C assay: increased

3. Prolactin level: increased in 30% of cases

C. Oral glucose GH suppression test:

o Normally: after overnight fasting, 50-100 g glucose I GH level o Failure of suppression of elevated GH to after 75 g oral glucose. D. Measurement of thickness of skin fold over dorsum of hands & lower part of triceps

O >3.5 mm at 25 years or > 3 mm at 65 years suggests acromegaly H. Radiological; A. X-ray: 1. Skull:

Thickening of cortex Pneumatization of frontal air sinuses

Prognathism with wide separation of teeth Ballooning (widening) of sella turcica

o o

2. Hands: o

Broadening of phalanges

o

Tufting of terminal phalanges(mushroom like).

B.

CT,MRI of sella turcica:

Accurate diagnosis of pituitary tumors & detect suprasellar extension ❖ Treatment:

1. Symptomatic treatment ofDM & hypertension . 2. Medical hypophysectomy (hormone antagonist): A. Somatostatin analogue(GHRIF): Octreotide

Lanreotide

Pasireotide

100 meg SC/

90mg SC

40 mg IM

8hr

/month

/month

B. GH receptor antagonist Pegvisomant

10- 30 mg SC /day

C. Dopamine-receptor agonists Bromocriptine

Cahergoline

Quinagolide

10 -30 mg orally /day

0.25 mg -1 mg orally

50-150 pg orally /day

/twice a week

3. o o 4. o o

Surgical hypophysectomy; Indications : failure of medical treatment or large tumor with pressure symptoms Technique: transsphenoidal(the most common) or transfrontal (in extrasellar extension) Pituitary irradiation: Indications: failure of medical treatment or contraindication of surgery Technique: conventional radiotherapy or by transsphenoidal implantation ofradio-gold or yttrium 90

37

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Hyperprolactinemia Physiology of prolactin hormone: 1. 2.

Hormone: polypeptide that works on surface receptors Gland: it is released from acidophils of anterior pituitary

3. Actions: a.

b. c.

Stimulate breast development; Growth of ducts & alveoli with estrogen during pregnancy Stimulate milk production by formation of casein & lactalbumin Inhibit ovulation by decreasing secretion of LH & FSH

d. GH like action 4.

t

o o o o

i

Stress, Sleep, Suckling, Serotonin o Prolactin inhibiting factor(dopamine) Thyrotropin-releasing hormone(TRH) o Drugs: Naloxone & methysergide Drugs: Opiates, metoclopramide Vasoactive intestinal peptide

Etiology:

A. Physiologic causes: pregnancy, lactation, stress, sleep. B. Pharmacological:

1. Dopamine antagonists : phenothiazine, metoclopramide 2. Dopamine depletion : methyl-dopa, reserpine

3. Others: estrogen, Opiates, tricyclic antidepressants and selective serotonin reuptake inhibitors C. Pathological:

W 1. Prolactin secreting pituitary tumors:

o Prolactinoma: pituitary adenoma(micro-adenoma lcm)secrete prolactin o Mixed pituitary adenoma: co secrete GH/Prolactin o Prolactin secreting pituitary carcinoma

2. Hypothalamic or pituitary staik lesions (inhibits releases of dopamine): o Granulomas, sarcoidosis, carotid aneurysm 3. 4. 5. 6.

hypothalamus

Primary hypothyroidism: f TRH Liver cell failure : J, metabolism of prolactin Renal failure : J, clearance of prolactin Polycystic ovarian syndrome

CnRH

anterior

pituitary

Pathogenesis:

❖ 1 Prolactin leading to :

FSH,LH

A. Galactorrhea:

o Milk production in men or

effects on ovary

o Milk production in women in absence of pregnancy, parturition or breastfeeding B. Inhibition of GnRH —> hypogonadism —> hypoandrogenism & hypoestrogenism

prolactin

4 effects on breast

38

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Clinical picture: Hormone action:

B. In females : amenorrhea galactorrhea syndrome

A. In males:

o

GALACTORRHEA

0 Testicular atrophy o Impotence

o Amenorrhea(|mid cycle LH surge.) o Breast atrophy

0 Loss of axillary and pubic hair

H

o Loss of libido & infertility o Osteoporosis

"

II. Of cause: pressure manifestations in pituitary macroadenomas: o Visual defects : bitemporal hemianopia o Hypopituitarism

Investigations:

I. Laboratory: A. Hormonal profile o Prolactin level : increased (N.B.: > 300 ng / ml is diagnostic of pituitary adenoma) B. Of the cause: thyroid functions test for myxedema 11. Radiological: CT,MRI of sella turcica: o CT scan can detect pituitary macroadenoma o MRI can detect pituitary microadenoma ❖ Treatment:

1. Treatment of cause e.g. myxedema 2. Prolactin antagonist = Dopamine receptor agonists C. Quinagolide B. Cahergoline A. Bromocriptine o 10 -30 mg orally /day o 0.25 mg -1 mg orally /twice a week o 50-150 pg orally /day

o After treatment resumption offertility and shrinkage of small tumors usually occurs 3. Surgical hypophysectomy :

o Indications : failure of medical treatment or large tumor with pressure symptoms

o Technique: transsphenoidal (the most common)or transfrontal (in extrasellar extension) 4. Pituitary irradiation.

o Indications: failure of medical treatment or contraindication of surgery

o Technique: conventional radiotherapy or by transsphenoidal implantation ofradio-gold or yttrium 90

39

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Syndrome OfInappropriate ADH(SIADH)Secretion i.e. fADH level in blood

❖ Physiology of Antidiuretic hormone(ADH): 1.

Hormone:

o Polypeptide hormone that works on vasopressin 1, and vasopressin 2 receptors 2. Gland:

o Posterior pituitary hormones are synthesized in supraoptic & paraventricular nuclei of hypothalamus & pass down the neural axon to be stored in posterior pituitary (neurosecretion). 3. Action:

o o 4. o

VI receptor : Vasoconstriction action V2 receptor : Stimulate water reabsorption by renal tubules water retention Regulation: Release is Stimulated by osmoreceptors in response to increase plasma osmolarity, hypovolemia, pain, stress, nicotine and carbamazepine. o Inhibited by: decreased plasma osmolarity, hypervolemia, hypertension & alcohol Etiology:

) 1. 2. 3. 4.

CNS: infection (abscess, meningitis), bleeding(SAH,ICH), tumors, head trauma. Cancer: small(oat) cell carcinoma of lung, leukemia, lymphomas, carcinoma of prostate, thymus, pancreas

Chest: pneumonia, TB,lung abscess Metabolic: Alcohol withdrawal, Porphyria 5. Drugs:

Compensatory

^ANP

inappropriate ADH

o Chlorpropamide, Carbamazepine, Cyclophosphamide Salt and Water

water

retention

Clinical picture:

excretion

Salt

Hyponatraemia Tendency to

❖ Hyponatremia :

Hyponatraemia Euvolaemia

hypervolaemia

o tADH —> water retention (intoxication) results in diiutional hyponatremia

o Then volume expansion —> secondary natriuresis (tAN?)^ euvoiemic hyponatremia i.e. hyponatremia without edema or hypertension

❖ Clinical picture: headache, anorexia, nausea, vomiting, Confusion, Convulsion, Coma & Death. Investigations: I.

Hormone function: 1. Serum:

o Low serum sodium ( 30 mmol/L) despite of significant hyponatremia o Low serum osmolarity ( 300 mosmol/L) H. HI.

Hormone level: increased ADH level

NORMAL renal, adrenal and thyroid functions. Treatment:

I.

Symptomatic treatment:

1. Restriction of fluid intake to 500-1000 ml/day 2. For severe hyponatremia:

o Hypertonic saline(3%)is given slowly IV with furosemide to avoid fluid overload,

o Serum Na should be corrected slowly to avoid central pontine myelinolysis. H.

Hormone antagonism:

A. Demeclocycline:

o Inhibit action of ADH on renal tubule is given for patients intolerant or unresponsive to fluid restriction B. Tolvaptan : ADH (vasopressin) V2 receptor antagonists HI.

Treatment of cause.

40

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Hypopituitarism in childhood: J, GH + > one of anterior pituitary hormone deficiency

1. Pituitary Dwarflsm Levi-Lorain syndrome Primary deficiency of GH in childhood

❖ Etiology: 1. Deficiency of GH-RH from hypothalamus 2. Deficiency of GH from pituitary (idiopathic, suprasellar cyst, craniopharyngioma). 3. End organ unresponsiveness (as in African pygmies) Clinical picture: Proportionate dwarfism: Upper segment = lower segment Span = height Childish features: small lips, silky hair

1. o o

2.

o

Hypoglycemic symptoms specially after eating which stimulate insulin release Hypogonadism may appear: dwarfism + hypogonadism = pituitary infantilism In males : cryptorchidism (testosterone stimulate gubemaculum)

o

In females : amenorrhea and infertility

3. 4.

❖ Differential diagnosis of short stature: see later. Investigations: A.

Fasting level of GH: low

B. GH Stimulation test:

1. Insulin tolerance test o

o o

0.1 U/kg IV insulin is injected to induce hypoglycemia 7pg//F

•

GH

•

Cortisol •

❖ Abnormal

• Hypopituitarism: GH deficiency(< 3 pg/F)

> 550 nmol/F. • Failure to increase above normal basal level:

• Hypopituitarism: 400 - 550 nmol/L. • Cushing's syndrome : < 170 nmol/L 2. Clonidine test

3. L-arginine infusion test

Treatment: 1. Recombinant DNA GH:

o o o 2. o

Start by 0.27 mg SC/day in the evening Increase every 4-6 weeks will 0.7 mg/day Follow up body weight, blood pressure, lipid profile, HBAIC,IGF-1 Gonadotrophin in case of cryptorchidism : Start at 9 years to prevent testicular atrophy.

41

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

2. Froelich's syndrome

❖ Etiology: Pstuitdry

•

. stjlk—

o Commonly idiopathic

o May result from hypothalamo- pituitary tumor as craniopharyngioma ❖ Clinical picture: 1. 2. o o

Posterior pituitary: Diabetes insipidus Anterior pituitary: Pituitary dwarfism : dwarfism only Pituitary infantilism : dwarfism & hypogonadism

3. Centers:

o Polyphagia, hypersomina.

o Samboxa shape obesity : fat is deposited in the face, shoulder, truck, hips but sparing the extremities o Genu valgum o ± Autonomic disturbance, mental retardation, visual disturbance.

3. Laurence Moon Biedl Syndrome

o A rare congenital autosomal recessive disease characterized by : 1. Features of Froehlich's syndrome 2. Polydactyly (or syndactyly) 3. Mental retardation

4. Retinitis pigmentosa.

Hypopituitarism in adults 'u .

1.!

I. Isolated hormone deficiency o I TSH: secondary hypothyroidism o 1 ACTH : secondary adrenal failure

II. Panhypopituitarism: Simmond's disease

42

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

II. Panhypopituitarism: Simmond's disease ❖ Etiology: jiim..

^Cj 1. Idiopathic: autoimmune disease 2. Ischemic: SHEEHAN SYNDROME : Post-partum anterior pituitary necrosis 3. Injury & destruction of pituitary gland by :

A. latrogenie: CNS surgery e.g. hypophysectomy, pituitary irradiation & head injuries (skull base fracture) B. Infiltrative/Granulomas: Gumma syphilis, sarcoidosis, tuberculosis, hemochromatosis & histiocytosis C. Empty seila syndrome: /4 ig

3Iltv

SOlv ""

1. Definition:

o Hemiation of the arachnoid membrane,through a defect in diaphragma sellae with extension into sella turcica so that the sella is filled with CSF (appears empty)compressing & flattening of the pituitary gland 2. Etiology:

a. Primary :

o Idiopathic, associated with females, obesity, HTN,CSF rhinorrhea & idiopathic intracranial hypertension b. Secondary: CNS surgery e.g. hypophysectomy, pituitary irradiation & head injuries. 3. Clinical picture:

o Asymptomatic (normal pituitary function) o Hypopituitarism o Pressure manifestations e.g. Headache & visual field defect May be associated with secreting pituitary tumor e.g. prolactin, GH,ACTH.

4. Pituitary tumor

Chlasm

Postertor

Ituitaiy Sella Turcica Pitulta

o Intrasellar tumor: e.g. acidophil, basophil & chromophobe adenoma o Suprasellar tumor: craniopharyngioma (remnant of Rathke's pouch).

❖ N.B.: pituitary apoplexy: ACUTE hemorrhage or infarction in pituitary adenoma

43

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Sheehan Syndrome

(Post-partum anterior pituitary necrosis) Etiology:

tsize

J,venous pressure

Risk factors during pregnancy :

The anterior pituitary gland double in size during pregnancy without corresponding increase in blood supply The anterior pituitary gland blood supply has low pressure venous system Hypercoagulable state at the end of pregnancy Pathogenesis :

Post-partum hemorrhage —> J, blood pressure —> V.C. with slow circulation—> coagulation -+ pituitary infraction ■ loss of anterior pituitary function

Posterior pituitary is not affected because of its direct blood supply ❖ Clinical picture

GH is the first hormone to be compromised followed by deficiencies of gonadotrophins,TSH & ACTH.

W A. Gonadotrophins(FSH & LH)& prolactin deficiency : secondary hypogonadism: A. In males:

0 Testicular atrophy o Impotence

B. In females :

o FAILURE TO ESTABLISH LACTATION (i prolactin) after delivery is the earliest manifestation followed by amenorrhea o Breast atrophy

o Loss of axillary and pubic hair o Loss of libido & infertility o Osteoporosis B. TSH deficiency : secondary hypothyroidism o Clinical picture of myxedema except: 1. Mild to moderate weight gain 2. Skin is thin, atrophic with wrinkling around eyes & mouth 3. Hypercholesterolemia is rare C. ACTH deficiency : secondary adrenal failure: o Clinical picture of primary adrenal failure except; 1. Hypotension is not severe due to continued release of aldosterone (not under ACTH control) 2. Depigmentation of body occurs (J, ACTH & J, MSH) D. Deficiencyof GH : o Atrophy of viscera (splanchomicria) o Skin wrinkling, weakness, wasting, o Fasting hypoglycemia (f sensitivity to insulin) o Alabaster skin : pallor with hairless skin E. Coma may occur in terminal cases due to : 1. Addisonian crisis (jcortisol) 2. Hypoglycemia (J, GH & cortisol) 3. Hypothermia (J.TSH) 4. Water intoxication (cortisol & thyroxin are essential for water excretion)

44

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Differential diagnosis from :

❖ Primary hypothyroidism : Thyroid

❖ Secondary hypothyroidism : Pituitary myxedema

myxedema o

Examination

o

Normal axillary & suprapubic hair t TSH, tcholesterol

0 o o o 0 o

TSH stimulation test shows no elevation of

o

Marked increase in BW, Macroglossia

o Hypertension, Hyperglycemia o Pallor with yellow tinge of skin 0 Normal gonadal function o o Investigations: o o

Mild increased in BW,No macroglossia Hypotension, Hypoglycemia Skin is depigmented Amenorrhea & breast atrophy Loss of axillary & suprapubic hair 1 TSH, ^cholesterol TSH stimulation test shows elevation of T3 &T4

T3 &T4

o Adrenal & gonadal function are abnormal

1) Pigmentation

o

2) Adrenal crisis & hypotension

o

o Adrenal & gonadal function are normal

❖ Primary adrenal failure (Addison's disease) Hyperpigmentation occurs due to excess ACTH

Common,absent aldosterone

»!• Secondary adrenal failure (Hypopituitarism) o Depigmentation due of deficiency of ACTH & MSH o Rare, due to presence of aldosterone which is not under ACTH control

3) Thyroid «& gonadal function 4) ACTH 5) ACTH stimulation test

o

Low

o High

o

Low

o

o

o

Normal

Cortisol doesn't increase after

ACTH injection

Cortisol increase after ACTH

injection

C. From primary hypogonadism: ❖ Clinical picture: o Features of hypogonadism

o Disproportionate gigantism if the condition starts in childhood ❖ o o D. ❖ o o o ❖

Investigations: High FSH/LH Thyroid & adrenal function are normal Anorexia nervosa (functional hypopituitarism): Clinical picture: More common in young female with psychiatric disturbances with aggressive attitude, Marked anorexia, weight loss, emaciation & dehydration Body hair & breast are normal Investigations: Thyroid & adrenal function are normal

❖ Investigations :

I.

Laboratory:

A. Blood picture:normocytic normochromic anemia B. Blood chemistry : hypoglycemia C. Hormonal profile:LOW 1. Prolactin : low

2. Gonadotrophins(FSH & LH)& sex hormones: low 3. TSH,T3 & T4: low 4. ACTH & Cortisol: low

5. GH: low, GH Stimulation test (see before) D. Triple bolus stimulation test(Combined insulin tolerance test):

o Technique: give IV insulin followed by gonadotropin-releasing hormone(GnRH)& thyrotropin-releasing hormone (TRH). o Normally : ttt GH, ACTH,FSH, LH,TSH & prolactin o Abnormally : Failure to increase in all hormones indicates panhypopituitarism 11. Radiological : o X-ray, CT scan & MRl sella tursica: normal in Sheehan syndrome

45

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Treatment:

A. Symptomatic: glucose, and saline infusion and avoid eold weather or stress. B. Hormone replacement: 1. Gonadal hormones:

A. If fertility is required :gonadotrophins are given

B. If fertility is not required: sex hormones are dven

❖ Males

o Human chorionic gonadotropin(HCG)supply LH

o Testosterone propionate

for spermatogenesis ❖ Females

o Pulsatile GnRH for ovary stimulation

o

Ethinyl estradiol

2. Hydrocortisone: 25-75 mg / day, BEFORE thyroxin 3. Thyroxin:

o Should be started in a gradual increasing dose 0.1 mg - 0.2 mg/day o Should FOLLOW cortisol to avoid adrenal failure since conversion of T4 to T3 needs cortisol. 4. ± GH replacement hy recombinant DNA derived GH :

o GH therapy improves body composition, work capacity & psychological well being C. Treatment of cause e.g. blood transfusion to correct hypovolemic shock D. Treatment of complications e.g. management of Addisonian crisis

❖ Simmond's disease:

Panhypopituitarism : anterior & POSTERIOR dysfunction Clinical picture the same as Sheehan Syndrome + Diabetes Insipidus(NB DI features may be HIDDEN BY ASSOCIATED CORTISOL DEFICIENCY in

panhypopituitarism as steroids are necessary for excretion of water load) Pressure manifestation e.g. bitemporal hemianopia in pituitary macroadenomas ± Galactorrhea in high prolactin lesions e.g. prolactinoma (pituitary adenoma secretes prolactin) or lesions causing pituitary stalk section or compression Causes of coma in Simmond's disease as Sheehan syndrome +: Pressure by tumor on brain stem reticular formation

Pituitary apoplexy; acute hemorrhage or infarction in pituitary adenoma Investigations as Sheehan Syndrome +: A. Prolactin level: high B. Radiological evidence of pituitary tumor : a) X-ray sella tursica: i.

