New Aspects in Thyroid Diseases: Medullary Thyroid Carcinoma, Thyroiditis, Peripheral Thyroid Hormone Metabolism. IV. Multilateral Symposium on Thyroid Reinhardsbrunn-Thuringia, 1991 [Reprint 2019 ed.] 9783110874051, 9783110137316

Table of contents :
PREFACE
Contents
IMMUNOLOGY
Polyendocrine autoimmunity in thyroid disease
The effect of anti-microsomal antibodies on thyroid peroxidase activity
Antithyroid antibodies in the synovial fluid in thyroiditis
Immunological and genetical aspects in T 3- predominant Graves' disease
Unexpected course in immunological pattern in Graves' Basedov's disease - Marine-Lenhart Syndrome?
Comparative investigations of sonography and TRAK - follow up of Graves' disease
Guanyl nucleotide regulatory proteins and GTPase activity in normal and hyperthyroid human thyroid tissue and human polymorphonuclear granulocytes
PERIPHERAL THYROID HORMONE METABOLISM
Peripheral thyroid hormone metabolism
Value of the estimation of peripheral serum T3 and rT3 for prognosis assessment in patients with liver cirrhosis - a prospective study
Thyroid hormones and TSH in acute myocardial infarction
Deiodination of thyroxine and reverse triiodothyronine in cells of human adipose tissue
Comparison of natural killer activity vith thyroid function in Graves' disease
The influence of the calcium antagonist nitrendipine on thyroid hormone status in the baboon
Effect of thyroid hormones on lipoprotein (a) level in hypothyroidism
THYROIDITIS
Thyrotoxicosis due to thyroiditis
Thyroiditis - a histopathological reviev
Clinical and cytological classification of lymphocytic thyroiditis
The role of ultrasound investigation in the diagnosis and treatment of thyroiditis
Subacute thyroiditis de Quervain in male subjects
Thyroid function in postpartum thyroiditis and its follov up
Riedel's thyroiditis - positive therapeutic response to glucocorticoids
Management of chronic lymphocytic thyroiditis in children and adolescents
Thyroiditis and thyroid hyperfunction
Clinical and laboratory evaluations of patients with different types of thyroiditis
Hashimoto-thyroiditis vith long-term negative auto-antibody determination: a case report
Combination of Hashimoto- and de Quervain thyroiditis
Occurrence of goitre and diffuse lymphoid thyroiditis (DLT) in secondary school adolescents in Bratislava
Spontaneous course of Graves' Basedow's disease into hypothyroidism (case report)
MEDULLARY CANCER
Epidemiology, clinical syndrome, follow up, and prognostic factors in medullary carcinoma
Neue Entwicklungen in der chirurgischen Therapie des Sipple-Syndroms: die Kompartment-orientierte systematische Mikrodissektion der Lymphknoten beim medullären Schilddrüsenkarzinom
Medullary cancer in histopathological view
Cytological view of medullary cancer
Imaging techniques in detection and follow up of MTC
Positive scintigraphy in medullary thyroid cancer
I-131-uptake in medullary thyroid carcinoma
Our experiences with medullary carcinoma and MEN-syndrome
Possibilities and limitations of tumor-scintigraphy for follow up of medullary thyroid cancer
Thyroid cancer - differentiated and medullary: the aftercare system
Medullary carcinoma of the thyroid - own experience
Prevalence of medullary thyroid cancer in the endemic goiter area
Family screening in medullary thyroid carcinoma (MTC)
Results of therapy in patients with medullary carcinoma of thyroid gland (Poster)
The place of ultrasonography in the evaluation of medullary thyroid cancer
Medullary thyroid carcinoma - results of some diagnostic procedures used at our institute
FREE PAPERS
Tumor markers in thyroid diseases
Effects of Propranolol enantiomers in hyperthyroidism (Poster)
Thyroglobulin pattern in hyperthyroidism factitia (Case report)
Parameters of bone-metabolism in patients with hyperthyrosis (Poster)
PARATHYROID
Clinical experience in parathyroid carcinoma
Unusual course of primary hyperparathyroidism
Long-term results operated hyperparathyroidism
Diagnostik problems of primary hyperparathyroidism (pHPT) - own experiences
X-ray-morphologic and radiomorphometric results in patients with primary hyperparathyroidism (Poster)
Authors' Index
Index

Citation preview

New Aspects in Thyroid Diseases

New Aspects in Thyroid Diseases Medullary Thyroid Carcinoma, Thyroiditis, Peripheral Thyroid Hormone Metabolism IV. Multilateral Symposium on Thyroid Reinhardsbrunn — Thuringia 1991 Edited by

H. F. Deckart • E. Strehlau

W G DE

Walter de Gruyter Berlin • New York 1992

Editors Prof. Dr. H. F. Deckart Dr. E. Strehlau Nuklearmedizinische Klinik Städtisches Klinikum Berlin-Buch Wiltbergstraße 50 0-1115 Berlin-Buch

This publication has been made possible by the kind support of E. Merck, Darmstadt. The project has also benefited from the support of Isocommerz, Leipzig