Intrasellar tumor:

o Ballooning of sella o

ii.

Double floor in eccentric tumor

o Destruction of dorsum sellae & posterior clenoid process o ± Encroachment on sphenoidal sinus Suprasellar tumor: saucerization of sella & calcification

b) CT scan & MRI sella tursica: the best.

5. o o o

Treatment: as Sheehan Syndrome + ADH : Desmopressin (N.B.: initiation of steroid therapy will unmask co-existing DI) Treatment of the cause e.g. surgical removal of pituitary adenoma. Treatment of the complications e.g. pituitary apoplexy: transsphenoidal surgical decompression of the tumor

46

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Diabetes Insipidus(DI)(Tasteless Diabetes) ❖ Definition :

o Impaired water reabsorption by kidneys due to decrease ADH secretion by posterior pituitary or impaired response of kidneys to ADH

❖ Etiology: I. II.

Gestational Dl: t vasopressinase enzyme form placenta —> f ADH destruction Neurogenic (cranial, pituitary) Dl :

Deficiency of ADH due to damage of hypothalamo-hypophyseal axis:

G

1. Idiopathic

2. Inherited : Familial DI: Wolfram syndrome

o Autosomal recessive genetic disorder, due to defects in osmoreceptors which are insensitive to changes in osmotic pressure of plasma

o 3. 4. 5.

Characterized by DIDMOAD: cranial Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness. latrogenic : CNS surgery e.g. hypophysectomy, pituitary irradiation & head injuries(SAH,ICR) Infiltrative/Granulomas: sarcoidosis, tuberculosis, hemochromatosis, histiocytosis. Leukemia, Lymphomas Intra or suprasellar pituitary tumors, hypotbalamic tumors or metastasis e.g. from breast

III.

Nephrogenic Dl: resistance of ADH

Jfii

A. Hereditary: X- linked disease, in which the renal tubules are insensitive to ADH. B. Acquired diseases: 1. Renal: Renal tubular acidosis, polycystic kidney 2. Blood: Sickle cell anemia, multiple myeloma 3. Electrolytes: Hypokalemia, Hypercalcemia 4. Drugs: lithium, demeclocycline & methoxyflurane

Clinical picture:

I.

Hormone action:

1. Polydipsia 2. Polyuria (2-20L/day)& nocturia. 3. Dehydration & hypovolemic shock may occur

H.

Features of cause e.g. pressure manifestation of pituitary tumors Differential diagnosis of polyuria: for more details see nephrology book:

1. 2. 3. A. B. 4.

Psychological(compulsive water intake): Psychogenic polydipsia. Physiological (functional): high fluid intake : water, coffee, tea, beer Pathological: Renal causes e.g. Diuretic phase of acute renal failure Endocrinal causes e.g. Diabetes insipidus & Diabetes mellitus Pharmacological e.g. excess diuretics

5. Miscellaneous e.g. transient polyuria occur after attacks of SVT.

47

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Investigations: For diagnosis of DI:

I.

2. Urine:

1. Serum:

o Polyuria (2-20L/day),low specific gravity (1001-1004) o Low urinary sodium (< 10 mmol/L)

o Increased serum sodium (> 145 mEq/L)

o Increased serum osmolarity (> 290 mosmol /L) o Low urine osmolarity(< 300 mosmoI/L) 3. Water deprivation test: after 8 hours water deprivation: A. Psychogenic polydipsia 1. Plasma osmolarity

o

J, (over-hydration)

B. Diabetes insipidus(DI) o

t

2. 8 hours water deprivation test: o

o i o t

Urine volume

o Urine osmolality

o t i-6- Polyuria persists o 1 i.e. Failure to concentrate urine (specific gravity fail to rise > 1010)

II. For diagnosis the type of DI: Desmopressin test: 20 pg intra-nasal spray: o If urine become concentrated ^ neurogenic DI o If urine fail to concentrate —> nephrogenic DI III.

Skull X-ray, CT scan & MRI to exclude pituitary tumors. ntAAMAff IIT)CAI5

Treatment;

A. Symptomatic treatment:

/:T^

o Replacement of fluids, electrolytes & vitamins o Avoid purines (coffee , tea) B. 1. o o 2. C. 1. 2. 3.

Minirin

Replacement therapy for neurogenic DI: Desmopressin (Des-amino D arginine vasopressin(DDAVP): Intranasal 10-20 pg / 12hours. Orally : 100 -200 pg / 12 hours Chlorpropamide: f ADH from hypothalamus in partial deficiency. Drugs for nephrogenic DI: sensitize renal tubules to endogenous ADH: Carbamazepine Thiazides diuretic (paradoxical effect). Amiloride: drug of choice in lithium toxicity induced DI . ♦:

Etiology

3. Chest e.g. pneumonia, TB 4. Metabolic e.g. Porphyria 5. Drugs e.g. Chlorpropamide

Infiltrative, tumors C. Nephrogenic DI: o Hereditary o Acquired(Renal, blood, electrolytes, drugs)

Serum osmolarity Urinary sodium Urinary osmolarity

o

Low

o o

High High

o

Low

o

Low

Treatment

1. Restriction of fluid intake

UOP

2. For severe hyponatremia: Hypertonic saline(3%) with furosemide

it,

0 Idiopathic, Inherited (Wolfram syndrome), latrogenic ,

o Hypovolemic o Polyuria o Hypematremia o High

Serum sodium

30

B. Neurogenic DI

High Luvolemic or hypervolemic Normal or low (oliguria) Hyponatremia

Volume status

Desmopressin acetate

A. Gestational DI

o o o o

ADH

0.1 mg

:♦ DI

SIADH

1. CNS e.g. SAH,ICH 2. Cancer e.g. small (oat) cell carcinoma of lung

Tablets

o

Low

1. Neurogenic DI: o Desmopressin , Chlorpropamide

2. Nephrogenic DI: o Carbamazepine ,Thiazides, Amiloride

3. Demeclocycline 4. Tolvaptan

48

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

The thyroid gland

❖ Physiology of thyroid hormone: 1.

Hormone structure & synthesis:

o Iodine trapping: circulating iodide is taken by the thyroid gland and converted to nascent iodine o Binding: Tyrosine bind to iodine to form mono-and di-iodotyrosine.

o Coupling: Thyroxin (T4)is formed by coupling oftwo molecules of di-iodotyrosine while T3 is formed by binding of mono and di-iodotyrosine molecules(T3 is four time more potent than T4) o Storage: T3 and T4 combine with globulin to form thyroglobulin o

Release:

■

Thyroglobulin is split by protease enzyme to release T4 (tetra- iodothyronine=thyroxin)& T3 (tri- iodothyronine)

■

Parafollicular C cells of thyroid glands secrete calcitonin

o Circulating hormone: is either free (physiologically active) or protein bound to thyroxin binding globulin(TBG), pre-albumin and albumin. II.

Hormone function:

o The thyroid hormone acts by binding to intra-cellular nuclear receptors to induce DNA transcription, o

The resulting action includes:

1. 2. 3. 4. 5. 6.

Calorigenic (tmetabolic rate): increased oxidative phosphorylation and oxygen consumption Carbohydrate: increase glucose absorption, utilization & glycogenolysis in the liver Protein: normal level T4 is anabolic while in high level increase protein catabolism Fats: decrease serum cholesterol level(|excretion in bile) Vitamin: essential for hepatic conversion of carotene to vitamin A BM:stimulate erythropoiesis

7. CVS:

o o o 8.

|heart rate & stroke volume —> f COP f systolic pressure & pulse pressure Peripheral YD j peripheral resistance —> jdiastolic pressure Promote skeletal, mental and sexual development

III.

o o o o

Regulation:

Regulation is through the hypothalamic-pituitary-thyroid axis TRH is released from the hypothalamus and stimulates the release of TSH from the pituitary, TSH stimulates the synthesis and release of thyroid hormones from the thyroid glands T3 & T4 has negative feed back effect on the pituitary and the hypothalamus

0——►

\ Hypothalamus

Pituitary

Thyroid gland Target tissues Heart Nerves Bone Liver. Muse e

49

Liver Muscle Glands

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Primary thyrotoxicosis(Grave's disease= Basedow disease)

Intolerance to Heat

Fine, Straight Hair

Bulging Eyes Facial Flushing Enlarged Thyroid

Tachy^ndla Finaer

t Systolic BP Breast Enlargement Weight loss

Ciubping 't Tnsmors

Muscle Wasting

't Diarrhea

Menstrual Changes (Amenorrhea) Localized Edema

Primary thyrotoxicosis

I TRH

Secondary thyrotoxicosis

Tertiary thyrotoxicosis J

iTRH

A

i TSH

t TSH

t TSH

D V

J

■!> t T3 & T4

r T3 «& T4

-a t T3 & T4

50

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

¥4

Myxedema

Intolerance to CoW

Receding Hairline

Facial & Eyelid Edema

Pull-Blank Expression

Hair Loss

Extreme Fatigue Thick Tongue Slow Speech

Apathy Lethargy Pry Skin

— Anorexia

(Coair&c 4 Scaly) Brittle Nails & Hair

Muscle Aches

& Weakness Menstrual Pisturhances

Constipation

ate Clinical Manifestations

Sybnormal Temp Bradycardia Weight Gain iLOC Thickened Skin

Cardiac Compiicationa

Primary Hypothyroidism

l)

Secondary Hypothyroidism

iTRH

T TRH

TTSH

iTSH

dd V

1 T3 & T4

Tertiary Hypothyroidism

i T3 & T4

w

iXSH J

i T3 & T4

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬ 51

H

Thyrotoxicosis (Hyperthyroidism)

Myxedema(Hypothyroidism) ♦♦♦ Etiology

I.

Primary thyrotoxicosis:

1. Grave's disease (the commonest): diffuse toxic goiter 2. Plummer's disease: Toxic multinodular goiter 3. Toxic thyroid adenoma (Toxic nodule)

4. Inflammatory : toxic phase of thyroiditis: A. Hashitoxicosis:

o Transient hyperthyroidism caused by inflammation associated with Hashimoto's thyroiditis B. o 5. A.

De Quervain disease: Subacute granulomatous thyi-oiditis due to viral infection latrogenic (drugs): Thyrotoxicosis factitia:

o Excess intake of L thyroxin B. Jod-Basedow thyrotoxicosis: o Excess intake of iodine in treatment of endemic goiter

According to age of onset is classified into: A. Cretinism during infancy leading to mental retardation with dwarfism e.g. Pendred's syndrome: Cretinism + congenital deafness B. Juvenile myxedema before puberty (4-12years) leading to normal mentality with dwarfism C. Adult myxedema after puberty, causes I. Primary hypothyroidism: Endemic myxedema : prolonged iodine deficiency 2. Goitrogenous substance :

Amiodarone, para-aminosalicylic acid, cabbage, iodine containing cough mixture & lithium . Destruction of thyroid gland: Primary idiopathic atrophy: auto-immune circulating antibodies latrogenic:

3. A.

C. Amiodarone

6. Struma ovarii: cancer ovary secretes TSH 7. Congenital (Neonatal) thyrotoxicosis : o Transmitted from thyrotoxic mothers to babies (self

B.

Antithyroid drugs, radio-iodine & thyroidectomy

o

Hashimoto's thyroiditis (lymphadenoid goiter): The commonest cause for primary myxedema

C.

limited) II. Secondary thyrotoxicosis: o TSH secreting pituitary adenoma III. Tertiary thyrotoxicosis: o TRH secreting hypothalamic tumor

Autoimmune disease due to RES over function

secreting antibodies against thyroid gland e.g. antithyroglobulin antibody & anti-

❖ N.B.: Hyperthyroidism: increased thyroxin due to thyroid gland hyperactivity ❖ N.B.: thyrotoxicosis increased thyroxin due to thyroid gland or any other cause e.g. ectopic hormone production or drug induced

microsomal antibodies

Gland structure is replaced by dense lymphocytic infiltration, with reduction of T4

and feedback | TSH with subsequent goiter A short period of thyrotoxicosis

Primary thyrotoxicosis: Grave's disease = Basedow disease Etiology

(Hashitoxicosis)followed by hypothyroidism

❖ Autoimmune disorder as evidenced by:

e.g. Addison's disease , rheumatoid arthritis , pernicious anemia with increased incidence of thyroid neoplasm De Quervain disease: Subacute granulomatous thyroiditis due to viral

Association with other autoimmune disorders

1. Association with HLA B8, DR3, where autoantibodies directed against TSH receptor:

A. Thyroid stimulating immunoglobulins (TSl): antibodies

ofIgG class; act as long-acting thyroid stimulants (LATS)that bind directly to the TSH receptor which stimulate synthesis of thyroid hormones

D.

infection

Riedel's thyroiditis: Fibrous tissue infiltration of thyroid (woody thyroid) simulating malignancy H. Secondary hypothyroidism: ❖ Pituitary myxedema:

E,

B. Thyroid growth immunoglobulins: antibodies that bind directly to the TSH receptor which increase growth of thyroid follicles 2. Association with other autoimmune disorders as thymic enlargement, splenomegaly, lymphadenopathy, myasthenia gravies, Addison's disease, pernicious anemia, and SEE.

o

o

Simmond's disease

o Radiation ,surgery HI. Tertiary hypothyroidism : o Hypothalamic dysfunction : neoplasm , radiation

Clinical picture 1. Incidence:

o

Female to male ratio is 8 :1

o

o

Occur in middle age (30-50 y)

o

Insidious onset, Course: remission & exacerbation

o Occurs in middle age (30-50 years) o Insidious onset with vague complaints

Common in female

2. Local

Toxic goiter:

❖ According to cause:

Thyroid gland is diffusely enlarged firm in consistency

1. Increased size:

with smooth surface

o In Hashimoto's disease, endemic goiter & goitrogenous substance 2. Atrophic: in primary idiopathic forms 3. Scars of previous operation 4. Hard & fibrotic in Riedel's thyroiditis

I Vascularity: systolic pulsation & systolic bruit at upper pole. Examine also for retrosternal extension

Rarely the gland is normal

52

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

3. General overview

A. B. C. D.

Appearance: irritable, alert, starring look Built: weight loss despite of increased appetite Mouth: tongue tremors when protruded unsupported Eye: classification of eye changes in Grave's disease :

I.

Class 0: no signs & no symptoms

II.

Non - Infiltrative (False) ophthalmopathy: Class 1 (only signs, no symptoms): ❖ Due to contraction of Muller's muscle leading to lid retraction(T4 sensitize muscles to effect of

a) Appearance: o

Puffy face, expressionless

o

Bloated with malar flush

b) Built: weight gain c) Mouth : o

Big tongue (Pseudo macroglossia) —>■ traumatic ulcers, difficult talking, deglutition & obstructive sleep apnea. Eye :

Puffy eye lids (mucopolysaccharides deposition)

catecholamines)

Loss of outer 1/3 of eye brows

1. Staring look

Eyelids droop ((.adrenergic drive)

2. Slight exophthalmos: retracted upper lid 3. o 4. 5.

Pallor(anemia) with yellow tinge (carotenemia)

Xanthelasma

Dalrymple's sign : Rim of sclera is seen between cornea & upper eyelid Von Graefe's sign: lid lag on looking down Rosenbach's sign :

± Cataract

o Tremors in upper eye lid when eyes are gently closed III. Infiltrative (true) ophthalmopathy: 1. Etiology :

o It is caused by an auto-antibody called exophthalmos producing substance (EPS). o It leads to infiltration of retrobulbar space, extraoccular muscle & lacrimal gland by lymphocytes, plasma cells & mucopolysaccharides with subsequent enlargement, fibrosis & failure of muscle relaxation.

2. Class 2: symptoms & signs: o Soft tissue involvement: periorbital edema & conjunctival edema & redness (injection)

o Joffroy's sign: lack of corrugation of forehead on looking upwards

3. Class 3: exophthalmos: unilateral or bilateral , occur even before thyrotoxicosis (ocular Grave's) 4. Class 4: External ophthalmoplegia : paresis of extraocular muscles

❖ Signs:

A. Mobius sign : lack of convergence on looking to near object due to weakness of Medial recti muscle B. Stellwag's sign : infrequent blinking (Normally = 5-8 times/min)

5. Class 5: Malignant exophthalmos: papilledema & comeal ulcers

6. Class 6: slight loss of vision (optic nerve involvement) B. Upper & lower limbs : 1.

Fine tremors in outstretched hands

o

2.

Palmer erythema

o

3. Plummer's nail : onycholysis with separation of the nail

Thick nails

Carotenemia in palm & soles (lack of conversion of carotene to vitamin A in liver due

to absence of T4)

from the nail bed

o LL: Pretibial myxedema 4. LL: thyroid dermopathy : pretibial myxedema which may be associated with thyroid acropachy (clubbing of fingers) & exophthalmos ❖ Pretibial myxedema: occur in Grave's disease & Hashimoto's thyroiditis o Nonpitting edema with thickening & pink/purple discoloration of skin giving peau d'orange appearance o

Site : over the shins of tibia

o Etiology: inflammatory cytokines —»■ stimulate fibroblasts to increase synthesis of glycosaminoglycans especially hyaluronic acid (mucopolysaccharides) —^ hydrophilic nature with compression of dermal lymphatics ^ nonpitting edema of the dermis

53

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

C. Skin changes 1.

Heat intolerance

1) Cold intolerance & hypothermia

2. Warm moist flushed skin (salmon pink) with excess

2) Cold, dry thickened non-sweaty skin

sweating

3) 4) 5) o

Hair is sparse & brittle Vitiligo in autoimmune cases Pallor with yellow tinge : Pallor due anemia (all types), VC & mucopolysaccharides deposition o Yellow tinge due to carotenemia

3. Hair: thin hair with excess falling & premature graying 4. Pigmentation is common 5. Vitiligo occurs in 7% of cases ❖ Others:

o Compression: mediastinal syndrome

o Mono-symptomatic: one manifestation predominates e.g. CNS,CVS, and chest.