Die Deutsche Bibliothek

— Cataloging-in-Publication

Data

New aspects in thyroid diseases: medullary thyroid carcinoma, thyroiditis, peripheral thyroid hormone metabolism / 4. Multilateral Symposium on Thyroid, Reinhardsbrunn — Thuringia, 1991. Ed. by H. F. Deckart ; E. Strehlau. - Berlin ; New York : de Gruyter, 1992 ISBN 3-11-013731-3 NE: Deckart, Harald [Hrsg.]; Multilateral Symposium on Thyroid

© Copyright 1992 by Walter de Gruyter & Co., Berlin 30. All rights reserved, including those of translation into foreign languages. No part of this book may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher. Medical science is constantly developing. Research and clinical experience expand our knowledge, especially with regard to treatment and medication. For dosages and applications mentioned in this work, the reader may rely on the authors, editors and publisher having taken great pains to ensure that these indications reflect the standard of knowledge at the time this work was completed. Nevertheless, all users are requested to check the package leaflet of the medication, in order to determine for themselves whether the recommentations given for the dosages or the likely contraindications differ from those given in this book. This is especially true for medication which is seldom used or has recently been put on the market and for medication whose application has been restricted by the German Ministry of Health. The quotation of registered names, trade names, trade marks, etc. in this copy does not imply, even in the absence of a specific statement that such names are exempt from laws and regulations protecting trade marks, etc. and therefore free for general use. Printing: Gerike GmbH, Berlin. — Binding: Dieter Mikolai, Berlin. — Cover design: R. Hubler. — Printed in Germany.

PREFACE Since 1981, every third year, thyroidologists have met together with specialists in Nuclear Medicine, Radiology, Surgery, Pathology, Ophthalmology and Laboratory Medicine in Reinhardsbrunn. Experienced teams from Austria, Czechoslovakia, Poland, Yugoslavia and East-Germany discussed variant topics of diagnostic strategies and treatment procedures in functional thyroid disorders, thyroiditis, thyroid cancer and immunogenic endocrine orbitopathy. The special atmosphere in the old hunting palace of the Dukes of Saxony Coburg-Gotha with remnants of Benedict monastery of the medivian ages with its lovely surroundings of the Thuringian forest were stimulating the scientific output. The proceedings of the first three symposia were published in the Isocommerz-Series (ISSN 0233-1268 and -0466). The Symposium was planned to be held in 1990. However because of the Basedow-Symposium in Halle-Merseburg, marking the 150th anniversary of the description of Basedow's disease, the Fourth Symposium on Thyroid was postponed to May 1991. This volume includes papers and discussions presented in this Meeting held for the first time in unified Germany in Reinhardsbrunn. Topics were: Medullary Cancer, Parathyroid, Thyroiditis, Immunology and Peripheral Thyroid Metabolism. The editors wish to express their sincere thanks to MERCK company and Isocommerz for their generous support. They also thank Dr. Radtke from Walter de Gruyter Publishers for promoting the editing of these Proceedings.

Berlin, January 1992

Harald F. Deckart Ernst Strehlau

Contents

IMMUNOLOGY Polyendocrine autoimmunity in thyroid disease (a preliminary report) M. Gryczynska, A. Baumann-Antczak, J. Kosowicz

1

The effect of anti-microsomal antibodies on thyroid peroxidase activity E. Mezösi, S. Szücs, S. Särközi, E. Forizs, J. Szabo

8

Antithyroid antibodies in the synovial fluid in thyroiditis K. Jiacka, M. Gembicki

18

Immunological and genetical aspects in T3predominant Graves' disease Sabine Gerlach, H.F. Deckart, Eva Deckart, Annemarie Blottner

23

Unexpected course in immunological pattern in Graves' Basedov's disease - Marine-Lenhart Syndrome? H.F. Deckart, Eva Deckart, Annemarie Blottner, E. Strehlau, G. Mühr

32

Comparative investigations of sonography and TRAK - follow up of Graves' disease Angelika Wünsche, Dietlind Sorger, G. Neumann, Susanne Schenk, L. Otto, G. Schneider

38

Guanyl nucleotide regulatory proteins and GTPase activity in normal and hyperthyroid human thyroid tissue and human polymorphonuclear granulocytes E. Forizs, A. Panyige, Zs. Jenei, T. Fülöp Jr., J. Szabo, E. Mezösi, I. Seres, A. Leövey

46

PERIPHERAL THYROID HORMONE METABOLISM Peripheral thyroid hormone metabolism H. Meinhold

54

Vili Value of the estimation of peripheral serum T3 and rT3 for prognosis assessment in patients vith liver cirrhosis - a prospective study Chr. Rink, U. Siersleben, J. Haerting, T. Mende, R. Nilius

73

Thyroid hormones and TSH in acute myocardial infarction J. Pechan, I. Vereg, J. Murin

83

Deiodination of thyroxine and reverse triiodothyronine in cells of human adipose tissue Ch.-F. Wolf, J. Wieberneit, L. Duntas, F.S. Keck

89

Comparison of natural killer activity vith thyroid function in Graves' disease A. Sztankay, Gy. Bako, E. Forizs, E. Mezosi, A. Leovey

96

The influence of the calcium antagonist nitrendipine on thyroid hormone status in the baboon J. Wieberneit, F.S. Keck, U. Loos, Ch.-F. Wolf