D. Manifestation of autoimmune disease e.g. adrenal insufficiency & myasthenia gravies 4. CNS

1. o o o

Mentality : Anxiety, restlessness, nervousness, insomnia Thyrotoxic psychosis Thyrotoxic crisis & coma

1) Mentality :

o Apathy, poor memory, slow cerebration, depression, tiredness, weakness

o Myxedema psychosis (myxedema madness)

2. Motor power: thyrotoxic myopathy:

o

o Chronic: proximal myopathy o Acute: bulbar palsy 3. Hyperactive reflexes

2) Motor power: proximal myopathy (pseudohypertrophic myopathy) 3) Sensation : peripheral neuritis (paresthesia of

Myxedema coma

hands & feet) due to: o Interstitial neuropathy o Entrapment neuropathy : carpal tunnel syndrome & tarsal tunnel syndrome 4) Hypoactive (suspended) reflexes: o Delayed relaxation oftendon jerks 5) Speech : slurred speech with hoarseness of voice 6) Conductive deafness, vertigo, & ataxia . 5. CVS

Marked in old age

1. Bradycardia

1. Palpitation is the commonest symptom due to:

2. Ischemic heart disease :

A. Tachycardia (sleeping pulse > 100 / min)

o ft peripheral resistance ^ hypertension

B. Hyperdynamic circulation C. Arrhythmia

3. Angina & intermittent claudication especially

o

D. Neurosis

on start of treatment.

2. Arrhythmia:

o o 3. o

Hypercholestrolemia —> atherosclerosis

Any arrhythmia can occur except heart block, The commonest arrhythmia is AF. Hyperdynamic circulation: Due to high systole BP (forcible heart) & low diastole BP

4. Cardiomegaly : due to o Cardiomyopathy

o Pericardial effusion (cholesterol pericarditis)

(arteriolar YD)leading to collapsing pulse, big pulse pressure, functional systolic murmur & ending in high CO heart failure 6. Chest

Tachypnea may be present due to: o Increased metabolic rate & development of heart failure

o Tachypnea may be present due to pleural effusion

7. GIT

1. Diarrhea & steatorrhea

2. Generalized lymphadenopathy & hepatosplenomegaly

1. Lips & Tongue: large in size & red glazed 2. Stomach: dyspepsia, hypochlorhydria (leading to Fe deficiency anemia) 3. Intestine

o Slow motility —> constipation o Slow absorption & bacterial overgrowth —>■ steatorrhea 8. Genital

■

o Males: impotence, gynecomastia o Females : infertility, irregular menstrual periods & Oligomenorrhea & amenorrhea

54

■ ■

Menorrhagia Galactorrhea (feed back f TRH^ tpro'actin)

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

9. Metabolic

Hyperglycemia up to DM due to increased glucose absorption and insulin antagonism

o

Hypoglycemia decreased glucose absorption 10. Blood :3 forms of anemia

10. Renal

❖ Polyuria may be present due to: 1. Increase water intake as a part of polyphagia 2. Increase water production from metabolism

1. Normocytic normochromic 2. Microcytic hypochromic 3. Macrocytic anemia ^ Refer to hematology book

3. Increased renal blood flow

4. Secondary DM —> glycosuria 11. Hyponatremia

11. Skeletal

o

Osteoporosis

o

J, cortisol ^ J, water excretion ■

dilntional

hyponatremia ❖ Variations :

o

Subclinical hyperthyroidism: Etiology: Same causes of thyrotoxicosis During treatment of primary thyrotoxicosis Clinical picture: asymptomatic Investigations :

a.

Low TSH

b.

o

❖ Subclinical hypothyroidism (borderline hypothyroidism - compensated euthyroidism): o Etiology: a. Same causes of hypothyroidism b. During treatment of primary hypothyroidism o Clinical picture: asymptomatic o Investigations : ■ t TSH ■ T3 & T4: low normal range

o

T3 & T4: upper normal range Treatment: radioactive iodine therapy T3 thyrotoxicosis: Etiology: excess conversion of T4 to T3 in tissues.

o

Clinical picture: as thyrotoxicosis but the main features

o

are cardiac(HF & AF). Investigations:

a.

Low TSH, Normal T4

o

2.

b. 3. o

o

Treatment:

■

It's better to treat thyroid failure early to avoid profound hypothyroidism specially if TSH > 10

■

Thyroxin : 50 -100 pg /day

mu/L

High T3 Masked or apathetic thyrotoxicosis: Etiology: depletion of catecholamine in long standing cases.

b.

Clinical picture: atypical thyrotoxicosis in older patient: Apathy, confusion, depression & dementia. Unexplained HF & AF

c.

Weight loss, weakness, constipation

o

a.

Differential diagnosis

1. Anxiety neurosis : cold hands, normal sleeping pulse 2. Increase appetite with loss of weight: DM, parasites, malabsorption 3. Hyperdynamic circulation 4. Muscle diseases: myopathies, myasthenia gravies 5. Monosymptomatic cases: differentiated from corresponding diseases syndrome ❖ Grave's

Cause

0

Autoimmune

o o

Age of onset Thyroid exam

o o

30-50 years Diffusely enlarged

3. Pernicious anemia

4. Myotonic syndrome 5. Thyroid from pituitary myxedema

❖ Plummer's

disease o

1. Nephrotic syndrome 2. CRF

disease

o On top of nodular goiter o >50 years o

multinodular Severe

o

CVS

o

Mild

o

o

CNS

o

Severe

o

Mild

o

Exophthalmos o

Infiltrative

o

Absent

o

Mono-

Uncommon

o

Common

Usually

o

Usually surgical

form o

symptomatic o

Treatment

o

medical

55

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Investigations A. ECG

o Tachycardia o Arrhythmias e.g. AF.

1. Serum cholesterol 2. Serum calcium

3. Blood glucose 4. CPK,AST levels

o Sinus bradycardia o

Low voltage

o

Flat or inverted T

B. Blood chemistry o i o t o i o T o Hyperglycemia o Hypoglycemia o Lag storage curve o Flat curve

o High due to muscle affection o Serum prolactin | : in primary hypothyroidism o 3 types of anemia

5. Others

C. Hormonal profile 1. Total T4&T3 2. FreeT3&T4

3. T3 resin uptake 4. Radioiodine uptake 5. TSH level

6. TRH stimulation test

7. Thyroid antibodies

o

Increased

o

o It decreases in primary thyrotoxicosis. o It increases in secondary thyrotoxicosis. o Confirming and assessing the degree of suppression in suspected hyperthyroidism. o TSH receptor antibodies

Decreased

o It increases in primary myxedema o It decreases in secondary myxedema

0 Differentiate pituitary(no increase in TSH) from hypothalamic (delayed increase in TSH) hypothyroidism o Antithyroglobulin antibodies o

Anti-microsomal antibodies

❖ Treatment 1. Medical : see details later

1. Cretinism:

2. 3. 4. A. B. C. o o

o

Radio-iodine therapy: see details later Surgical : see details later Treatment of complications e.g.: Pretibial Myxedema: local betamethasone cream Thyrotoxic crisis: see later. Ocular Complications: Protect eye by ointment, and sun glasses, Guanethidine 5% eye drops or B-blocker to decrease lid retraction, & conjunctival injection o Lateral tarsorrhaphy o Severe cases: prednisone 120 mg /day. o Surgical: Naffziger's operation : supraorbital deroofmg (decompression)

Treatment should start before first 6 months to

prevent mental retardation, o L - Thyroxin 25ug / day to be increased up to 200 pg / day. 2. Adult hypothyroidism: ❖ Levo- thyroxin (L-T4)for life : o

Start by 50 ug /day & increase gradually up to 100-200 pg / day. o Old people & ischemic heart disease need lower dose (to avoid HF & angina) o Follow up: ECG,cholesterol level , TSH level drop to normal (the most important) 3. Treatment of complications e.g. Myxedema coma

56

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

o

months, since radio iodine does not

Allergy: fever, rash, generalized lymphadenopathy, arthritis,

Aplasia cutis congenita in fetus Granulocytopenia : sore throat, fever GIT upset, cholestatic jaundice , SEE (drug induced)

Goiter due to t TSH

Hypothyroidism especially in newborn with thyrotoxic mother Relapse: on sudden stoppage

o o o

o

o o

Side effects:

6.

o

Blood picture (to exclude aplastic anemia)& TSI antibody titre

o

5. Follow up by:

4. Add 0.1 - 0.2 mg T4 / day after 3 months to prevent hypothyroidism, goiter & exophthalmos

3. Duration of treatment: 12-18 months

57

—

—

I , II I

■ a»ll

4. Relieve systemic effects mediated by adrenergic over activity by propranolol,

C. Corticosteroids

A. Propylthiouracil B. Propranolol

1. Inhibit hormone production by antithyroid drugs 2. Inhibit release of preformed hormone in thyroid gland by iodide solution 3. Inhibit peripheral conversion of T4 to T3 in tissues by :

❖ Aim of medical treatment:

achieve its effect till then.

2. Dose: 10 mg/8hours then when the patient reaches euthyroid state (after

4-6 weeks) reduce the dose gradually to 5 mg/8hours

The response is slow within 8 -12 weeks so give antithyroid drugs for the next 6

b. Methimazole e.g. Carbimazole: 1. The most commonly used drug in Egypt.

For 2 weeks preoperative then 2 week postoperative

o o Results:

t incidence of thyroid malignancy or other malignancy (not proved)

a. Propylthiouracil:

Has in addition the ability to inhibit peripheral conversion of T4 to T3 Dose: 100 mg/8hours then reduce dose after 4-6 weeks to 50 mg/8hours o It's preferred during Pregnancy & lactation.

N.B.: if euthyroid state is not reached H', Iodides will act as substrate for synthesis of new thyroid hormone. Propranolol

Lugol's iodine solution (iodine 5 % in 10 % K iodide) 10 drops orally / 8 hours

vascularity of gland : Potassium iodide solution 5 drops /8hours

Iodides for 2 weeks to reduces size &

Preoperative preparation: Antithyroid drugs till euthyroid state

Malignant exophthalmos

Fetal anomalies if taken in pregnant

Inhibit peroxidase & interfere with binding of iodine with tyrosine

■

Hypothyroidism BM inhibition

o

1. Failure of medical treatment in older peitient. pregnancy & primary cases (diffuse or multinodular goiter) 2. Huge goiter & retrosternal goiter 3. Suspicion of malignancy

Subtotal Thyroidectomy

females

Mechanism of action :

o

D. Antithyroid drugs:

over activity e.g. arrhythmia Dose: 20- 40mg/8hours, Side effects (see cardiology) Side Effects:

C. Propranolol (P-blocker): relieve systemic effects mediated by adrenergic

B. Sedative & tranquilizers e.g. diazepam, phenobarbitone

Dose:

Lines of treatment

l'^' 6-8 millicuries or 150 microcuries /I gm thyroid tissues. Repeat after 1 year if needed

❖

A. Nutritious diet, proteins & vitamins

pressure symptoms and exophthalmos 2. Huge goiter & retrosternal goiter

Contraindications

4. Malignant thyroid secreting excess T4 ❖

2. Suspicion of malignancy

/

1. Failure of medical treatment or age > 40 y 2. Patient is unfit for surgery or patient refusing surgery 3. Recurrence after thyroidectomy

1. Huge goiter & retrosternal goiter as TSH level rise will increase

>

Radioactive Iodine therapy Indication

1. During pregnancy, lactation, childhood (better not in child bearing period)

4. Treatment of complications e.g. arrhythmia

3. Thyrotoxicosis with pregnancy

2. Plummer's disease (toxic multinodular goiter) as pre-operative preparation or if there is contraindication for surgery.

1. Grave's disease (diffuse toxic goiter)

Medical treatment;

Treatment of thyrotoxicosis:

Thyrotoxic crisis -thyroid storm

1

Myxedema (hypothermic) coma

❖ Definition : life threatening endocrine emergency with o Sudden release of thyroid hormones into circulation leading to severe o Long standing untreated hyperthyroidism

I

hypothyroidism especially in elderly

❖ Etiology

1 1. 2. 3. 4. 5.

Lack of preoperative preparation. Withdrawal of antithyroid drugs Thyroid surgery & manipulation lodinated contrast dyes in thyrotoxic patient Non-thyroid illness e.g. non thyroid surgery. Stress, Stroke , MI & infections

1 o Precipitated by : 1) Cold

2) CNS depression e.g. narcotics, 3) Non thyroid illness

Clinical picture 1. General:

1.

o Sweating, hyperthermia : temperature may reach > 41 C°

2.

o In old age there is apathy & bulbar palsy from acute myopathy. 3. CVS: acute HF, hypotension, tachycardia, arrhythmia e.g. AF , SVT 4. GIT: abdominal pain, nausea, vomiting, diarrhea, dehydration

Hypothermia( Caicitriol

t absorption of Ca

M

\7 Serum Ca to normal level

61

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

D

Hyperparathyroidism

Etiology:

W 1. Primary hyperparathyroidism :

o Primary autonomous secretion ofPTH i.e. not secondary to hypocalcemia o Due to adenoma (90 % of cases), hyperplasia & carcinoma of parathyroid gland o Sometimes associated with MEN I, IIA. 2. Secondary hyperparathyroidism:

o Due to chronic hypocalcemia (e.g. malabsorption syndrome or chronic renal failure(CRF)leading to compensatory (secondary) hyperplasia of parathyroid gland. 3. Tertiary hyperparathyroidism:

o Prolonged secondary hyperparathyroidism will lead to adenomatous transformation in parts of the hyperplastic parathyroid glands. 4. Ectopic hyperparathyroidism (Paramalignant syndrome): o PTH related peptide(PTHrP)secretion by some tumors e.g. oat cell carcinoma of the lung

*** Clinical picture: bones, stones, abdominal moans and psychic groans: 1. II.

Of cause: e.g. CRF. Hormone effect:

A. Skeletal manifestations due to Ca^ mobilization from bone: -

-

,1

1. Osteoporosis:

o Bony pains & pathological fractures that heal rapidly secondary to hypercalcemia 2. Premature loosening of the teeth due to resorption of lamina dura 3. Bone cysts:

a. In the teeth (epulis) b. Osteitis fibrosa cystica(Brown tumor): replacement of bone by fibrous tissue with cyst formation B. Extra-skeletal manifestations due to hypercalcemia : A. Renal manifestations :

1. 2. o 3.

Polyuria with polydipsia (nephrogenic diabetes insipidus) Stones: bilateral, multiple, recurrent: Presents by renal eolie, hematuria, recurrent urinary tract infection, hydronephrosis ending in CRF. Nephrocalcinosis (metastatic calcification)

B. Abdominal manifestations :

o o o

Anorexia, nausea, vomiting & CONSTIPATION Peptic ulcer Acute Pancreatitis & calcification of the pancreas (metastatic calcification)

C. Neuromuscular manifestations:

o Apathy, psychosis, depression, confusion, convulsion & coma o Muscle: proximal myopathy o Joint: chondrocalcinosis (metastatic calcification) & pseudogout D. Skin: dry and pruritus

E. Eye: keratoconjunctivitis & corneal calcification (band keratopathy) F. CVS:

o

Hypertension

o Arrhythmia, Bradycardia & short Q-T interval

62

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ N.B.: acute hypercalcemia: hypercalcemic crisis:

o Definition: Emergency condition characterized by elevated serum Ca^ > 14 mg/dl o o 1. 2. 3. 4.

Causes of hypercalcemia:see below Clinical picture : Abdominal pain, Anorexia, nausea, vomiting Poiyuria & dehydration CVS: arrhythmias & cardiac arrest Confusion, convulsion & coma

Differentia! diagnosis from other causes of hypercalcemia: I.

Increase Ca^^ intake:

1. Milk alkali syndrome: A0V4WCED

o Hypercalcemia with metabolic alkalosis due to excess ingestion of milk, alkaline, calcium carbonate antacids for treatment of peptic ulcer 2. Over treatment of hypocalcemia II. I ncrease Ca^^ absorption: A. Idiopathic: Idiopathic hypercalcemia with nephrocaicinosis

m

•j .

B. Endocrinal:

1. Hyperparathyroidism (primary, tertiary, ectopic, not secondary). 2. Hyperthyroidism 3. Acromegaly 4. Addison's disease

5. Pheochromocytoma 6. Chronic granulomas(T.B, sarcoidosis) due to secretion of a-1 hydroxylase enzyme. 7. Vitamin D & Vitamin A intoxication III.

Increased mobilization from bone:

1. Malignancy: bone metastases & secretion of hypercalcemic substances: o E.g. Multiple myeloma, oat cell carcinoma of the lung, lymphoma, breast cancer.

2. Prolonged immobilization: absence of normal postural stimuli for bone formation

t bone resorption

o E.g. Heart failure, Paget's disease ofthe bone, bone fractures & post-operative. IV. Decreased calcium excretion by kidney: 1. Familial hypocalciuric hypercalcemia: o Benign autosomal dominant o Symptomless disease with mild hypercalcemia & hypocalcuria

o < 100 mg Ca"^ /24 hours urine & PTH level is normal. 2, Drugs: Thiazides diuretics & lithium.

❖ Investigations: I.

Laboratory

A. Biochemical:

Hyper parathyroidism o

Serum Calcium

o

Urinary

❖ Primary

t

Calcium o

Serum

o

Phosphorus Urinary Phosphorus

o

CRE

Secondary o Malabsorption

♦:♦ Tertiary o

CRE

i or normal

T

i

T

i

T

i

T

i

o

❖ Malignancy

Malabsorption T

T

X

;

X T

Alkaline

phosphatase o

❖

o

Parathormone

T

T T

T t

]. but PTHrP is

level

elevated

B. Hormone end product:

1. Increased urinary 24 hours hydroxyproline(when collagen is broken down excessively). 2. Increased urinary C-AMP (characteristic of hypercalcemia due to hyperparathyroidism).

63

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

II. III.

ECG: bradycardia & short Q-T interval. Radiological:

A. Renal X-ray: bilateral multiple stones and nephroealcinosis. B. Bone X-ray: 1. Absence of lamina dura of teeth

2. Bone cysts: osteitis fibrosa cystica 3. Cod fish spine: intervertebral discs indent the surface of softened vertebra 4. Decalcification ofthe bone gives ground glass appearance

5. Erosion: Subperiosteal resorption (erosion) of phalanges (especially middle phalanges)

ill

6. Mottling of skull (Salt & pepper in skull). C. Localizing studies to visualize parathyroid adenoma: 1. Neck US 2. CT&MRIneck

3. Radioisotope subtraction scanning of parathyroid using: o Neck is imaged during injection of thallium (taken by thyroid & parathyroid gland)& followed by technetium (taken by thyroid only), o Digital subtraction of the two images reveal a parathyroid image. IV.

Investigations of the cause:

1. Renal function tests

2. Investigation for Malabsorption syndrome. 2 hours 3. Steroid suppression test(Dent test): o Hydrocortisone (40 mg orally 8 hourly for 10 days orally) —>■ I action of vitamin D on intestine —> | vitamin D mediated hypercalcemia e.g. multiple myeloma, lymphoma & sarcoidosis not due to hyperparathyroidism 16 m nines

❖ Treatment of hyperparathyroidism : 1. Treatment of the Cause

2. Calcimimetics e.g. Cinacaicet: sensitize the parathyroid calcium receptor to serum calcium I PTH secretion 3. Surgery : parathyroidectomy Surgical removal of parathyroid followed by Ca & vitamin D supplements to prevent tetany(Hungry bone syndrome) Indications :

1. Serum Calcium > 1 mg/dl above the normal 2. 24 hour urinary Calcium > 400 mg/dl 3. Creatinine Clearance < 60 ml/min

4. Age < 50 years old 5. Bone density T-score < - 2.5 at any site

❖ Treatment of hypercaicemic crisis: 1. Food : I calcium intake in foods e.g. milk & J, absorption e.g. phytate 2. Fluids(normal saline) in excess to correct dehydration & wash out calcium in urine. 3. Furosemide diuretic (not thiazides): 40-80mg every 1-2 hours

4. Corticosteroids —> f action of vitamin D on intestine —> J, vitamin D mediated hypercalcemia e.g. multiple myeloma,lymphoma & sarcoidosis not due to hyperparathyroidism 5. Calcitonin: I activity of osteoclast & hypercalciuric effect o Dose : 2-8 lU/kg/day SC

6. Bisphosphonate (Pamidronate): | activity of osteoclast o Dose: 30-90 mg IVI over 24 hours 7. Dialysis in severe cases or in renal failure

64

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Hypocalceinia - Tetany Definition :

o It's a state of spastic contraction of skeletal muscle due to increased neuromuscular excitability due to J, ionized Ca"^ ,I Mg or alkalosis. Etiology : I.

II.

Hypocalcemia:

1. HYPOPARATHYROIDISM:

1) 2) o o

Hypomagnesemia

1. Miscellaneous

1) Alcoholism : chronic use of large

Idiopathic atrophy (Autoimmune) latrogenic: Accidental removal during thyroidectomy Parathyroidectomy(Hungry bone syndrome)

amount of alcohol

2) Bums 3) Bartter's syndrome and Gitelman's syndrome 4) Total parenteral nutrition

3) Irradiation & infiltrative diseases.

4) Intraglandular hemorrhage : Tetania neonatorum 5) Ischemic:

o Goiter causing obstruction of blood supply to parathyroid gland 6) Di-George syndrome: congenital absence of thymus and parathyroid 7) PSEUDOHYPOPARATHYROIDISM (resistance to PTH) 8) Electrolytes: Hypomagnesemia :functional paralysis of the gland 2. Diminished intake: malnutrition & starvation

3. Diminished absorption:

1) Malabsorption syndrome & diarrhea. 2) Deficiency of vitamin D (rickets &osteomalacia)

2) Intestinal resection & fistula

4. Increased renal loss:

1) 2) 3) o o 4)

Loop diuretics Endocrine: Hypothyroidism Electrolytes : Hypokalemia Hypomagnesemia & Hyperphosphatemia Chronic renal failure

1) 2) 3) o o 4)

Loop & thiazide diuretics Endocrine: Hyperthyroidism Electrolytes: Hypokalemia Hypercalcemia & Hypophosphatemia Diabetic ketoacidosis

5. Increased precipitation in tissues :

1. Acute pancreatitis 2. Citrated blood transfusion

3. Hungry bone syndrome 4. Drugs : o Phenytoin, Bisphosphonate, Cinacalcet, Calcitonin & Corticosteroids 5.

HYPOALBUMINEMIA:

o

J, Total calcium while ionized calcium is normal —> so no tetany

III.

0 Amphotericin, Aminoglycosides, Pentamidine & Cisplatin

Alkalosis :

1. Respiratory alkalosis; see nephrology 2. Metabolic alkalosis: see nephrology

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬ 65

❖ Clinical picture: 1.

Latent tetany:

o Serum Ca"^:7-9 mg/dl o

There are no spontaneous manifestations but it can be induced by provocative tests:

A. Chvostek's test:

o Tapping of facial nerve in front of the ear causes facial muscle contraction.

o Tapping the peroneal nerve over the head of fibula causes peroneal muscle contraction. B. Trousseau's sign:

o Sphygmomanometer inflation around the arm above systolic pressure for 5 minutes causing carpal spasm C. Erb's sign:

o Current < 4mA causes muscle contraction (normally at least 8 mA is needed). II. Manifest tetany : o Serum Ca-H-: < 7 mg/dl A. All provocative tests are +ve & hyperreflexia

B. Nerves:irritability & paresthesia ; numbness & tingling in perioral area, fingers & toes C. Muscles: muscles twitches & spasm in the form of:

Carpopedal spasm:

7.

Carpo: flexion of wrist, flexion of MCP joint & extension of PIP & DIP joints, thumb addueted Pedal : planter flexion & inversion Spasm of the facial muscle (risus sardonicus) Spasm of Jaw (trismus) Spasm of larynx (Laryngismus stridulous) Spasm of the diaphragm (hiccough) Spasm of the back muscles (Opisthotonus) Spasm of wall of the urinary bladder (enuresis) or the sphincter (retention).

D.

CNS: Confusion, convulsion, coma in severe cases

o

2. 3.

4. 5. 6.

E. CVS:

Hypotension(Ca^ is given before measurement)

Xy

Heart failure o

F.

Long Q-T Interval

Arrhythmia & prolonged Q-T interval Effect on ectodermal structures: in hypoparathyroidism with long standing hypocalcaemia :

1. Lens: cataract. 2. Nails: loss of luster & brittle 3.

4.

Hair: premature loss of hair Skin: desquamation, atrophy, roughness, alopecia, and monilial infection

5. Teeth:

6.

Hypoplastic, transverse furrows and punctuate holes if the condition develops before formation of permanent teeth GIT: Malabsorption due to desquamation of GIT mucosa

G.

Clinical picture of the cause e.g. in primary hypoparathyroidism only:

1.

Parkinsonism due to calcification of basal ganglia Pseudotumor cerebri: f ICT with papilledema

2.

•\

N.B.: Magnesium deficiency causes neuromuscular irritability simulating tetany with 2 differences :

1. Cramps don't occur

|

2. Trousseau's sign is negative

i

66

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

*> Investigations: A. Biochemical

1. Hvpocalcemia

2. Hypomagnesemia

3. Alkalosis

0 i

0

B. Other causes e.g.

A. Hypoparathyroidism

CRF

Serum total Ca"^"^ Ionized Ca"^"^

0 i

0 Serum phosphate

0 t 0 i

0 0 0

Parathormone

0 1 (or normal)

0 f by feedback

Normal

0

J,

0

Normal

0

Normal

mechanism

level

B. ECG: Prolonged Q-T interval Treatment:

I.

In acute attacks:

o 10 ml of 10 % calcium gluconate solution IV slowly over 10 minutes up to 3 ampules II.

Treatment of the cause:

2. In hypomagnesemia

1. In hypocalcaemia

3. In Alkalosis

A. Treatment of the cause

B)Respiratory &

B)oral Mg

B. Oral calcium:l-3gm/day C. Calcitriol 1 pg/day

metabolic alkalosis

treatment: See nephrology

D. Thiazide diuretics to decrease calcium excretion in urine

❖ N.B.: Pseudohypoparathyroidism (PHP): Etiology :

Congenital disease characterized by end organ resistance to parathormone due to congenital defect in G protein which is coupled to PTH receptor leading to chemical (pseudo) hypoparathyroidism (J, Ca^,f PO4 & f PTH)

o

Variants of pseudohypoparathyroidism: Pseudohypoparathyroidism type lA : Albright's osteodystrophy : skeletal defect with biochemical abnormalities

o

N.B.: Pseudopseudohypoparathyroidism: P'degree relatives of the patient with pseudohypoparathyroidism

A.

B.

C.

having skeletal defect without biochemical abnormalities. Pseudohypoparathyroidism type IB Pseudohypoparathyroidism type 2 Clinical picture of type lA:

1. CNS: Choroid plexus calcification & mental retardation 2. Ca: Hypocalcaemia & Cataract 3. Short stature, obesity & round face

4. Short 4"^ & 5"^ metacarpals & metatarsals (brachydactyly) with knuckle-dimple (Archibald's) sign 5. Subcutaneous ossifications

❖ Investigations: 0 Appearance

0

PTH levels

0 Hypoparathyroidism

■

Normal

■

Low

0 Pseudohypoparathyroidism 0 Type lA

■

Skeletal defect

■

High

■

Normal

■

Skeletal defect

■

Normal

0

Condition

0 Type IB,2

0 Pseudopseudohypoparathyroidism

0

Calcium

0

Calcitriol

■

Low

■

High

■

Normal

■

Normal

Treatment: Calcium & Calcitriol

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬ 67

0 Phosphate

Suprarenal glands(adrenal glands)

❖ Anatomy:

Adrenal gland

Capsule ■ Zona GkHnerulosa Cwtex Medulla

7^5

-Zona Fasdculata

-Zona Reticularis Medirila

Two glands, yellowish- brown in color. o

Each is related to the medial part of the upper pole ofthe kidney.

o

Each lies on the cms of diaphragm opposite the vertebral ends of 11* interspace and the12* rib. Arterial supply:

1. Superior suprarenal artery from phrenic artery 2. Middle suprarenal artery from aorta 3. Inferior suprarenal artery from renal artery Venous drainage 1. Right suprarenal vein to IVC 2. Left suprarenal vein to left renal vein ❖ Histology & hormones:

❖ Adrenal glands formed of: A. Adrenal cortex:

1. Zona glomerulosa

2. Zona fasciculata

3. Zona reticularis

o

0

•

Secretion

o

Mineralocorticoid

•

Hormone

o Mainly aldosterone

Glucocorticoids

o Mainly cortisol

o

•

o

Control

• Hyperfunction o o • Hypofunction

o

o

Sex Hormones

o Mainly androgen Small amount of

estrogen & progesterone Renin (juxtaglomemlar o Adrenocorticotropic hormone(ACTH)from anterior apparatus of the kidney) pituitary Primary hyperaldosteronism: 0 Cushing syndrome 0 Congenital adrenal (hypercorticism) Conn's syndrome hyperplasia Secondary hyperaldosteronism (adrenogenital syndrome) Isolated mineralocorticoid o Isolated 0 Hypogonadism deficiency glucocorticoids (hypoaldosteronism) deficiency (hypocorticism) Combined: Addison's disease (adrenocortical insufficiency = hypoadrenocorticism)

B. Adrenal medulla: Chromaffm cells secrete adrenaline & noradrenaline.

o Hyperfunction: pheochromocytoma

68

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Hyperaldosteronism Physiology of Aldosterone: Angiotensin-converting enzyme(ACE)

»

Angiotensin II stimulates aldosterone secretion by adrenal cortex

Aldosterone stimulates

Na+ and H2O reabsorption In the nephrons

Kidney releases renin into blood

Angiotensin 1

Liver releases

Angiotensin II

Aldostorone

In pulmonary

angiotensinogen

blood

into blood

1.

Hormone: aldosterone which is steroid hormone that works intracellular.

2.

Gland: secreted by zona glomerulosa in suprarenal cortex Function: Increase Na,and water reabsorption and increases K,and H secretion in:

3.

o

Distal renal tubules

o o

Sweat glands Salivary glands

o

Intestine

4.

Regulation:

A.

Renin angiotensin aldosterone system(RAAS):

Release of renin is stimulated by renal hypoperfusion, Na depletion & sympathetic stimulation Renin stimulate conversion of angiotensinogen to angiotensin I, then to angiotensin II by angiotensin converting enzyme(ACE)from lungs. o

B. C. 5.

Angiotensin II produce powerful VC and stimulate secretion of aldosterone Hyperkalemia & hyponatremia ACTH: only in stress (does not affect basal level) Normal level: 3-15 ngm/dl ❖ Etiology of Hyperaldosteronism:

1. Primary hyperaldosteronism: CONN'S SYNDROME due to:

Adenoma

Autonomous overproduction of aldosterone independent of RAAS(frenin): 1. Adenoma of zona glomerulosa(65%)

2. Hyperplasia ofzona glomerulosa(30%) 3. Carcinoma ofzona glomerulosa(5%)

Bowmsis

Macula

2. Secondary hyperaldosteronism:

Dbta tubue

liiiMi

❖ Pathogenesis : J, intravascular volume —> renal ischemia —> secondary activation of RAAS(frenin) ❖ Etiology:

1. Diuretics e.g. thiazides & loop diuretics : the most common cause 2. Decreased effective circulating volume e.g. congestive heart failure, liver cirrhosis & nephrotic syndrome 3. Depletion of salt(hyponatremia) e.g. J, Na intake or t Na loss via GIT or kidney 4. Renal artery stenosis(RAS)& Malignant hypertension 5. Renin secreting tumors e.g. Bartter's syndrome (hyperplasia of JGA)

69

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Clinical picture: A.

Na & HzO retention: hypertension and edema which is MILD due to:

1.

Hypokalemic nephropathy :

2.

Unresponsiveness to ADH —♦ nephrogenic diabetes insipidus —> polyuria. Renal escape phenomena : t blood volume —>1 GFR polyuria

B.

K excretion: hypokalemia that manifests by:

1.

2.

CNS : Apathy —> mental confusion, convulsion & coma CVS: Arrhythmia:

o

EGG : Prolonged PR interval, ST depression with inverted T wave & prominent U wave

o

4.

GIT : Atony | peristalsis, constipation up to paralytic ileus Muscle : Asthenia-^ weakness, hyporeflexia up to flaccid paralysis

5.

Kidney: nephrogenic diabetes insipidus

3.

6. Glucose intolerance

Hydrogen excretion:

C.

Leading to alkalosis which is exaggerated by intracellular shift of hydrogen with extracellular shift of K to compensate for K loss ^ this will manifest by tetany (J. ionized Ca"^)

o

❖ Differential diagnosis:

❖ Primary hyperaldosteronism: Conn's syndrome.

❖ Secondary hyperaldosteronism Initiating event

T Intravascular v

^ volume

^

T Na* retention

^

I Renin

i Intravascular v

volume

T Na* retention T Wdosterone

production

V

©

o

Mild hypertension Mild or no edema

y

production

Initiating event

o

T Aldosterone

T Renin

o No hypertension except with RAS o Marked edema in HF,liver & renal causes.

o t serum aldosterone level unsuppressed after normal

o t serum aldosterone level suppressed after

saline infusion

normal saline

o 1 Renin (due to negative feedback)

o

t Renin

o

o

Hypertrophy of juxta-glomerular apparatus

Normal renal biopsy

❖ Investigations: 1.

Laboratory : Biochemical:

❖ Primary hyperaldosteronism 1. Serum 2. Serum renin

3. Urinary

o o o o

(Conn's syndrome) t Serum aldosterone level t Na, J.K, alkalosis i I Na, fK, and aciduria

❖ Secondary hyperaldosteronism

o

t

o Hormone end product: f urinary tetrahydro-aldosterone II. Radiological: localizing studies o Abdominal sonar, MRI,CT to detect adrenal adenoma o Selective adrenal vein sampling for aldosterone level ❖

Treatment:

1. Symptomatic: reduce Na & increase K in diet 2. Medical treatment:

A. B. C. 3.

Aldosterone antagonists : spironolactone 100-400 mg/day ACE inhibitors (captopril): J, aldosterone secretion Metopyrone (11-p hydroxylase blocker): i aldosterone synthesis Surgical removal of adrenal adenoma

70

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Gushing syndrome ❖ Physiology of hormones: 1. Adrenocorticotropic hormone(ACTH): Stressors

(physical, emotional,fever, hypoglycemia, hypotension)

Circadian Rhythm

ACTH

counteraction

Inflammation

Neurotransmitters

Hypothalamus Metabolic effects

CRM

e Inflammation

(mainly provision of glucose and energy)

Zona reticuians

Zona fasciculata Mi

Antenor

pituitary^ ACTH

Androgens

Cortisol

Inflammation

Adrenal gland

Cortisol

Synthetic GCs Kidney

❖

ACTH function:

A. Responsible for maintenance of structure and size of adrenal cortex B. Responsible for regulation of hormone secretion. C. Stimulate secretion of glucocorticoids, a lesser on androgens, minor on aldosterone. D. Extra adrenal action:

1. 2. 3. 4.

Delays inactivation of cortisol in liver Adipose tissue: lipolytic (mobilize fatty acids) Skin: pigmentation BM:\ erythropoiesis

i 2. Cortisol:

cortisol curve

* .J

12am

1. Hormone: cortisol which is steroid hormone that works intracellular. 2.

Gland: secreted by zona fasciculata in suprarenal cortex

3. Function: see below 4.

Transport: 10 % is free, 90% bound to proteins(75% transcortin, 15% to albumin)

5.

Regulation: Stress—>• stimulate hypothalamus to release corticotropin releasing hormone(CRM) There is circadian rhythm for ACTH secretion: a. Highest level in the early morning : 4-9 AM (5-25 pg/dl) b. Lowest level in the evening : 9-12 PM (3-12 pg/dl) Normal level : 5-25 pg/dl

o

6.