101

Effect of thyroid hormones on lipoprotein (a) level in hypothyroidism S. Oravec

111

THYROIDITIS Thyrotoxicosis due to thyroiditis A. Leovey

118

Thyroiditis - a histopathological reviev H.G. Peschel

127

Clinical and cytological classification of lymphocytic thyroiditis Z. Limanova

134

The role of ultrasound investigation in the diagnosis and treatment of thyroiditis Z. Novak, V. Zamrazil, J. Nemec, P. Vlcek

142

Subacute thyroiditis de Quervain in male subjects P. Hnilica, J. Podoba, V. Strbak, S. Nyulassy

145

IX

Thyroid function in postpartum thyroiditis and its follov up Nina Simova

152

Riedel's thyroiditis - positive therapeutic response to glucocorticoids M. Ventz, G. Knappe, D. Ziegelitz

161

Management of chronic lymphocytic thyroiditis in children and adolescents I. Hniková, J. Zikmund, M. Finková

165

Thyroiditis and thyroid hyperfunction V. Zamrazil, J. Némec

172

Clinical and laboratory evaluations of patients vith different types of thyroiditis I. Sztojka, Zs. Karányi, A. Leovey

177

Hashimoto-thyroiditis vith long-term negative auto-antibody determination: a case report Marie-Luise Weiss, A. Blottner, H.F. Deckart

184

Combination of Hashimoto- and de Quervain thyroiditis K.P. Schmidt, Eva Deckart, R. Pilz, E. Strehlau

193

Occurrence of goitre and diffuse lymphoid thyroiditis (DLT) in secondary school adolescents in Bratislava J. Podoba, P. Hnilica, M. Srbecky

205

Spontaneous course of Graves' Basedow's disease into hypothyroidism (case report) Eva Deckart

210

MEDULLARY CANCER Epidemiology, clinical syndrome, follov up, and prognostic factors in medullary carcinoma F. Raue

216

Neue Entwicklungen in der chirurgischen Therapie des Sipple-Syndroms: die Kompartment-orientierte systematische Mikrodissektion der Lymphknoten beim medullären Schilddrüsenkarzinom H. Dralle, I. Damm, G.F.W. Scheumann

228

X

Medullary cancer in histopathological viev H.G. Peschel, T. Decker

241

Cytological viev of medullary cancer Marie-Luise Weiss

246

Imaging techniques in detection and follow up of MTC H.F. Deckart, Katharina Djakowa, H. Marciniak, E. Strehlau, Marie-Luise Weiss

253

Positive scintigraphy in medullary thyroid cancer V. Holub, M. Neradilovä, J. N&mec, M. Benovä, T. Bla2ek, P. Vldek

265

I-131-uptake carcinoma G. Riccabona, in A. medullary Stöger, D.thyroid Ladurner, K. Schmid

272

Our experiences vith medullary carcinoma and MEN-syndrome H.F. Deckart, S. Birke, E. Deckart, Ch. Koloc, W. Lobers, R. Pilz, E. Strehlau, C. Wardius, M.L. Weiss

280

Possibilities and limitations of tumor-scintigraphy for follow up of medullary thyroid cancer Chr. Reiners

291

Thyroid cancer - differentiated and medullary: the aftercare system J. N^mec, M. Neradilovä, V. Zamrazil

302

Medullary carcinoma of the thyroid - own experience M. Neradilovä, J. Nemec, P. Vlcek, V. Holub, J. BednäJr, M. Soutorovä

309

Prevalence of medullary thyroid cancer in the endemic goiter area Z. Szybinski, E. Mazurek

316

Family screening in medullary thyroid carcinoma (MTC) P. Groth, Ursula Zarmstorf, Irmtraud Stoll, R. Reincke

324

XI

Results of therapy in patients with medullary carcinoma of thyroid gland (Poster) D. Gottschild, Gabriele Zinner, Carmen Luck, N.M. Granzow

330

The place of ultrasonography in the evaluation of medullary thyroid cancer P. Vl6ek, M. Neradilova, J. N^mec, J. Bednalf, Z. Novak

333

Medullary thyroid carcinoma - results of some diagnostic procedures used at our institute D. Bergant, M. Auersperg, M. Us-Krasovec, F. Pompe, J. Petric, T. Movrin, Z. Zemva, N. Besic

337

FREE PAPERS Tumor markers in thyroid disease J. Bednäf, J. Nemec, M. Neradilova, M. Soutorovä

345

Effects of Propranolol enantiomers in hyperthyroidism (Poster) B. Obermayer-Pietsch, C. Stiegler, H. Warnkroß, G. Obermayer, S. Sager, W. Lindner, G. Leb

354

Thyroglobulin pattern in hyperthyroidism factitia (Case report) Eva Deckart

355

Parameters of bone-metabolism in patients vith hyperthyrosis (Poster) P. Dietel, H.J. Heberling, D. Lohmann

360

PARATHYROID Clinical experience in parathyroid carcinoma G. Knappe, Helga Gerl, M. Ventz