71

ACTH

cortisol

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Actions

Side effects & contraindications

1. Metabolic :

1) CHO:

1- Hyperglycemia (diabetogenie)

o I glucose uptake by museies o t gluconeogenesis 2) Proteins:

o Catabolic effect on collagen in BVs wall, SC tissue, muscles & bone

o Anabolic effect on liver & visceral organ

2- Myopathy & sublaxation ofjoint 3- Osteoporosis & stunted growth in children (Cortisol block ability of GH to produce Somatomedin, a hepatic peptide responsible for bone growth) 4- Delayed healing of the wound 5- Cataract

6- Teratogenicity 3) Fats:

o Lipolysis: f free fatty acids o Redistribute of body fat to the trunk and the faee from the limbs

7- Lipemia

8- Moon face & buffalo hump

4) Electrolytes : A. Aldosterone like:

9- HF, Hypertension, edema & weight gain

o Excretion of potassium & hydrogen. B. Anti-vitamin D effect (prevents renal hydroxylation to the active form of the vitamin) | —> Ca absorption

11- Hypocalcemia

C. Uric acid : uricosuric effect

5) t free water clearance in DCT

2. Anti-inflammatory:

1) Synthesis of lipocotin —>j,phospholipase | A2 arachidonic acid —> 1 PGs & leukotriene synthesis 2) 1 capillary permeability 3) J, migration of neutrophils 4) 1 circulating eosinophils, basophils, lymphocytes & monocytes 5) 1 production of inflammatory mediators

12- Mask infection

6) Stabilization of lysosomes 3. Blood :

1) 2) 3) 4)

t erythropoiesis & RBCs 1 platelets & coagulability of blood fcirculating neutrophils 1 eosinophils, basophils, lymphocytes & monocytes (as cortisone redistribute them from blood to lymphoid tissue)

4. 5. o o

Anti-allergic : J, Ag-Ab reaction Immunosuppressive : J, T cell proliferation & activation i IgG production

13- Polycythemia 14- Thrombosis

15-1 liability of infection 16- Flare up infection e.g. IB

6. CNS:

1) -ve feedback on CRH & ACTH ^ adrenal atrophy

17- latrogenic Gushing 18- Depression, psychosis & insomnia 19- Sudden stop : Addisonian Crisis

2) Euphoria & psychosis 3) Anti-stress 7. CVS:

1) Hypervolemia & hypertension 2) Anti-shock : potentiate the effect of catecholamines on BVs

20- Hypertension

8. Chest:

0 t Surfactant production in fetal lung at term 9. GIT:

o Peptic ulceration due to J, protective gastric mucus secretion & f

21- Peptic ulcer

pepsin and gastric acidity 10. Androgen like action

22- Acne, baldness & Hirsutism

72

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Therapeutic uses of steroids

I.

Endocrinal diseases :

1. Thyrotoxic crisis & myxedema coma

w

2. Addison's disease & Addisonian crisis

3. Congenital adrenal hyperplasia 4. Hypercalcemia 5. Insulin antibodies (insulin resistance) II. Non endocrine disease: A. Anti-stress & anti-shock

B. 1. 2. 3.

Anti-inflammatory and anti-allergic: CNS: in cerebral edema associated with neoplasm & t ICT CVS; rheumatic carditis, Dressier's syndrome Blood : hemolytic anemia & ITP

4. Respiration: COPD, bronchial asthma,& sarcoidosis 5. 6. 7. o

GIT: ulcerative colitis, Crohn's disease & chronic hepatitis Urinary : glomerulonephritis & nephrotic syndrome Rheumatic & collagen disease : Rheumatoid arthritis & gout

o

PAN&SLE

o Myositis & polymyositis

8. Allergic diseases : hay fever, serum sickness, angioneurotic edema & anaphylaxis III.

Suppression therapy:

1. Suppress rejection in tissue transplantation 2. Shrinkage of lymphatic tissue in lymphoma & leukemia IV. Perioperative steroid cover : A. Patient currently taking steroids:according to the dose:

1. < 10 mg prednisolone /day (assuming normal hypothalamic pituitary adrenal axis): additional steroid cover not required. 2. > 10 ms nrednisolone /dav : according to the tvne of the surgerv :

b. Moderate surgery e.g. hernia or

a. Minor surgery e.g. dental surgery or endoscopy

c. Major surgery e.g. hip replacement or vascular surgery

varicose veins

o Pre-operative usual dose of steroic s o Intraoperative : 25 mg hydrocortis>one at induction of anesthesia induction of anesthesia o Postoperative : 100 mg o Postoperative : 100 mg hydrocortisone/day for 2- 3 days hydrocortisone/day for 24 h o Resume normal preoperative dose when gastrointestinal funetion has returned

o 25 mg hydrocortisone at

B. Patients stopped taking steroids: a) < 3 months o

Treat as if on steroids

b) > 3 months o No peri-operative steroids eover

❖ N.B.: Equivalent Drug Doses: o 20 mg hydrocortisone = 5 mg prednisolone = 4 mg methyl prednisolone = 0.8 mg dexamethasone or betamethasone. ❖ N.B.: Precautions in steroid therapy:

1. Measure blood glucose, BP & weight 2. X-ray to detect early osteoporosis 3. Diet rich in calcium, potassium, protein and restrict sodium 4. Do not stop suddenly especially if used for > 3 weeks with prednisolone 10 mg/day or more or an equivalent dose to avoid Addisonian crisis.

73

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Gushing syndrome Ttiinning of heir

Acne

Red cheeks ■ Moon face

Buffalo hump Suproclavicuiar fat pad

Increased body end facial hair

Weight gain

Purple striae Thin extremities with muscle

Pendulous abdomen

atrophy

Ecchymosis resulting from easy bruising

Thin skin and subcutaneous tissue

Slow wound

healing

Etiology:

I.

❖

N.B.:

o o

Pituitary Gushing : Gushing disease Adrenal Gushing : Gushing syndrome

o

Exogenous AGTH or corticosteroids therapy: Gushingoid syndrome

Tumor In

ACTH dependent:

PA / "T

anMnw p^jftary

ACTH

CotUsa

J

1 /— Lunge mMf

1 *CTH

^ Cotwoi

^

(orO&

noogntJocrtne

i-:/

1. Pituitary Gushing: Gushing disease: o Basophil microadenoma secreting excess ACTH(70%)

2. Ectopic AGTH secreting tumors: Para-malignant syndrome e.g. A. Bronchogenic carcinoma B. Pheochromocytoma.

3. Exogenous AGTH therapy (Gushingoid syndrome) —> AGTH dependent —> bilateral adrenal hyperplasia II.

Non AGTH dependent:

Cortsoi

/ Gushingoid syndrome

Tumof

Nodiiar t)yiMiplatj«

1. Adrenal Gushing: Gushing syndrome(20%): o Adrenal hyperplasia, tumor(adenoma or carcinoma) ofzona fasciculata secreting exeess eortisol —» The other adrenal gland is atrophic from suppression 2. Exogenous corticosteroids therapy (Gushingoid syndrome)

74

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Clinical picture: 1.

General overview :

Type of patient: Age: 30-40 years , Sex: females > males A. Head : Cushingoid feature :

o

1. Moon face : rounded face with bloated cheeks

o

Due to deposition of fat on the temporal & buccal regions Plethoric face : secondary polycythemia Trunkal obesity(samboxa shaped obesity): Fat deposition in breast & abdomen

o

Not in buttocks ^ sunken buttocks

o

2. 3.

o

Thin limbs

4.

Supraclavicular pad of fat

5.

Buffalo hump : fat deposition in interscapular & dorsocervical region Effect of DM on teeth, eye, skin, .... 30% of cases have DM (insulin resistance

6.

steroid DM)

Upper & lower limbs: ulcers, infections & LL edema C. Skin changes : B.

1.

Skin hyperpigmentation occurs only in ACTH dependent cases (Pituitary or Para-malignant causes).

2.

Thin skin: visible as cigarette paper. Skin ulcers : delayed healing of wounds Skin infections :fungal & bacterial infections

3. 4.

5. Striae : a.

b. 6.

Striae rubra: red lines due to rupture of collagen fibers in the dermis with exposure of vascular subcutaneous tissue Striae alba: white lines due to prolonged stretch of abdomen Vascular purpura with easy bruising (Rupture of BVs)

7.

Androgenic manifestations:

❖

Etiologv :

o o

acth

I

I1

ACTH dependent cases : ACTH —> stimulate adrenal androgen production Adrenal carcinoma : co-secrete cortisol & androgen

T

m B. Females

A. Males

Acne

o

Scalp baldness o Frontal baldness & Hirsutism

11.

o

Zona tascicu ata

o

Acne

Zona reticulans

i Androgens

Cortiso

Systemic examination :

1. CNS:

A. B. o o C.

Mentality for psychosis & depression Motor power: Muscle weakness, wasting & proximal myopathy Tetany (alkalosis) Sensation: diabetic neuropathy

Hypothalamus Inhibition

D. Joint:

o o o 2. 3.

Osteoporosis with bone aches and pathological fractures Stunted growth in young children, Kyphosis CVS: HP, Hypertension Chest for the cause e.g. Bronchogenic carcinoma, steroid therapy in bronchial asthma

GnRH

Anterior pituitary

4. Abdominal:

A. Skin changes

B. Bleeding tendency : Vascular Purpura C. Peptic ulcer

LH & FSH

D. Palpable abdominal mass in adrenal tumors (suprarenal mass) E. Genital examination :

1 Cortisol

❖ Etiologv:

o Hypogonadotrophic hypogonadism: tcortisol^ I gonadotrophin-releasing hormone pulsatility

i LH & FSH

❖ Clinical picture : b. Females

a. Males

o

Loss of libido

o

Impotence

75

o

Amenorrhea

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Differential diagnosis: 1. Obese, hypertensive diabetic patient: normal plasma cortisol. 2. Females taking oral contraceptive pills: o Obese & hypertensive, o t Cortisol due to t cortisol binding globulin 3. Liver cell failure

4. Osteoporosis of Gushing: form other causes of osteoporosis as hyperparathyroidism 5. Differential diagnosis of the cause: pituitary, adrenal, ectopic. Investigations: I.

Biochemical:

a. Serum

❖ Serum cortisol level by radioimmunoassay: o Earliest change is loss of circadian rhythm i.e. cortisol 9 am is normal & cortisol 12 pm is high (the usual fall of cortisol by night doesn't occur) o Later : persistent high level

o t serum glucose 0 i serum calcium o t Na, J,K, and alkalosis

❖ 24 hours urine collection reveals:

b. Urinary 0 i Na,t K,and

o t Free cortisol 0 t Hormone end product: f 17-hydroxy-corticosteroids

aciduria

II. Blood picture : o I: Polycythemia, Neutrophilia (polymorphonuclear leukocytosis)

o I: Eosinopenia, basopenia, lymphopenia & monocytopenia III. Cause of Gushing syndrome: 1. Serum ACTH(N=60 pg/ml): A. Low (< 20 ng/L): o

B. High (> 200 ng/L): o Pituitary Gushing or ectopic ACTH secreting tumors

Adrenal tumor

0 Abdominal CT or sonography

o

SellaCTorMRI

o Chest X-ray and CT 2. CRH stimulation test: Exogenous CRH :

Exogenous CRH No response

Exaggerated ACTH response

o Exaggerated ACTH response

Pituitary Gushing disease

o No response : ectopic ACTH tumor or adrenal tumor

76

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

3. Dexamethasone suppression test: A. Low dose dexamethasone suppression test: CRH

ACTH

>

>

Cortisol

Negative Feedback

Dexamethasone

o Normal: suppression o Abnormal: No suppression i.e. abnormal high level of cortisone ❖ Test:

1.

Overnight low dose dexamethasone suppression test:

11.

o Dexamethasone 1 mg at 11 pm ,then cortisol measured at 9 am on the second day

Standard low dose dexamethasone suppression test:

o Dexamethasone 0.5 mg /6 hrs for 48hrs

'I* Interpretations : Cortisol serum level measured before and after the test

a. Suppression of plasma cortisone level ( high dose test o Obesity & Depression

cortisone level(> 5 pg/dl)

B, High dose dexamethasone suppression test: ACTH

ttt Cortisol

Dexamethasone

o Suppression of plasma cortisone level: Pituitary Cushlng disease o Failure of suppression of plasma cortisone level: ectopic ACTH tumor or adrenal tumor ❖ Test:

1.

Overnight high dose dexamethasone suppression test:

11.

Standard high dose dexamethasone suppression test:

o Dexamethasone 8 mg at 11 pm ,then cortisol measured at 9 am on the second day

o Dexamethasone 2 mg/6 hrs for 48 hrs

❖ Interpretations : Cortisol serum level measured before and after the test: a. Suppression of plasma cortisone level (reduced by > 50%) o Pituitary Gushing disease

b. Failure of suppression of plasma cortisone level(no reduction):

o Other causes of Gushing: ectopic AGTH tumor or adrenal tumor: 1) AGTH level is high in ectopic tumor 2) AGTH level is low in adrenal tumor

4. Insulin tolerance test:

o Differentiates between Gushing syndrome from obesity & depression o t Cortisol after insulin exclude Gushing syndrome 5. Inferior petrosal venous sampling of ACTH: o Invasive procedure used to confirm pituitary origin of the tumor in difficult cases.

77

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Treatment:

I. II.

Symptomatic treatment e.g.: Correction of hyperglycemia : may need high doses of insulin Treatment of the cause:

A. 1. 2. 3. a. b. o o

Surgical: Surgical removal of the source e.g. pituitary, ectopic ACTH secreting tumor, or adrenal tumor Stress dose of corticosteroids in preoperative, intraoperative & postoperative period I Steroidogenesis: J, cortisol Synthesis: Aim: preoperative control of cortisol level decreases morbidity & mortality Drugs : Aminoglutethimide Mitotane, Metyrapone

o

Ketoconazole

B. Radiation :

o Pituitary irradiation o Post-surgical removal of adrenal carcinoma C. Medical treatment:

1. In Adrenal Gushing:

o After unilateral adrenalectomy, the contralateral gland remains suppressed by the previous high cortisol so the patient need corticosteroids replacement therapy for several months until the remaining normal adrenal tissue regains its ability to produce cortisol . 2. J, steroidogenesis: see before

N.B.: Nelson syndrome:

o Bilateral adrenalectomy was done in the past in Pituitary Gushing diseases o

Occur in 20% of cases

o Loss of-ve feedback effect of cortisol on pituitary adenoma secreting AGTH —> f AGTH ^ f size of pituitary tumor f Pressure symptoms + f Pigmentation.

❖ N.B.: Alcoholic pseudo-Cushing syndrome: ❖ Etiology: o Ghronic alcoholism results in impaired metabolism of corticosteroids due to impaired liver function o

Direct effect of alcohol on cortisol or AGTH release.

❖ Glinical picture and investigations: o as Gushing syndrome ❖ Treatment: stop alcohol intake

78

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Congenital adrenal hyperplasia (adrenogenital syndrome) ❖ Etiology: Cholesterol

4. 17-hydroxyprogesterone

Progesterone

4r

-> Adrenal androgena

i

ACTH

4

DeoxycorUcosterone

11-deoxycortisGl

I

Cortisol

i

Corlisosterone

Cortisol

i 18-hydroxyprogesterone

i

Arrdrogen

Aldosterone

o The condition results from autosomal recessive deficiency of one of enzymes involved in the pathway of synthesis of cortisol commonly 21-hydroxylase & 11-p-hydroxylase. o Reduced cortisol secretion will lead to increased ACTH —> diversion of steroid precursors into the androgenic steroid pathway (androstenedione, testosterone, and hydroxyprogesterone) —> virilizing syndrome.

❖ Clinical picture: Depends on age & sex of the patient:

I. o

II.

Prenatal:

In males

o

In females

Post-natal & before puberty o

In males

III. o

After puberty

In females

❖ Presentation

1. Salt wasting & adrenal crisis if there is severe aldosterone deficiency

❖ Isosexual

precocious pseudopuberty: macrogenitosomia

2. Female

o o o

pseudohermaphroditism: Ambiguous genitalia Small vagina Big clitoris Big fused labia majora

praecox:

o

Muscularization,

o

deepening of voice Fused epiphysis &

simulating scrotum

1. Primary amenorrhea

1) Secondary amenorrhea &

Sterility 2. Hirsutism , Virilization 3. Breast atrophy 4. Dwarfism

■ 4) Enlarged clitoris

dwarfism o

Small testicle and

no spermatogenesis

❖ N.B.: Hirsutism developing before menarche is suggestive ofcongenital adrenal hyperplasia Investigations:

1. ttt- ACTH,adrenal androgens, 17-Hydroxy progesterone, urinary pregnanetriol level 2. Ill: cortisol & aldosterone (1/3 of cases) NB: lip Hydroxylase less Treatment:

common used in treatment because |

1. Glucocorticoid replacement to decrease ACTH & androgen secretion 2. Mineralocorticoids replacement in low aldosterone 3. Anti-androgen drugs : fiutamide

79

it is associated with hypertension

|

due to I of 11 deoxycorticosterone. J

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Pheochromocytoma Adrenal Medula

❖ Etiology:

o Pheochromocytoma is a neuroendocrine tumor of the medulla of the adrenal glands (originating in the chromaffm cells) secreting excess catecholamines o Tumor RARELY secretes dopamine, ACTH,VIP, PTHrP o

Catecholamine

Inherited as autosomal dominant trait alone or with combination with MEN II A & IIB ❖ 90%:

o

From adrenal medulla

❖ 10%: rule of 10%

o From extra-adrenal: in regions that contain sympathetic ganglia (paraganglioma) e.g. Organ of Zuckerkandl near the bifurcation of the aorta

o Secreting epinephrine & norepinephrine o Benign

o o

Secreting norepinephrine Malignant

o

Unilateral

o

Bilateral

o

Solitary tumor

o

Multiple tumors

❖ Clinical picture: I.

Hormone effect: The tumor secretes catecholamines:

1. 2. o o o

Triad of headache, sweating & palpitation (tachycardia & tachyarrhythmias) Hypertension: At first paroxysmal hypertension lasting minutes to hours Later on persistent hypertension(1% of secondary causes of Hypertension, 0.5% of severe hypertension), Hypertension decreases circulatory blood volume (hypovolemia) causing hemoconcentration & orthostatic hypotension o N.B.: presence of normal BP despite increased catecholamines levels in plasma indicates a decreased number of a receptors(down regulation) in response to high catecholamines levels. H. Complications:

( )c> 1. CNS:stroke secondary to hypertension 2. CVS:

o o o 3. 4.