362

Unusual course of primary hyperparathyroidism R. Hehrmann

370

Long-term results operated hyperparathyroidism U. Krause, Ch. Jeziorowski, Th. Olbricht

373

XII

Diagnostik problems of primary hyperparathyroidism (pHPT) - own experiences H.J. Heberling, B. Bierwolf, P. Dietel, E. Kuhlmann, D. Lohmann

380

X-ray-morphologic and radiomorphometric results in patients with primary hyperparathyroidism (Poster) K.P. Schröder, P. Dietel, H.J. Heberling, D. Lohmann

389

Authors' Index

391

Index

395

1 IMMUNOLOGY Polyendocrine autoimmunity in thyroid disease (a preliminary report) M. Gryczynska, A. Baumann-Antczak, J. Kosowicz Department of Endocrinology, University School of Medicine, Poznan, Poland Autoimmunity plays an essential role in the pathogenesis of a number of thyroid diseases such as Graves' disease, Hashimoto's thyroiditis and primary myxoedema. In autoimmune thyroid diseases various autoantibodies were detected anti-thyroglobulin, antithyroid peroxidase, anti-TSH receptor stimulating and blocking antibodies, anti-tubulin antibodies and:antibodies reacting with orbital muscles and connective tissues. In other autoimmune diseases such as diabetes type I, Addison's disease, pernicious anaemia, and rheumatic disease the presence of thyroid antibodies was of much higher incidence than in control subjects /1,2/. In our study /3/ we found anti-thyroglobulin antibodies in 23 %, and anti-thyroid microsomal antibodies in 57 % of patients with Addison's disease. In recent years we introduced a sensitive and simple radioimmunoassay for the detection of antiadrenal antibodies by solid phase technigue in tubes coated with solubilised microsomal fraction of adrenal cortex /3/. The aim of the study was to examine the occurence of adrenal and pituitary antibodies in blood sera of patients with autoimmune thyroid disease. Material and methods Blood samples were taken in 45 patients with autoimmune thyroid diseases: 25 (20 females, 5 males) with autoimmune hyperthyroidism, and 20 patients (18 females, 2 males) with autoimmune hypothyroidism. The diagnosis was based on typical clinical manifestations supported by hormones concentration and on the presence of anti-thyroid antibodies. The patients had no evident clinical

2 s y m p t o m s and s i g n s of a d r e n a l or p i t u i t a r y d y s f u n c t i o n .

Serum

b l o o d s a m p l e s of 30 h e a l t h y y o u n g v o l u n t e e r s served as a c o n t r o l group. B l o o d s a m p l e s w e r e c o l l e c t e d a f t e r o v e r n i g h t fast at 8 a . m . , s e r u m s a m p l e s w e r e f r o z e n at - 2 0 ° C u n t i l the

and

assay.

The a d r e n a l and p i t u i t a r y a n t i b o d i e s w e r e d e t e r m i n e d b y

solid

phase radioimmunoassay

preli-

as p r e v i o u s l y d e s c r i b e d /3/. For

m i n a r y s c r e e n i n g s e r u m s a m p l e s w e r e d i l u t e d 1:600. T h e of I - 1 2 5 - P r o t e i n A e x c e e d i n g two s t a n d a r d d e v i a t i o n s

binding

(SD)

o b t a i n e d for c o n t r o l s a m p l e s w e r e c o n s i d e r e d as w e a k l y

positive

(+), t h o s e e x c e e d i n g

exceeding

3 SD - as p o s i t i v e

4 SD as s t r o n g l y p o s i t i v e

(+++). The p o s i t i v e sera w e r e

s e q u e n t l y e x a m i n e d at the d i l u t i o n s 1:76800,

(++) a n d t h o s e

1:1200,

1:4800,

sub-

1:19200,

1 : 3 0 7 2 0 0 and c o m p a r e d w i t h c o n t r o l sera at the

same

dilution. Results S o l i d p h a s e RIA for a d r e n a l and p i t u i t a r y a n t i b o d i e s

were

p e r f o r m e d in 25 c a s e s w i t h a u t o i m m u n e h y p e r t h y r o i d i s m 20 c a s e s w i t h a u t o i m m u n e

and

hypothyroidism.

In the g r o u p w i t h a u t o i m m u n e h y p e r t h y r o i d i s m

in 19 c a s e s

the r e s u l t s w e r e p o s i t i v e for a d r e n a l a n t i b o d i e s . had very high titer adrenal antibodies p a t i e n t s the titer w a s 1 : 7 6 8 0 0 ,

Eight

(1:307200),

in five

in the o t h e r four w a s

one p a t i e n t h a d the a n t i b o d i e s titer

(76 %) patients

1:19200,

1:4800 and a n o t h e r

one

1:1200. The p i t u i t a r y a n t i b o d i e s w e r e f o u n d in 19 (76 %) p a t i e n t s . The t i t e r of the a n t i b o d i e s w a s c a s e s , in four c a s e s it w a s

hyperthyroid

1 : 3 0 7 2 0 0 in t w e l v e

1:76800; two p a t i e n t s h a d the

1:19200 a n d one h a d 1:1200. The p r e s e n c e of a d r e n a l

titer

antibodies

w i t h o u t p i t u i t a r y a n t i b o d i e s w a s f o u n d in two p a t i e n t s o n l y . o t h e r two c a s e s we d e t e c t e d p i t u i t a r y a n t i b o d i e s of a d r e n a l a n t i b o d i e s . p i t u i t a r y nor a d r e n a l

O n l y four p a t i e n t s antibodies.

in the

(16 %) h a d

In

absence

neither

3 Among patients with autoimmune hypothyroidism adrenal antibodies. four c a s e s ,

13 (65 %) h a d

The titre of the a n t i b o d i e s w a s 1 : 3 0 7 2 0 0

1 : 7 6 8 0 0 in o t h e r four, in a n o t h e r four w a s

in

1:19200

a n d 1:4800 in one case. P i t u i t a r y a n t i b o d i e s w e r e f o u n d in 12 (60%) p a t i e n t s .

S e v e n of these p a t i e n t s h a d w e r y h i g h

titre 1 : 3 0 7 2 0 0 ,

in t h r e e c a s e s the t i t r e w a s 1 : 7 6 8 0 0 and in two

c a s e s 1:4800. T w o p a t i e n t s h a d a d r e n a l a n t i b o d i e s

antibodies

in the

absence

of p i t u i t a r y a n t i b o d i e s and one p a t i e n t h a d p i t u i t a r y b u t no adrenal antibodies.

In six c a s e s

pituitary a n t i b o d i e s w e r e

(30 % ) n e i t h e r a d r e n a l

nor

found.

D e t a i l e d r e s u l t s of a d r e n a l and p i t u i t a r y a n t i b o d i e s s o l i d R I A in b o t h g r o u p s of p a t i e n t s w i t h a u t o i m m u n e t h y r o i d are l i s t e d in T a b l e 1 and 2. In the c o n t r o l g r o u p no

phase

diseases

adrenal

a n t i b o d i e s w e r e d e t e c t e d and o n l y in one c a s e the p i t u i t a r y b o d i e s at 1:600 s e r u m d i l u t i o n w a s

anti-

found.

Conclusions 1. In m a j o r i t y of p a t i e n t s w i t h a u t o i m m u n e t h y r o i d d i s e a s e s d e t e c t e d by s o l i d p h a s e r a d i o i m m u n o a s s a y

adrenal and

we

pituitary

antibodies. 2. In a u t o i m m u n e h y p o t h y r o i d i s m a m o n g 20 p a t i e n t s

13 (65 %) h a d

a d r e n a l a n t i b o d i e s and 12 (60 % ) h a d p i t u i t a r y a n t i b o d i e s . patients

(30 % ) a d r e n a l and p i t u i t a r y a n t i b o d i e s w e r e

In 6

not

detected. 3. In 25 p a t i e n t s w i t h a u t o i m m u n e t h y r o t o x i c o s i s we f o u n d

the

p r e s e n c e of a d r e n a l a n t i b o d i e s in 19 (76 %) p a t i e n t s , a n d of pituitary antibodies

in 19 (76 % ) p a t i e n t s . Only in 4 (16 % )

p a t i e n t s n e i t h e r a d r e n a l nor p i t u i t a r y a n t i b o d i e s w e r e

detected.

4. In the m a j o r i t y of a u t o i m m u n e t h y r o i d d i s e a s e s the t i t r e s of a n t i - a d r e n a l and a n t i - p i t u i t a r y

antibodies were high although

p a t i e n t s d i d n o t p r e s e n t clinical m a n i f e s t a t i o n s of a d r e n a l Or pituitary

dysfunction.

5. R e s u l t s of our study i n d i c a t e that a u t o i m m u n e

thyroid

d i s e a s e s c o n s t i t u t e a p a r t of a m o r e g e n e r a l i z e d

autoimmune

process.

the

4 References 1. Scherbaum, W.A.: Acta Endocrinol. (Kbh), Suppl. 281 (1987), 325. - 2. Batterle, C., G. Callegari, F. Presotto, F. Zanette, B. Pedini, T. Rampazzo, R.S. Slack, M.E. Girelli, B. Busnardo: Acta Endocrinol. (Kbh), 114 (1987), 321. - 3. Kosowicz, J., M. Gryczynska, G.F. Bottazzo : Clin. Exp. Immunol. 63 (1986), 671. Table 1 Autoimmune Hyperthyroidism No.

Patient

Sex F/M

Autoantibodies adrenal

pituitary

1.

H. M.

F

+

1 : 19200

++

1 : 76800

2.

K. M.

F

+

1 :307200

++

1 : 307200

3.

K. E.

F

-

4.

R. B.

F

+++

1 : 19200

++

1 307200

5.

S. M.

F

+++

1 :307200

+++

1 307200

6.

P. E.

F

+++

1 : 19200

+++

1

76800

7.

Z. K.

F

+++

1 : 4800

+++

1

76800

-

8.

K. I .

F

+

1 : 19200

++

1 307200

9.

S. K.

F

+++

1 : 76800

+

1

10.

S. E.

F

-

11 .

0. M.

F

+++

1 :307200

+++

12.

B. M.

F

+

1 : 76800

-

19200

-

1 : 307200

13.

K. S.

F

+++

1 :307200

+++

1 : 307200

14.