Coronary Artery Disease : Myocardial infarction (coronary spasm + HTN) Hypertrophic cardiomyopathy Sudden death due to arrhythmia DM:catecholamine antagonize insulin release Cashing syndrome(ACTH secreting tumors), diarrhea(VIP secreting tumor)& hypercalcemia(PTHrP secreting tumor)

HI.

Associations:

1. Neurofibromatosis.

2. Multiple endocrine neoplasia syndrome,type IIA and type IIB 3. Von-Hippel Lindau syndrome:

o CNS and retinal hemangioblastomas, renal and pancreatic cysts, and renal cell carcinoma. 4. Sturge Weber syndrome: o CNS arteriovenous malformations, and cutaneous angioma of the face.

80

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Differential diagnosis

1. Anxiety disorders, including benzodiazepine withdrawal syndrome 2. Paroxysmal supraventricular tachycardia 3. Carcinoid syndrome 4. Von Hippel-Lindau Disease

5. Elevated BP: Essential Hypertension & Renovascular Hypertension 6. Endocrine : Hyperthyroidism & Insulinoma Investigations: I.

Laboratory

A. Biochemical: a. Serum

b. Urine

o t Blood glucose o 1 Catecholamines o I Catecholamines o 24 hours urine collection | : hormone end product: ■ t Vaniliyl mandelic acid ■ t Metanephrines or nor metanephrines

B. Clonidine suppression test: a. Normal: catecholamines < 500 pg/ml o It suppress norepinephrine secretion in an essential hypertension & normal subjects because clonidine decreases neuronal release of norepinephrine

b. Pheochromocytoma: catecholamines > 500 pg/ml o It does not suppress norepinephrine secretion because clonidine does not affect chromaffln cell

release of norepinephrine.

C.ECG & ECHO for complications

II. Radiological : localization of the tumor: 1. CT, MRI or abdominal US.

2. Iodine'^' Metaiodobenzylguanidine(MIBG)scanning in extra-abdominal tumors. 3. Selective adrenal venous catheterization & sampling ❖ Treatment:

A. B. 1. a. o o b.

Surgical removal of the tumor (adrenalectomy). Preoperative preparation : Block adrenergic activities: a-hlocker FOLLOWED BY p-hlocker: a-blocker e.g. Phenoxybenzamine 20-40 mg/day or Phentolamine or Prazosin P-blocker e.g. Propranolol 120-240 mg/day Combined a and p blocker e.g. labetalol

N.B.: it's important to give u-blocker FOLLOWED BY p-blocker because if p-blocker given first, unopposed a action occurs causing severe hypertension which causes congestive heart failure, pulmonary edema & even cardiac arrest due to increased afterload on the heart & no pi inotropic action.

2. Correction of hypovolemia by 1 -2 units of blood to increase intravascular volume. 3. Cortisone cover is used if bilateral adrenalectomy is planned.

C. Postoperative complication should be corrected e.g.: o Hypotension : corrected by IV fluids

o Hypoglycemia corrected by glucose containing solutions.

81

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Adrenocortical insufficiency (adrenal failure)

Chronic adrenal failure

Etiology:

I. Primary adrenal failure : adrenal gland disease: 1. Idiopathic atrophy: autoimmune adrenalitis:

Addison's disease

JO- /A V

o The most common cause(80%)

o Associated with other autoimmune disorders e.g. DM type I, pernicious anemia, thyroiditis, vitiligo 2. Inherited : Congenital adrenal hypoplasia

3. Infection: TB, HIV, Fungal infection & MENINGOCOCCAL SEPTICEMIA Dark brown

4. Inflltrative:

o o 5. o o

Pigmentation

Hypogtyccmia

of Skin — Hemochromatosis, amyloidosis, and sarcoidosis Metastasis especially from oat cell carcinoma of the lung I Axillary'& pubic hair latrogenic : surgical - drugs Bilateral or unilateral adrenalectomy without corticosteroid replacem ent Gi Disturbances Bilateral adrenal hemorrhage due to anticoagulant over dose

Hypotension

Weight loss

6. Irradiation

II. III.

- Postural

Weakness

Secondary (pituitary) adrenal failure : Sheehan syndrome Tertiary adrenal failure : Hypothalamic dysfunction Adrenal Crisis:

❖ Clinical picture^ j

frofound Fatigufi Oehydrstion

Vascular CoWapee Renal Shut Pown ■i'Serum NA

I.

Manifestation due to hormonal deficiency | & ACTH:

tSerum K

B. I Mineralocorticoid : o J, Aldosterone in primary adrenal failure only Asthenia: marked muscle weakness, fatigue & weight loss 2) Hyponatremia & Hypoglycemia : Drowsiness, lack of concentration, confusion, HYPERKALEMIA convulsion & hypoglycemic coma that is 3) Hypotension, hypovolemia characteristically devoid of promontory & pre-renal failure symptoms (due to lack of catecholamine) Postural hypotension: ❖ N.B.: Aldosterone is not Systolic BP > llOmmHg exclude adrenal failure. deficient in secondary

"aT I Glucocorticoid : J, Cortisol

2. o

3. o

4.

GIT:

adrenal failure as it's under

o

Anorexia, nausea, vomiting, diarrhea or

control of renin angiotensin aldosterone system(RAAS)

constipation and abdominal pains D.

I Sex hormones : J, Androgen

I Axillary & pubic hair in females only

Hyper-pigmentation of skin & mucus membrane:

Etiology: primary adrenal failure only, not in secondary adrenal failure. Mechanism: Direct action of t ACTH on melanocytes Site & color : a. o

b. 1.

Mucous membrane : Slate colored

Inner side of lips, gums, buccal mueosa

Skin : Tanning (dark brown): Persistent tanning following sun exposure :face, neck, neck lace, dorsum of hands

2.

Hands: Palm (palmer creases)& Dorsum (knuckles & nail folds)

3.

4.

Pressure areas: elbow, knee, extensor surfaee of limbs Friction area : axilla, inner thigh

5.

Previously pigmented area became more pigmented : areola, nipple , umbilicus

6.

Scars of operations after the onset of the disease

H III

Clinical picture of the cause e.g. TB

Clinical picture of the complications e.g. Addisonian Crisis

82

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Differential diagnosis : 1. Other causes of generalized pigmentation:

Primary

Secondary

Tertiary

a. Familial & racial

b. Primary Addison's diseases. Primary biliary cirrhosis c. Pituitary Gushing disease , Pellagra, Pregnancy

tCKH

TCRH

tACTH

iACTH

d. Neurofibromatosis , Hemochromatosis

2. Other causes of hypotension & hyperkalemia 3. Other causes of hypoglycemia and asthenia e.g. malabsorption syndrome, CRF, pellagra. 4. Primary from secondary adrenal failure : o see Sheehan Syndrome + see below

|Acm

❖ Investigations i AdnsMlSteroids

I.

o o

A. Serum B. Urine : 24 hours urine collection reveals II.

X AdrenalSteroida

X AdrmalSteroids

Biochemical:

i Cortisol, i Glucose & J, Na I Hormonal end product: J. 17-hydroxy-corticosteroids

Blood picture : Anemia, neutropenia ,eosinophilia, basophilia, lymphocytosis & monocytosis

To diagnose adrenal failure: short ACTH stimulation test: Synacthen (synthetic ACTH)250 pg IM/IV

III.

o o o

Measure plasma cortisol before and 30 and 60 minutes after injection Result:

1) Normal response: cortisol level > 20 pg/dl 2) Abnormal response (cortisol level < 20 pg/dl): primary or secondary adrenal failure IV. To diagnose the cause of adrenal failure : I. Corticotrophin releasing hormone(CRH)level: o Low in tertiary adrenal failure o High in primary & secondary adrenal failure 2. Aldosterone & potassium level 3. ACTH level

A. Primary adrenal failure o Low & hyperkalemia

B. Secondary adrenal failure o

Normal & so normal K level

o

High

o

Low

o

Failure to rise in cortisol

o

Rise of cortisol level > 550

4. Renin

5. Long ACTH stimulation test: o Synacthen 1 mg IM daily for 5 days o

Measure cortisol before and at the end of the

pg/dl

level > 550 pg/dl

test

6. 24 hours urinary 17

hydroxycorticosteroids(170HCS)test: o Synacthen 250 pg IV infusion over 8 hours for 2 days o

17 OHCS level.

o Rise in urinary 17 OHCS level (t2-5 Folds)

Adrenal antibodies for

o

CT skull

autoimmune cases

o

Other hormones level e.g. TSH,Prolactin

o Failure to rise in urinary

Measure 17 OHCS before and at the end of the test

7. Other investigations:

o

o

CXR for pulmonary TB

Treatment

1. Symptomatic: diet rich in CHO,Protein, Na with low K 2. Hormone replacement:

A. Glucocorticoid replacement: Oral hydrocortisone:

o 20 mg at 10 am & 10 mg at 6 pm (N.B.: f dose in stressful conditions e.g. trauma, infection or surgery.) B. Mineralocorticoid replacement: 9-alpha fludrocortisone 0.1-0.2 mg/day if BP is still low with cortisol replacement

3. Treatment of the cause (e.g. TB.)& complications (e.g. Addisonian Crisis)

83

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Acute adrenal failure: Addisonian Crisis

❖ Etiology : I.

Primary adrenal failure: adrenal gland disease:

A. Acute from the start:

1. o o 2.

Intraglandular hemorrhage: bilateral adrenal hemorrhage due to : Infection : Meningococcal septicemia (Waterhouse-Friderichsen syndrome) Drugs : Anticoagulant over dose latrogenic:

o

Sudden withdrawal of chronic corticosteroid treatment

o Bilateral or unilateral adrenalectomy without corticosteroid replacement B. Acute on top of chronic: o Patient with adrenal failure exposed to stress o E.g. trauma, infection, or surgery without adequate corticosteroid replacement. 11. Secondary adrenal failure: pituitary disease: 1. Pituitary apoplexy: hemorrhage in pituitary adenoma 2. Sheehan syndrome: when treatment starts with T4 before cortisone

f

❖ Clinical picture :

1. Severe hypotension, hypovolemia, dehydration & oliguria up to shock 2. Severe hypoglycemia up to coma 3. Severe weakness

4. Severe nausea, vomiting and diarrhea with abdominal pain (acute abdomen) 5. Hyperpigmentation in Addison's disease

❖ Investigations : as chronic adrenal failure

❖ Treatment :

❖ It is a MEDICAL EMERGENCY: Saline, Sugar, Steroids. 1. Symptomatic : Fluids; o Hypovolemia : loading 2 L of normal saline then 3L/day o Hypoglycemia : glucose 10% infusion 11. Hormone replacement:

o Hydrocortisone 200mg IV bolus then 100 mg/8hrs till the patient is stable then 20mg/8 hours, then 20 mg at 10 am & 10 mg at 6 pm III. Treatment of the cause e.g. infection

84

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

A.

o o

r»„:

1

1

- —i

i

1 j:

activation of RAAS(|renin)

Supraclavicular pad of fat Buffalo hump : fat deposition in interscapular & dorsocervical region Effect of DM on teeth, eye, skin ... 30 % of cases have DM (insulin resistance ^ steroid DM) Upper & lower limbs: ulcers, infections & LL edema Skin changes : Skin hyperpigmentation occurs only in ACTH dependent cases (Pituitary or Para-malignant causes). Thin skin: visible as cigarette paper. Skin ulcers : delayed healing of wounds Skin infections : fungal & bacterial infections

o

4) 5)

EGG : Prolonged PR interval, ST depression with

(1 ionized Ga++)

Leading to Alkalosis which is exaggerated by intracellular shift of hydrogen with extracellular shift of K to compensate for K loss —► This will manifest by tetany

Hydrogen excretion:

Glucose intolerance

Kidney: nephrogenic diabetes insipidus

Muscle: Asthenia ^ weakness, hyporeflexia up to flaccid paralysis

ileus

GIT: Atony^ peristalsis, constipation up to paralytic

inverted T wave & prominent U wave

2) 3) 4)

85

Thin limbs

o

GVS: Arrhythmia :

GNS: Apathy

6) o B. G. 1)

Not in buttocks —> sunken buttocks

2) 3) o

polyuria K excretion: hypokalemia that manifests by:

mental confusion, convulsion & coma

Head : Cushingoid feature : Moon face : rounded face with bloated cheeks due to deposition of fat on the temporal & buccal regions Plethoric face : secondary polycythemia Trunkal obesity (samboxa shaped obesity): Fat deposition in breast & abdomen

is MILD due to:

A. 1)

General overview :

Clinical picture:

Hypokalemic nephropathy: Unresponsiveness to ADH —nephrogenic diabetes insipidus ^ polyuria. Renal escape phenomena : t blood volume GFR —>

I.

syndrome)

Exogenous corticosteroids therapy (Cushingoid

Type of patient: Age: 30-40 years , Sex: $ > c?

2.

Adrenal Gushing : Gushing syndrome(20%): Adrenal hyperplasia, tumor(adenoma or carcinoma) ofzona fasciculata secreting excess cortisol

o

Na & H20 retention: hypertension and edema which

Renal artery stenosis & Malignant HTN Renin secreting tumors e.g. Bartter's syndrome

loss via GIT or kidney

Depletion of salt(hyponatermia): i Na intake or f Na

Decreased effective circulating volume e.g. congestive heart failure, liver cirrhosis & nephrotic syndrome

Diuretics: the commonest

Etiology:

secondary

G.

o

3.

A

only

I Sex hormones : I Androgen: J, Axillary & pubic hair in females

under control of RAAS

N.B.: Aldosterone is not deficient in secondary adrenal failure as it's

Hyponatremia & HYPERKALEMIA Hypotension, hypovolemia & pre-renal failure

Asthenia

only

GIT: Anorexia, nausea, vomiting, diarrhea or constipation and abdominal pains J, Mineralocorticoid : J. Aldosterone in primary adrenal failure

failure.

hypoglycemic coma that is characteristically devoid of promontory symptoms (due to lack of catecholamine) Postural hypotension: systolic BP > IlOmmHg exclude adrenal

Drowsiness, lack of concentration, confusion, convulsion &

Asthenia: marked muscle weakness, fatigue & weight loss Hypoglycemia :

J. Glucocorticoid : J, Cortisol

Manifestation due to hormonal deficiency & T AGTH:

Tertiary adrenal failure : Hypothalamic dysfunction

Secondary (pituitary) adrenal failure : Sheehan syndrome

Irradiation

Hemochromatosis, amyloidosis, and sarcoidosis Metastasis e.g. small (oat) cell carcinoma ofthe lung latrogenic : surgical - drugs Bilateral or unilateral adrenalectomy without corticosteroid replacement Bilateral adrenal hemorrhage due to anticoagulant over dose

Infiltrative:

SEPTICEMIA

pernicious anemia Inherited : Congenital adrenal hypoplasia Infection: TB, HIV, Fungal infection & MENINGOCOCCAL

The most common cause(80%) Associated with other autoimmune disorders e.g. DM type I,

Non AGTH dependent :

renal ischemia

zona glomerulosa Secondary hyperaldosteronlsm

1.

A

Pathogenesis: J, IVV

1

Ectopic AGTH secreting tumors: Para-malignant syndrome e.g. Bronchogenic carcinoma Exogenous AGTH therapy (Cushingoid syndrome)

Etiology

Adenoma (65%), hyperplasia(30%) carcinoma(5%)of

❖ DISEASE

J-_A.

Idiopathic atrophy: autoimmune adrenalitls;

J

Chronic primary adrenocortical insufficiency Chronic primary adrenal failure Hypoadrenocorticism

reticularis.

Combined hypofunction ofzona glomerulosa, fasciculata &

microadenoma secreting excess ACTH(70%)

A

o o o

o

Pituitary Gushing: Gushing disease: Basophil

A

Hyperfunction ofzona fasciculata Hypercorticism

.-Vddison's disease

Autonomous overproduction of aldosterone independent

1

o o

❖ Synonyms

Gushing syndrome

of RAAS (J,rentn):

Hyperfunction ofzona glomerulosa Primary hyperaldosteronism

Conn's svndrome

I

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

f Renin (due to negative feedback)

Normal renal biopsy

o

o

infusion

o

o

t serum aldosterone

Hypertrophy ofjuxtaglomerular apparatus

t Benin

normal saline

o

o

liver & renal causes.

Clinical picture :

Systemic examination :

❖ Differential diagnosis

Clinical picture of the complications e.g. Addisonian Crisis

Clinical picture of the cause e.g. TB

Pressure areas: elbow, knee, extensor surface of limbs Friction area : axilla, inner thigh Previously pigmented area became more pigmented : areola, nipple , umbilicus Scars of operations after the onset of the disease

Differential diagnosis

Loss of libido & amenorrhea

cortisol.

Liver cell failure

ectopic

86

test

stimulation

4) ACTH 5) ACTH

function

3) Thyroid & gonadal

hypotension

crisis &

2) Adrenal

Cortisol doesn't

ACTH injection

increase after

High o

Normal

aldosterone

Common,absent

o

o

o

injection

after ACTH

Cortisol increase

Low

Low

control

is not under ACTH

aldosterone which

Rare, due to presence of

due of deficiency of ACTH & MSH

occurs due to excess ACTH

o

(Hypopituitarism) Depigmentation

o

adrenal failure

❖ Primary adrenal failure (Addison's disease) Hyperpigmentation

o

o

o

o 1) Pigmentation

S'. Loss of libido & impotence

Clinical picture:

❖

Secondary

Other causes of hypotension hypoglycemia, asthenia, hyperkalemia Primary from secondary adrenal failure

Hemochromatosis

Primary Addison's diseases. Primary biliary cirrhosis. Pituitary Cushing disease , Pellagra, Pregnancy, Neurofibromatosis &

Etiology: Hypogonadotrophic hypogonadism: tcortisol^ GnRH -> f LH & FSH

Genital examination :

Skin changes Bleeding tendency : Vascular Purpura Peptic ulcer Palpable abdominal mass in adrenal tumors

Abdominal:

Other causes of generalized pigmentation:

III.

II.

6.

3. 4. 5.

Familial & racial

Osteoporosis of Cushing: form other causes of osteoporosis as hyperparathyroidism 5. Differential diagnosis of the cause: pituitary, adrenal,

3.

dorsum of hands

2. Hands: Palm (palmer creases)& Dorsum (knuckles & nail folds)

Chest for the cause e.g. Bronchogenic carcinoma, steroid

2. Females taking oral contraceptive pills: o Obese & hypertensive. o I Cortisol due to f cortisol binding globulin 4.

Mucous membrane : Slate colored:

o Inner side of lips, gums, buccal mucosa b. Skin:Tanning(dark brown): 1. Persistent tanning following sun exposure : face, neck, neck lace,

Site & color :

❖ a.