T. S.

F

+++

1 :307200

++ +

1 : 307200

15.

L. D.

F

-

16.

S. D.

F

+

1 : 1200

+

17.

S. M.

F

-

18.

M. B.

F

+++

19.

R. W.

F

-

20.

N B.

M

+++

21.

R. F.

M

22. 23. 24. 25.

K. F. A. K. L. W. S. H.

M M M M

-

1 : 76800

-

++

1 : 19200

+

1 : 307200

1 :307200

+

1:

+++

1 :307200

+++

1 : 307200

++

1.: 76800 1 :307200

++

1 : 307200 1 : 307200 1 : 307200

++ +

1 : 76800

+++

-

+++

+++

1 : 76800

-

1200

5 Table 2 Autoimmune Hypothyroidism No.

Patient

Sex F/M

adrenal

1.

P.R.

F

+

2.

Autoantibodies

pituitary

1 : 19200

+

1 :307200

G.E.

F

-

3.

M.M.

F

++

1 : 19200

+

4.

M. I.

F

+++

1 : 307200

-

5.

M.M.

F

+

1 : 76800

+

6.

M. Ü.

F

-

7.

W.M.

F

+++

8.

P.J.

F

-

9. 10.

G. A. P.M.

F F

-

11.

K. C.

F

++

1 : 307200

++

1 : 76800

12.

T. A.

F

+++

1 : 19200

+++

1 :307200

13.

K.L.

F

-

14.

B.B.

F

-

+

1 307200

15.

G.D.

F

+

1 : 76200

+++

1 307200

+++

-

1 : 4800 1 : 4800

-

1 : 307200

+++

1 : 76800

-

1 :307200

-

-

-

16.

K. E.

F

+

1 : 76800

+++

1 307200

17.

D.M.

F

+++

1 : 307200

+++

1 307200

18.

N.J.

F

++

1 : 19200

+

1

76800

19.

T.M.

M

+

1:

++

1

76800

20.

S.M.

M

-

4800

-

Discussion Benker: 1. What is the prevalence of adrenal autoantibodies in Addison's disease, using your assay system? 2. Can you comment as to the nature of the microsomal antigen which is recognized by your assay? Remark: We have once studied adrenal autoantibodies in autoimmune Addison's disease using immunofluorescence where the prevalence was only 50 %. Lacka: The prevalence in autoimmune Addison's disease is about

6 85 % using our assay system, solid phase immunoassay. And for the pituitary antibodies only immunofluorescenca technique was used up to now. Radioimmunoassay is more sensitive than immunofluorescence. And of course it depends on the purification of the antigens and we used very pure microsomes. And to the second question: I think there is no information about the characterisation . Limanova: We highly appreciate your paper, it will be used in the diagnosis of endocrinopathies in future. One question. As far as the adrenal glands are infiltrated by lymphocytes in a large amount of autopsies, are there any correlations between the histological findings of adrenal from autopsie or from surgery you used for antibody method and the results you found in your studies? - I.E. don't you think that the adrenal material can influence the antibodies you got from patients? Lacka: The adrenals are from patients with Cushing syndrome. Gembicki: Material is taken from these cases, not from the autopsies. It is taken from patients treated by surgery. Simova: 1. Is there a

difference in the titre of antiadrenal

antibodies in autoimmune thyroiditis and in Addison's disease? 2. Whether all functional tests for adrenal and pituitary functions have been applied to exclude a dysfunction of these glands? Gembicki: The answer for the second question is: yes, all of them were controlled according to the functional status of adrenals and pituitary. Lacka: This method is developed at our department and they have got the antigens, it means microsomes. They obtain microsomes for human pituitary gland and adrenal pituitary gland obtained from operated patients. Everything was prepared by the laboratory of our department. Only protein which can bind F c -fragment of immunoglobuline, IGG is commercial. Gembicki: I just would like to make a short comment: Since many years our department is working on different determination of different antibodies to different organs. And this is some kind of conclusion that

with

the progress of the methods whith

possibility of the determination of different antibodies against pituitary, against thyroid, suprarenal gland and so on, we come to the conclusion that probably most of the endocrinopathies

7 have multiimmune process as the basis for pathological changes. Of course some of the directions, some of ways are connected more or less with one organ, but usually we have several autoantibodies to several organs detected if we have autoimmunity process in some endocrine cases.