D. Hyper-pigmentation of skin & mucus membrane: ❖ Etiology: primary adrenal failure only. ❖ Mechanism: Direct action of t ACTH on melanocytes

therapy in bronchial asthma

Osteoporosis with bone aches, pathological fractures & kyphosis Stunted growth in young children. CVS: HP, Hypertension

Joint:

Mentality for psychosis & depression Motor power: Muscle weaknees, wasting & proximal myopatby Tetany (alkalosis) Sensation: diabetic neuropathy

CNS:

1. Obese, hypertensive, diabetic patient: normal plasma

1.

Acne, Frontal baldness &. Hirsutism

c?: Acne & Scalp baldness II.

❖

o

after normal saline

I serum aldosterone

o

o

Etiology:

o ACTH dependent cases : ACTH —> stimulate adrenal androgen production o Adrenal carcinoma co- secrete cortisol & androgen

♦t*

5) Striae : Striae rubra & Striae alba 6) Vascular purpura with easy bruising 7) Androgenic manifestations:

No hypertension except with RAS Marked edema in HF,

level suppressed after

Mild or no edema

o

o

Secondary hyperaldosteronism

level unsuppressed

Mild hypertension

Conn's syndrome.

Primary hyperaldosteronism:

Differential diagnosis

o

❖

❖

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

J, in primary hyperaldosteronism t in secondary hyperaldosteronism

o o

C. Radiological : localizing studies o Abdominal sonar , MRI,CT to detect adrenal adenoma o Selective adrenal vein sampling for aldosterone level

2. Hormone end product; t urinary tetrahydro-aldosterone

1. I Na, tK, aciduria

B. Urinary :

Serum renin :

3.

1. 1 Na, J.K, alkalosis 2. t Serum aldosterone level:

A. Serum ;

J, Cortisol, I Glucose & J, Na Urine : 24 hours urine collection reveals

J, Hormonal end product:) 17-hydroxy-corticosteroids

B.

o

Low : Adrenal tumor —>

Abdominal CT or US

Results :

Overnight(8 mg at 11 pm)or standard(2 mg /6 hrs for 48 h) Results :

o ❖

ACTH level is low in adrenal tumor

o o

87

syndrome from obesity & depression o I Cortisol after insulin exclude Gushing syndrome 5. Inferior petrosal venous sampling of ACTH: invasive procedure used to confirm pituitary origin of the tumor in difficult cases.

4. Insulin tolerance test: differentiates between Gushing

reduction): ectopic ACTH tumor or adrenal tumor: ACTH level is high in ectopic tumor

a) Suppression of plasma cortisone level (reduced by > 50%); Pituitary Gushing disease h) Failure of suppression of plasma cortisone level (no

Technique :

❖

a) Normally: suppression of plasma cortisone level( 5 pg/dl): Gushing syndrome. Obesity & Depression ii. High dose dexamethasone suppression test:

❖

h. High : Pituitary Gushing or ectopic ACTH secreting tumors —♦ Sella CT or MRI & Chest X-ray and CT 2. CRH stimulation test: Exogenous CRH : a. Exaggerated ACTH response —+ Pituitary Gushing disease b. No response ; ectopic ACTH tumor or adrenal tumor 3. Dexamethasone suppression test: i. Low dose dexamethasone suppression test: ❖ Technique : Overnight(dexamethasone 1 mg at 11 pm)or standard(dexamethasone 0.5 mg/6 hrs for 48hrs)

Serum ACTH:

1.

i Na,t K, and aciduria 24 hours urine collection reveals : t Free cortisol t Hormone end product: f 17-hydroxy-corticosteroids Blood picture : t • Polycythemia, Neutrophilia I : Eosinopenia, basopenia, lymphopenia & monocytopenia Cause of Gushing syndrome:

a.

1) 2) o o C. O O D.

B. Urinary :

Aldosterone &

Renin

Long ACTH stimulation

4.

5.

7.

o

o

6.

Measure cortisol before

o

Other investigations:

and at the end of the test

Measure 17 OHGS before

2 days

infusion over 8 hours for

24 hours urinary 17 hydroxycorticosteroids (I70HCS)test: Synacthen 250 pg IV

and at the end of the test

Synacthen 1 mg IM daily for 5 days

o

test:

ACTH level

potassium level 3.

2.

o

o

o

o

o

o

TB

pulmonary

CXR for

cases

autoimmune

antibodies for

Adrenal

OHCS level.

in urinary 17

Failure to rise

pg/dl

level >550

in cortisol

Failure to rise

High

hyperkalemia

Low &

o

o

o

o

o

o

TSH, Prolactin

level e.g.

hormones

Other

GT skull

(12-5 Folds)

OHGS level

urinary 17

Rise in

pg/dl

level > 550

cortisol

Rise of

Low

level

so normal K

Normal &

adrenal failure

B. Secondary failure

High in primary & secondary adrenal failure A. Primary

o

adrenal

Results:

Normal response: cortisol level > 20 pg/dl Abnormal response: cortisol level < 20 pg/dl: Primary or secondary adrenal failure To diagnose the cause of adrenal failure: Corticotrophin releasing hormone(CRH)level: Low in tertiary adrenal failure

❖

Synacthen (synthetic ACTH)250 pg IM/IV Measure plasma cortisol before and 30 and 60 minutes after injection

1) 2) o E. 1) o

Technique:

❖

o o

o ): Anemia, neutropenia o ): eosinophilia, basophilia, lymphocytosis & monocytosis D. To diagnose adrenal failure: short ACTH stimulation test:

C. Blood picture :

A. Serum :

o

f serum glucose, J, serum calcium t Nn, J,K, and alkalosis Cortisol level by radioimmunoassay: Earliest change is loss of circadian rhythm Later : persistent high level

1) 2) 3) o o

Investigations : A. Serum :

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

synthesis 3. Surgical removal ofadrenal adenoma

B. ACE inhibitors (captopril): J, aldosterone secretion C. Metopyrone(ll-p hydroxylase blocker): I aldosterone

/day

A. Aldosterone antagonists : spironolactone 100-400 mg

2.

i steroidogenesis: see before

gland Ifom suppression

88

After unilateral adrenalectomy, corticosteroids replacement therapy to activate the other atrophic adrenal

In Adrenal Gushing:

Medical treatment:

Pituitary irradiation Post-surgical removal of adrenal carcinoma

Radiation :

Ketoconazole

J, Steroidogenesis: I cortisol Synthesis: Aim: preoperative control of cortisol level decreases morbidity & mortality Drugs : Aminoglutethimide Mitotane , Metyrapone

Stress dose of corticosteroids in preoperative, intraoperative & postoperative period

secreting tumor, or adrenal tumor

Surgical removal ofthe source e.g. pituitary, ectopic ACTH

Surgical:

Treatment of the cause:

: may need high doses of insulin

Medical treatment:

2.

Treatment

Symptomatic treatment e.g.: Correction of hyperglycemia

1. Symptomatic: reduce Na & increase K in diet 1.

3.

B.

A.

2.

Symptomatic: diet rich in CHO,Protein, Na with low K Hormone replacement: Glucocorticoid replacement: Oral hydrocortisone: 20 mg at 10 am & 10 mg at 6 pm (N.B.: | dose in stressful conditions e.g. trauma, infection or surgery.) Mineralocorticoid replacement: 9-alpha fludrocortisone 0.1-0.2 mg/day if BP is still low with cortisol replacement Treatment of the cause (e.g. TB.)& complications (e.g. Addisonian Crisis)

Multiple endocrine neoplasm(MEN)- Polyendocrine Adenomatosis(PEA)

men ^

MEN 2A

WEOAAEB'S SYfffiROME

91PPUE -SYNDEOME

MEN 2B MARFM(Ot&

'^ WTUITART

PMSNorrps

MUCOSAL

MEDUUABY

NEUROMAS

THTR01D FAOAL

ANG^OnBROMAS mrCSTINAL

AND COLLAGENOAUW

GANGUONHJROMAS

RARATVfTROID ,

TOMORS (

GANGUO-WHAT?

BtSUUNOMAS

GASTSmOMftS

❖ Definition;

o Group of inherited syndromes characterized by tumor formation in several endocrine organs, o The tumors maybe functional & non functional. ♦♦♦ Types: 1.

MEN type 1

MEN Type II A. Type II A ❖ Sipple's syndrome

❖ Wermer syndrome

❖ Wagenmann-Froboese syndrome

1. Pituitary tumors e.g. Acromegaly, 1. Pheochromocytoma prolactinoma, Gushing disease 2. Medullary thyroid carcinoma 3. Parathyroid tumors (hyperplasia & adenoma) e.g. hyperparathyroidism 3) Multiple Mucosal neuroma 4. Pancreatic tumors e.g. Gastrinoma, 4) Marfanoid appearance Insulinoma, VIPoma, Glucagonoma 5) Ganglioneuromatosis ofthe bowel 5. Less commonly: Angiofibroma & lipoma !

I

Autoimmune polyendocrine (polyglandular)syndromes(APSs)

❖ Definition :

o Group of inherited syndromes characterized by autoimmune activity against endocrine organ & non-endocrine organs.

❖ Types:

I.

Autoimmune polyendocrine syndrome I

II.

= Autoimmune PolyendocrinopathyCandidiasis-Ectodermal Dystrophy(APECED) ❖ Whitaker syndrome o

Autosomal recessive inheritance

o

Autoimmune polyendocrine syndrome

❖ Schmidt's syndrome Autosomal dominant(or recessive) inheritance

❖ Common features include :

1 1. Mucocutaneous candidiasis

1. DM Type I

2. Autoimmune hypoparathyroidism

2. Autoimmune thyroid disease e.g. hypo or hyperthyroidism

3. Adrenal insufficiency Other autoimmune features include:

1. Alopecia & vitiligo 2. Primary hypogonadism 3. Pernicious anemia

4. Autoimmune chronic hepatitis 5. Autoimmune hypothyroidism 6. Ectodermal dystrophy

4. Myasthenia gravis 5. Celiac disease

6. Serositis

89

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

I

Disorders of growth

Assessment of growth :

1. Height: o It is measured form growth curve

o It ranges between 3"''' &

percentile of same age & sex

2. Skeletal proportions:

Upper segment

i

The height

Lower segment

Span

o o o o o

Assessed by measuring height and span or the ratio between upper and lower segments The height: distance from occiput to heel in upright position Span: the distance between the tip of middle fingers with outstretched hands Upper segment: distance from the occiput to the symphysis pubis Lower segment: distance from symphysis pubis to the floor

o

Measurement:

A. In infants upper segment; lower segment = 1.7:1 & height exceeds span. B. As growth proceeds, ratio lessens so that in adults : o The height and span are equal(proportional)& lower and upper segment are usually equal. Differential diagnosis of tall stature: ❖ Definition:

o Height above ❖ Etiology:

percentile of normal people of the same age & sex.

1. Familial & racial (the commonest): o

Parents are tall

o Proportionate gigantism & normal GH level

2. Pituitary gigantism: increased GH secretion before fusion of epiphysis 3. Cerebral gigantism (Soto's syndrome):

o Accelerated growth in the P' 5 years of life followed by normal growth o Mental retardation, big skull, normal GH 4. Marfan syndrome 5. Sexual precocity:

o Sex hormones initially increase long bone growth but the final adult height is shorter than normal due to early closure of epiphysis 6. Hypogonadism (Eunuch):

o Sex hormones deficiency before closure of epiphysis —> no epiphyseal closure of long bone —> disproportionate gigantism (occur only after puberty) with hypogonadism (flabby muscle, infertility) 7. Homocystinuria: o

Autosomal recessive disorder

o Tall stature, arachnodactyly, dislocated lenses, vascular thrombosis, homocysteine in urine 8. Hyperthyroidism:

o Initial accelerated growth, but final adult height shorter than normal

90

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Differential diagnosis of dwarfism, stunted growth,short stature: Definition:

Height below the 3'"'' percentile of normal people of the same sex & age Etiology: Familial: The commonest.

I.

Endocrinal causes:

II.

1. 2.

3. 4.

5. 6. III 1.

2. 3.

I GH: Levi-Lorain syndrome, Froelich's syndrome & Laurence Moon Biedl Syndrome I T4: cretinism & juvenile myxedema I Calcium :Pseudohypoparathyroidism 1" Cortisol: Gushing syndrome or excess steroid treatment(cortisol block the ability of GH to produce somatomedin, a hepatic peptide responsible for bone growth). 1 Sex hormones: precocious puberty (excess sex hormones cause premature fusion of epiphysis). t Sugar :Juvenile DM (excess glucose —>■ J,GH) Chronic severe illness during childhood: CVS: rheumatic fever, congenital heart disease Chest: polycystic lung, TB Blood: anemia e.g. thalassemia

4.

5. IV A.

GIT: malnutrition, malabsorption, parasitic infestation, liver cirrhosis & lipid storage disease Kidney: chronic nephritis Skeletal causes:

Congenital:

1. Achondroplasia: short limbs & normal trunk 2. Osteochondrodystrophy: limbs & trunk are short and deformed 3. Osteogenesis imperfecta:

o

Fragile bone, pathological fracture + malfusion & dwarfism, joint dislocation, blue sclera, deafness due to otosclerosis

B. Acquired: 1.

Rickets

2. Pott's disease of spine 3. Pagefs disease of bone V.

Genetic disorder:

2. Turner's syndrome : monosomy 45 XO: Absence of X chromosome (45 XO instead of 46 XX)

o

1. Down syndrome: trisomy 21 Extra chromosome 21 (47 chromosome instead of 46)

o

Mental retardation

o

Ovarian dysgenesis. Primary amenorrhea

o

Hypotonia

o

Poor breast development

o Upward slanting of the eyes with epicanthic folds

o

Webbing of neck

o o

Low set ears, small mouth & protruded tongue Single palmer crease

o

Low set ears low hair line

o

Increase carrying angle

o

Cardiac anomalies e.g. VSD

o

Coarctation of aorta

o

o

Short stature

91

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Disorders of puberty

❖ Definition of puberty :

o Process leading to physical and sexual maturation that involves the development of secondary sexual character as well as growth and changes in body composition.

o Pubic hair distribution is used to stage puberty, along with breast size and contour in girls and testicular volume in boy

❖ Normal development: A. In females

B. In males

o Puberty begins between 8 and 14 years o Puberty begins between 9 and 14 years o Girls begin puberty with breast buds and o Boys start by testicular enlargement followed by pubic skeletal growth, followed by pubic, axillary hair, enlargement of penis & spermarche hair and menarche o Skeletal and muscle growth are late events in male puberty ❖ Puberty related disorders:

I.

Early (precocious) puberty:

❖ Definition :

o ❖ 1. 2. o

Precocious puberty exists if any sign of puberty appears < 8 years in females & < 9 years in males Types: Iso-sexual precocity:if the signs of premature sexual development consistent with phenotypic sex Hetero-sexual precocity: If the signs of premature sexual development are of the opposite sex e.g. aromatase excess syndrome Etiology of iso-sexual precocity:

1.

Central precocious puberty: true precocious

II.

puberty:

o Increased production of sex steroids in gonadotropin dependent manner

Peripheral precocious puberty: precocious pseudopuberty:

❖ Definition : I o Increased production of sex steroids in gonadotropin independent manner

❖ Etiology :

A. Constitutional (idiopathic): run in the family, diagnosed after exclusion of other causes B. Pathological:

❖ Secondary sexual development induced by sex

1. Damage to the inhibitory system of the brain : due to infection, trauma, or irradiation 2. Hypothalamic Hamartoma produces pulsatile gonadotropin-releasing hormone(GnRH) 3. Hydrocephalus 4. Langerhans cell Histiocytosis 5. McCune-Albright syndrome. 6. CNS tumors e.g. Astrocytoma 7. Angelman syndrome 8. Suprasellar Arachnoid cysts

steroids from abnormal sources:

A. Endogenous sources :

1. Gonadal tumors e.g. Arrhenoblastoma 2. Germ cell tumor 3. Adrenal tumors

4. 5. B. 1.

Congenital Adrenal hyperplasia McCune-Albright syndrome Exogenous hormones : Environmental exogenous hormones

2. Treatment for another condition.

❖ Diagnosis o

Pubertal level of sex steroids

o T Basal LH & FSH o Exogenous GnRH —> pubertal t LH & FSH

o

Pubertal level of sex steroids

o

i Basal LH & FSH

o Exogenous GnRH —> no pubertal t LH & FSH

92

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

I

II.

Delayed puberty:

♦> In males

❖ In females ❖ Definition :

❖ Delayed puberty exists if no signs of puberty appear beyond : o

o 14 years ❖ Examination:

13 years

1

1 I

o Absence of any secondary sexual characters by age of o Lack of testicular enlargement by age of 14 years o Lake of pubic hair by age of 15 years 13 years o Or passage > 5 years to complete genital enlargement o Or failure to menstruate by age of 16 years o Or passage > 5 years from breast growth & menstrual period

❖ Etiology : 1. Constitutional(idiopathic): run in the family, diagnosed after exclusion of other causes II.

Pathological:

1. Anatomic abnormality in genital tract 2. Chronic diseases e.g. Thalassemia major & malabsorption syndrome

onadotropic hypogonadism

3. Hypogonadotropic hypogonadism : Pathogenesis

o Due to primary hypogonadism (j, sex hormones) —> t gonadotrophins(LH & FSH)due to lack of hypogonadism(|sex hormones) negative feedback ❖ Etiology: o Turner's syndrome o Kallmann syndrome: anosmia or hyposmia, cleft lip & congenital deafness o Klinefelter syndrome o

Due to i gonadotrophins(LH & FSH)from

hypothalamus or pituitary gland —> secondary

o Prader Willi syndrome

o

Ovarian or testicular failure.

Investigations: 1. Clinical:

o

Clinical examinations

o 2. A. o B. 3. o o

Pubertal milestones and growth charts Laboratory : Hormonal assay: FSH,LH,estradiol, testosterone, hCG,GnRH test, prolaetin, TSH and T4 if suspected. 17-hydroxyprogesterone and Dehydroepiandrosterone(DHEA)especially in girls with virilization Radiological: X ray of left wrist for bone age MRI for brain and pituitary. Treatment:

A. Treatment of the cause

B. Drugs: I. A. o B. o o o o

In case of precocious puberty: Central: long acting synthetic GnRH analogues :

Leuprolide, nafarelin & histrelin Peripheral: j, sex hormones Steroid synthesis inhibitors e.g. ketoconazole Antiandrogen: spironolactone Aromatase inhibitors e.g. testolactone

2. In case of delayed puberty; Hormonal replacement to stimulate development of secondary sexual characteristics 1. Male: Testosterone 2. Female: estradiol

Antiestrogen e.g. tamoxifen

93

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Disorders of weight Obesity i& metabolic syndrome Definition of obesity:

o Excessive accumulation offat in the subcutaneous tissue & deep tissue o BMI>30kg/m2 Classification of obesity:

Body mass index (BMl)= (Height ^ody weight in Kg in meters)2 ❖ Body mass index kg/m^

❖ Category o Underweight o Normal weight o Overweight

o

40

Abdominal

cavity

Gall bladder

Intra-abdominal fat

Small Intestine

Body fat distribution :

1. According to shape: A. Pear shape or gynecoid distribution: B. Apple shape or android distribution: o Female obesity, lower body obesity o Male obesity, upper body obesity 2. According to site: A. Peripheral(gluteo-femoral) obesity:

B. Central (Visceral) obesity :

o Subcutaneous fat accumulation mainly around hips &

o

thigh

Intra-abdominal fat accumulation around viscera

e.g. Peritoneum, intestine & kidney

Visceral

Metabolic syndrome:

Obesity Low HDLChoiesterol

Insulin Resistance Metabolic

Syndrome

High

Trigiycerides /\/\^ Hypertension ❖ Other names for metabolic syndrome :

o Insulin resistance syndrome, Syndrome X, Metabolic syndrome , Reaven's syndrome, Cardiometabolic syndrome o CHAOS : for Coronary artery disease. Hypertension, Adult onset diabetes. Obesity, and Stroke ❖ Definition :

A. The International Diabetes Federation (IDF)

B. National Cholesterol Education Program Adult Treatment Panel HI(NCEP-ATPIII):

definition :

❖ Central obesity (waist circumference >102 cm in males and >88 cm in females) plus 2 of the o o o o

❖ Requires at least three of the following: o Central obesity (waist circumference >102 cm in following: males and >88 cm in females) Reduced HDL cholesterol: < 40 mg/dL in males < 50 mg/dL in females, or specific treatment for this lipid abnormality Raised trigiycerides: >150 mg/dL or specific treatment for this lipid abnormality Raised blood pressure(BP): systolic BP > 130 or diastolic BP >85 mm Hg, or treatment of previously diagnosed hypertension Raised fasting plasma glucose(FPG): >100 mg/dL or previously diagnosed type 2 diabetes

94

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

❖ Etiology of obesity: I.

Simple obesity:

t Several factors have been linked to several factors:

Leptin

ob gene on chromosome 7

Neuropeptide Y

V

Genetic factor:

o Mutation of ob gene on chromosome 7 which is responsible normally for the production of Leptin that normally Lowers appetite by suppression of feeding center in the hypothalamus.

o Impaired leptin receptor in the hypothalamus with increased release of neurotransmitters as neuropeptide Y which stimulates feeding.

o Decreased p3-adrenergic receptor activity with consequent reduction in catecholamine induced lipolysis 2. Excessive food intake with decreased energy expenditure 3. Familial or racial:

o Due to sharing the same pattern of life or due to genetically determined factor. XL Secondary obesity: A. Hypothalamic disturbances:

o Tumors or inflammation e.g. encephalitis —> inflammation destroy hypothalamic satiety centers Adren^

B. Endocrinal causes:

H,poth.i-nu. /%

k COftON

1.

Hypopituitarism: Froehlich's syndrome

2.

Hypothyroidism

Atro

.

Thyroid

f

3.

Hypogonadism and ovarian deficiency

4.

Genetic syndromes with hypogonadism : Trader - Willi syndrome

Posterior

5.

Hypercorticism (Gushing Syndrome)

C.

Drugs e.g. Corticosteroids, Contraceptive pills, Chlorpromazine, sulphonylurea & insulin

\

Ovary

^ 1.

Compiications of obesity:

Psychosoclal Eating disorders Poor self-esteem

Neurological

Body image disorder Social isolation and stigmatisation Depression

Pseudotumour cerebri

(idiopathic intracranial hypertension)

Pulmonary Caitliovascuiar

Exercise intolerance

Hypertension

Obstructive sleep apnoea

Dyslipidaemia Goagulopathy

Asthma

Chronic inflammation

Gastrointestinal

Endothelial dysfunction

Gallstones

Gastro-oesophageai reflux Non-alcoholic fatty liver disorder

Endocrine Insulin resistance

Impaired fasting glucose or glucose intolerance Type 2 diabetes Precocious puberty Menstrual irregularities Polycystic ovary syndrome (females)

Renal

Glomerulosclerosis Musculoskeletal

Ankle sprains Flat feet Tibia vara

Slipped capital femoral epiphysis Forearm fracture

95

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Complications of obesity: 1. CNS: o

Pseudotumor cerebri : idiopathic intracranial hypertension

o

Stroke

o

o

2.

Depression

Entrapment syndrome e.g. Carpal tunnel syndrome Musculoskeletal: Osteoarthritis & Gout due to impaired urate clearance

3. CVS: o o o

o

Atherosclerosis due to increased levels of LDL and decreased level of HDL

BP: Hypertension is related to insulin resistance and hyperinsulinemia Coronary artery diseases (angina & Ml), arrhythmia and sudden death. Varicose veins: DVT with secondary pulmonary embolism

Blocked airway

4. Chest: A.

Obstructive sleep apnea:

Once sleep begins ^ upper airway obstruction by large tongue & uvula heavy snoring, hypoxia & hypercarbia —> arousal(noctumal awakening) with retum of normal respiration o

B.

In chronic condition, sleep deprivation occurs leading to daytime somnolence. Obesity hypoventiiation syndrome: restrictive hypoventilation (Pickwickian syndrome): Extremely obese patient —>■ hypoventilation —+ hypoxia & hypercarbia ^ secondary polycythemia —> pulmonary hypertension & cor pulmonale ( RVF)

5. Gastro-intestinal: o

GERD & Hiatus hernia

o

Fatty liver , gall bladder stones and cholecystitis

6. Genital : o

Females: menstrual irregularities, amenorrhea, PCOs

o

Males: Hypogonadism & gynecomastia (excess transformation of androgen to estrogen in fat cells)

7. Endocrinal: o

Increased basal metabolic rate resulting in increased oxygen consumption & CO2 production

o

Diabetes mellitus Type II & metabolic syndrome : due to insulin resistance

o

Dyslipidemia: | total cholesterol, triglycerides, LDL, J, HDL

8. Cutaneous; o o

Acanthosis nigricans Increased risk of Bacterial & fungal infection

9. Cancer: increased incidence of: o o

Endometrial and postmenopausal breast cancer Cancer prostate in men

10. Others : increased incidence of: o

o

Anesthetic & surgical complications Pregnancy & delivery complications e.g. gestational DM, preeclampsia & prematurity Diagnosis of obesity:

1. Comparison of individual weight with charts for ideal body weight compared to height. 2. Calculation of body mass index (BMI) 3. Measurement of skin fold thickness (SFT) over the middle of the triceps muscle : o

Normally in male < 20 mm and in females < 30 mm.

4. Regional fat distribution can assessed by: A. CT or MKT of the abdomen to provide accurate estimation of the visceral fat B. Waist circumference:

❖ t risk

C. Waist-hip ratio:

❖ Substantial risk

0

Male

0

>94 cm

0

> 102 cm

0

Female

0

>80 cm

0

>88 cm

Waist circumference in cm

Hip circumference in cm

1. Low waist-hip ratio 0

2. High waist-hip ratio

< 0.9 in males and < 0.8 in females

0

> 0.9 in males and > 0.8 in females

0 Peripheral (gluteo-femoral) obesity 0 Central (visceral) obesity

96

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

I ■

❖ Treatment of obesity:

❖ Goals:

o Loss initially 10% in body weight over 6 months by losing 1-1.5 kg/week

3 ❖ Methods: w.

1. Treatment of the cause. 2.

Behavioral therapy to encourage the patient to take personal responsibility for changing lifestyle

3. Diet: o

Subtraction 1000 Kcal/day from total calories after 24 hours dietary assessment

4.

Low caloric diet regimen (1200Kcal/day) or very low caloric diet regimen (800Kcal/day) under medical supervision Regular exercise: will help dietary control

5.

Drugs :

o

XenicalM20mg hard capsules Orlistat

A. Orlistat: o

Mechanism of action: | pancreatic & gastric lipase —>• J, 30% of fat absorption

o

Side effect: steatorrhea

B.

Liraglutide: Mechanism of action : Glucagon like peptide 1 (GLP-1)analogue Side effects: pancreatitis & medullary thyroid carcinoma (in rats)

o o

C. Others: o o

o

6.

Lorcaserin : Selective serotonin 2c receptor agonist Phentermine/Topiramate: appetite-suppressant sympathomimetic amine and anticonvulsant Bupropion/naltrexone: Bupropion (a dopamine and norepinephrine reuptake inhibitor) and naltrexone (an opioid receptor antagonist). N.B.: drugs not used any more for their CVS side effects: Drugs enhancing noradrenaline release from hypothalamus e.g. amphetamines, diethylpropion & mazindol Drugs enhancing serotonin release from hypothalamus e.g. sibutramine Surgical:

A. Indications: o o

BMI > 40 kg/ml BMI > 35 kg/m^ with obesity comorbidities e.g. IHD & DM

B. Methods Cannula

Muscle''

1) 2) 3) 4) 5) 6)

Gastric sleeve: vertical part of stomach removed, creating a smaller reservoir for food. Gastric bypass: roux-en-y gastrojejunostomy Gastric banding: an adjustable band is applied laparoscopically around stomach Gastric balloon: by inflation of endoscopically placed balloon in the stomach. Liposuction for regional obesity. Jejunoileal bypass: not done anymore

o Anastomosis of the proximal part ofjejunum to the distal part of the ileum resulting in malabsoprtion

97

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Hirsntism

Definition:

o Excessive hair on body & face offemale simulating male distribution in androgen dependent area e.g. tip of the nose, upper lip, moustache, beard, axilla, chest, baek, abdominal midline, pubic triangle, anterior thighs & buttocks ❖

N.B.:

A. Hypertrichosis:

o Diffuse increase in veiins hair (fine, downy, non- pigmented hair) in non-androgen dependent areas B. Virilization:

o Hirsutism, acne, breast atrophy, menstrual irregularities, male pattern hair loss, masculinization (f musele mass, deepening of voice, elitoromegaly),

o Results from high level of circulating androgens close to male range e.g. androgen secreting tumors : congenital adrenal byperplasia Mechanism

1. Idiopathic :

o t activity of hair follicle 5a reductase ^ eonversion of testosterone to more potent dibydrotestosterone (even with normal androgen level) o I skin sensitivity to androgen 2. Hyperandrogenism(|Androgen/ Estrogen ratio) 3. I sex hormone binding globulin(SHBG)—>■ f fi^ee testosterone Etiology: 1. Idiopathic 2. Simple hirsutism (familial or racial):

o o

The Commonest type Ethnic tendency to have higher density of hair follicle per unit area of skin

3.

Ovarian cause:

A. Ovarian hyperthecosis & virilizing ovarian tumor B. Polyeystic ovarian syndrome 4.

Adrenal causes:

A. B. C. 5.

Virilizing adrenal tumor Congenital adrenal byperplasia Cashing syndrome Pituitary causes e.g. aeromegaly, prolactinoma

6. Thyroid causes e.g. hypothyroidism 7. Drugs: B. Hypertrichiosis : o Phenytoin, Penicillamine, Psoralens

A. Hirsutism :

o

Testosterone, Anabolic steroids, Phenothiazines

o

Corticosteroids

o o

Oral Contraceptive pills containing norgestrel & norethindrone Danazol & Metyrapone.

98

o

Streptomycin

o

Diazoxide & Minoxidil

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Clinical approach to a patient with hirsutism: ❖ 1. 2. 3. 4.

Symptoms : Age of onset of hirsutism, progression & extent of hair growth Age of menarehe, regularity of menses & fertility Current measures of hair removal & frequency of use

Change of voice & change of libido

5. Drugs

6. Symptoms of the cause e.g. Gushing syndrome 7. Family history of hirsutism ❖ Signs:

1. The presence of excess coarse & dark hair growth assessed at multiple sites e.g. face, chest, back, abdomen, thigh & buttocks 2. Virilization: see before

3. Signs of the cause e.g. Gushing syndrome ❖ Investigations: 1. o o o

Hormonal assay : Free testosterone, sex hormone binding globulin(SHBG),FSH / LH Dehydroepiandrosterone(DHEA), 17 hydroxyprogesterone Serum TSH, Prolaetin , Cortisol (if there is clinical suspicion)

2. Pelvic ultrasound & adrenal CT.

❖ Treatment:

I.

II.

Of cause

Local therapy:

1. Weight reduction in obese patient is helpful : J, free androgen by f sex hormone binding globulin 2. Cosmetic methods:Plucking, bleaching, depilatory cream, wax,shaving & electrolysis 3. Laser

4. Eflornithine HCL: irreversible inhibits hair follicle cell division

111.

Systemic treatment for widespread cases :

1. Estrogen as oral contraceptives : J, free androgen by f sex hormone binding globulin 2. Antiandrogens:Spironolactone, Flutamide, Finasteride

3. GnRH agonist: leuprolide(IM monthly): jovarian Androgen & Estrogen production 4. Progestational agents: Cyproterone acetate: potent progestin & moderate antiandrogen

N.B.:

Results will be seen after 3-6 months

❖ N.B.: Androgens are the major determinants of hair distribution in hoth sexes, so according to the effect of androgen on hair growth the following types are classified : 1. Hair not affected by androgen e.g. eyebrow & eye lashes 2. Hair depends on adrenal androgen e.g. axillary hair & low pubic hair

3. Hair depends on testicular androgen e.g. upper pubic hair, facial, ear, extremity & truncal hair 4. Hair inhibited by testicular androgen e.g. scalp hair

99

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Polycystic ovary syndrome(PCOS): Stein-Leventhal syndrome FSH

❖ Etiology:

granuiosa ceil

eitrogen • stimulate secretion of LH not FSH:

A. t LH stimulation of ovarian theca cells ^ t androgens (testosterone & androstenedione) B. J, FSH ^ inability of ovarian granuiosa to aromatize androgen to estrogen —> I estrogen ^ anovulation 2. Insulin resistance with hyperinsuiinemia & obesity

Clinical picture: 1. 2. 3. 4.

Incidence : Affect 5 - 10 % of women of reproductive age Hyperandrogenism : Hirsutism, acne, baldness Menstrual irregularities:amenorrhea, oligomenorrhea & infertility Obesity, insulin resistance & hyperinsuiinemia.

Investigations:

o

Hormonal assay: Hyperandrogenism : f free testosterone & LH relative to FSH(LH/FSH>2) Impaired glucose tolerance

2. Ovarian ultrasound : o

PCOs > 12 follicles in at least one ovary measuring 2-9 mm in diameter

❖ Treatment:

1. If fertility is needed : A. Weight reduction B. Clomiphene to induce ovulation C. Metformin:

o Insulin resistance, body weight, blood glucose o Improve menstrual irregularities, fertility & hyperandrogenism 2. If hirsutism or menstrual irregularity is the main concern : A. Oral contraceptive pills to induce regular menses B. Treatment of hirsutism

3. Surgical(ovarian wedge resection): if medical treatment failed,

100

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Gynecomastia

❖ Definition:

o

Hypertrophy of glanduiar tissue of male breast usually with prominent nipple and tender breast (tender disk-like structure under areola)

❖ N.B.: Lipomastia: fatty breast ■ It means hypertrophy of adipose (fat) tissue of male breast without true glandular enlargement ■ It occurs with obesity ❖ Etioiogy:(.Androgen/ Estrogen ratio 1.

II.

7

Idiopathic Physiological :

1. Newborn : for few weeks after birth due to persistent maternal and/or placental lactogens 2. Adolescence : transient fof plasma estradiol before completion of puberty 3. Gynecomastia of aging: in 40% of old men due tof conversion of androgen to estrogen in extraglandular tissues. III.

Pathological :

1. Deficient production or action of testosterone(hypogonadism): A. Primary: o Congenital anorchia, Klinefelter syndrome (atrophic testis) o End organ unresponsiveness(Androgen resistance) B. 2. 3.

Secondary : castration, trauma, viral orchitis Hyperprolactinemla: acromegaly, prolactinoma, hypothyroidism Hyperestrogenemia:

A. Tumors:

o Feminizing tumors of suprarenal & testes o Paramalignant syndrome ; oat cell cancer secreting gonadotrophin B. Liver failure & renal failure

C. Extreme obesity IV. Pharmacological: 1. Estrogenic: Estrogen in treatment of prostatic cancer, gonadotrophins Estrogen-like: digitalis o 3.

Antiandrogens : spironolactone , cimetidine Drugs increasing prolactin : Phenothiazine, Metoclopramide, Methyl-dopa, Reserpine

4.

Others:INH, Ketoconazole, Cytotoxic drugs

2.

("

❖ Investigations: | 1. Hormonal assay: testosterone, estradiol & gonadotrophin levels 2. According to cause e.g. liver function tests Treatment: 1. Of the cause

2. Cosmetic surgery

101

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

‫[\‪S9;0‬‬

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

‫[\‪sa^o‬‬

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

Other available books by the author .Cardiology & Nephrology .Pulmonology, Hematology & Infection .Neurology & Rheumatology .Sewilam's Internal Medicine Revision:

MCQs,Cases, Written & Oral Questions .Sewilam's Clinical Medicine

.Paraclinical Made Easy:

X-Rays, Clinical pathology & ECG .Dermatology

.Psychiatry

lii"f- vi #v:

‫اﺷﺗري ﻧﺳﺧﺗك إذا ﻧﻔﻌك اﻟﻛﺗﺎب وادﻋم ﺗﺣدﯾﺛﮫ ﺑﻧﯾﺔ ﻧﺷر اﻟﻌﻠم‬

■ ■1