8 The effect of anti-microsomal antibodies on thyroid peroxidase activity E. Mezosi, S. Sziics, S. Sarkozi, E. Forizs, J. Szabo and A. Leovey University Medical School, I. Department of Medicine, Debrecen, Hungary Thyroid microsomal antibodies (MAbs) are detectable in the serum of most patients with autoimmune thyroid disease (AITD). The nature of microsomal antigen (M-ag) remained unknown for more than twenty years after its discovery. Recently, it has become evident that the M-ag is very closely related to, if not identical with thyroid peroxidase (TPO) /2,4,5,11,12/. The TPO is a glycosilated hemoprotein bound to membranes with a mol. wt. of about 100-110 kD /2,5/. It is involved in two major steps of thyroid hormone biosynthesis: iodination of tyrosine residues on thyroglobulin and coupling of iodotyrosines into T4 arid T3. The M-ag/TPO is expressed on the apical surface of thyroid cells /l/. The expression of M-ag is TSH dependent both on the surface and in the cytoplasm of the cells. By this time the complete cDNA and protein sequence of both human and porcine TPO has been revealed and a homology of 72 % was found /I/. The presence of circulating anti-TPO antibodies in patients with AITD was independently identified by many investigators using different techniques /3,7,9,10,11/. It is well known since 1986 from Kohno's experiments that MAbs can inhibit TPO activity /8/. The aim of our study was to investigate the effect of a relative large series of sera and IgG fractions from patients with AITD on TPO acticity. Materials and Methods 82 untreated patients with Graves-Basedow disease (aged 16-64 yr, mean 39 yr, 69 women and 13 men) and 23 normal subjects (aged 20-72 yr, mean 43,4 yr, 16 women and 7 men) were included in the study.

9 The g l o b u l i n f r a c t i o n of sera w a s i s o l a t e d by p r e c i p i t a t i o n ammonium-sulphate.

with

In the f i r s t p a r t of our w o r k we p r e p a r e d

f r a c t i o n s f r o m 25 p a t i e n t s and 6 c o n t r o l s u s i n g ion c h r o m a t o g r a p h y on D E A E - S e p h a c e l

IgG

exchange

column.

Microsomal antibodies were assayed with Boyden's passive

haem-

agglutination. P o r c i n e TPO w a s p r e p a r e d and p u r i f i e d a c c o r d i n g to A. T a u r o g al. / 1 5 / . B r i e f l y a f t e r h o m o g e n i z a t i o n the m a t e r i a l w a s ised by s o d i u m - c h o l a t e

(1 % final c o n c e n t r a t i o n ) ,

by a c e t o n e and a m m o n i u m - s u l p h a t e

precipitated

a n d t h e n we u s e d ion

exchange

D E A E - c e l l u l o s e c o l u m n c h r o m a t o g r a p h y and gel f i l t r a t i o n

(Sephadex

G - 7 5 ) for p u r i f i c a t i o n of the e n z y m e . T h e s p e c i f i c a c t i v i t y 14.1 G U / m g p r o t e i n , the r a t i o A 4 1 3 / A 2 8 O

w a s

et

solubil-

was

0.11.

The c a t a l y t i c a c t i v i t y w a s m e a s u r e d by g u a i a c o l and i o d i d e a c c o r d i n g to H o s o y a et al. /6/. T h e g u a i a c o l a s s a y w a s

assay

followed

by the c h a n g e in a b s o r b a n c e at 470 nm, the i o d i d e s u b s t r a t e

was

m e a s u r e d at 350 nm. One u n i t w a s d e f i n e d as the a m o u n t of

enzyme

r e q u i r e d to p r o d u c e an o p t i c a l d e n s i t y c h a n g e of 1.0/min.

20 / u l

of TPO w a s i n c u b a t e d w i t h d i f f e r e n t a m o u n t of s e r a or IgG f r a c tions

(20-80 / u l ) at r o o m t e m p e r a t u r e for one h o u r . The

i n h i b i t i o n of T P O a c t i v i t y w a s c a l c u l a t e d as A

1 m i n w i t h TPO + s e r u m

% inhibition = 1 -

x A

percent

follows:

1 min with TPO

100

alone

Results In the f i r s t p a r t of our w o r k we c o m p a r e d the e f f e c t of

globulin

f r a c t i o n s and p u r i f i e d IgG f r a c t i o n s f r o m 25 G - B p a t i e n t s 6 c o n t r o l s u s i n g g u a i a c o l a n d iodide s u b s t r a t e s . The effect was dose-dependent

and

inhibitory

in e v e r y c a s e s . In the i o d i n e

assays

b o t h the p a t i e n t s ' a n d c o n t r o l s ' sera i n h i b i t e d the a c t i v i t y TPO, we d i d n ' t find any d i f f e r e n c e b e t w e e n the two g r o u p s . s h o w s the e f f e c t of g r a d e d a m o u n t

(20-80/ul) of IgG

fractions.

T h e r e is a s i g n i f i c a n t d i f f e r e n c e b e t w e e n the m e a n v a l u e s . normal

IgG d i d n ' t d e c r e a s e TPO a c t i v i t y ,

of

Fig. 1

IgG f r a c t i o n s f r o m

The 13

10 out of 25 p a t i e n t s degree

(52 % ) s h o w e d i n h i b i t o r y e f f e c t in v a r y i n g

(10-52%, m e a n 1 4 . 9 + 1 6 . 6 % ) . Sera f r o m all the 25 p a t i e n t s

i n h i b i t e d the p e r o x i d a t i o n of g u a i a c o l . U s i n g 80 /ul s e r a inhibition ranged from 30-100 %

(Mean 53+^18 %) c o n t r o l

c a u s e d a m o d e r a t e d e c r e a s e of e n c y m a t i c a c t i v i t y w h i c h s e e m s to be a n o n s p e c i f i c e f f e c t

the

sera

(less t h a n 20 % ) ,

(Fig. 2). U s i n g IgG

frac-

t i o n s in the g u a i a c o l a s s a y , IgG f r o m 22 out of 25 p a t i e n t s (88 %) i n h i b i t e d TPO a c t i v i t y . The i n h i b i t i o n w a s less t h a n in the c a s e of sera, r a n g e d f r o m 15 to 45 %, m e a n 34^+14 %. i n h i b i t o r y e f f e c t of c o n t r o l IgG w a s d e t e c t e d (Fig.

No

(less t h a n 5 %)

3).

In the s e c o n d p a r t of our w o r k w e e x a m i n e d sera f r o m 82 s u f f e r e d f r o m G - B d i s e a s e a n d 23 n o r m a l s u b j e c t s u s i n g

patients guaiacol

assay. Fig. 4 d e m o n s t r a t e s our r e s u l t s . The m a j o r i t y of sera i n h i b i t e d TPO a c t i v i t y . The m e a n of p a t i e n t g r o u p

patients' was

4 9 . 5 %, r a n g e d f r o m - 1 5 to 100 %. The v a l u e of c o n t r o l g r o u p w a s 18.3+^15.3 %. 85 % of p a t i e n t s s h o w e d s i g n i f i c a n t

inhibition

when

we d e f i n e d the p o s i t i v e v a l u e as m o r e t h a n the m e a n + SD of control

group.

F i n a l l y , we i n v e s t i g a t e d the r e l a t i o n s h i p b e t w e e n the e f f e c t of sera a n d m i c r o s o m a l a n t i b o d i e s m e a s u r e d by haemagglutination

(Fig. 5). We f o u n d a c o r r e l a t i o n

inhibitory passive

characterized

by the f o l l o w i n g p a r a m e t e r s : r = 0 . 3 5 9 , p = 0 . 0 0 0 8 , y = 4 . 1 * l o g 2 X + 18.87. T h i s p r o v i d e d f u r t h e r e v i d e n c e of r e l a t i o n s h i p b e t w e e n the M - a g and TPO.

the

11

The inhibition of TPO activity by IgG fraction of sera Iodide assay

60

inhibition %

r

50

40

30

20

14.9i16.6 10

cm cm -10

controls n-6

patients n«25

Figure 1 T h e I g G f r a c t i o n f r o m 13 o u t o f 2 5 G - B p a t i e n t s (52 % ) s h o w e d i n h i b i t o r y e f f e c t on TPO activity using iodide assay. The i n h i b i t i o n r a n g e d f r o m 10 t o 5 2 % , m e a n 14.9+16.6 %. The IgG fractions from other patients and controls didn't inhibit the T P O a c t i v i t y . E a c h p i n t is t h e m e a n o f triplicate assays.

12

The inhibition of T P O activity by sera from patients and controls Guaiacol assay %

lul sera] -patients

—controls

Mean (*SD) of 25 patients Mean (+SD) of 6 contrails p 1:32 antinuclear

synovial fluid n = 2

negative

negative

factor

>1:20 gastric

parietal

cells 11

mitochondrial

"

smooth-muscle

"

"

biliaris ductuli

"

"

T a b l e 2: O c c u r e n c e of a n t i t h y r o g l o b u l i n / a n t i - T g / a n d a n t i m i c r o s o m a l / a n t i - M o / a n t i b o d i e s in s e r u m a n d s y n o v i a l f l u i d of two p a t i e n t s w i t h H a s h i m o t o ' s t h y r o i d i t i s / d e t e c t e d by s o l i d - p h a s e R I A , h a e m a g g l u t i n a t i o n / Hg / a n d i m m u n o f l u o r e s c e n c e / IF / t e s t

Anti-Mc

case 1

serum synovial fluid

case 2

Anti-Tg

RIA

Hg

IF

RIA

Hg

IF

neg

neg

neg

neg

neg

neg

60 %

serum

neg

synovia} fluid

36 %

1 : 25600

+

neg

neg

1:640

+

55 % 1 : 2 5 6 0 0 neg

neg

20 % 1:640

+ neg 4

21 Discussion The diagnosis of Hashimoto's thyroiditis can be confirmed by biochemical test showing euthyroidism or mild hypothyroidism, by estimation of the thyroid antibodies in serum and by thyroid gland biopsy examination. According to our knowledge there are no patients described with Hashimoto's disease with elevated antithyroid antibodies in their synovial•fluid. Blake and al. showed the presence of thyroid antibodies in the synovial fluid aspirated from the knees in patients with various rheumatoid diseases /2/. The presence of antithyroid antibodies detected in the synovial fluid without elevated antithyroglobulin and antimicrosomal antibodies in serum in two patients described in this paper seems to be the result of local production of antithyroid antibodies by synovial leucocytes /2,4/. Conclusion Antithyroglobulin and antimicrosomal antibodies in synovial fluid aspirated from the elbow cyst in patients with Hashimoto's disease were found. References 1. Amino, N. et al. Clin. Endocrinol. 5 (1976), 115. - 2. Blake, D.R. et al. Lancet II (1979), 224. - 3. Cayzer, I. et al. J. Clin. Pathol. 31 (1978), 1147. - 4. De Groot, L.J. et al. Endocrine Reviews 10 (1989), 537. - 5. Johnson, J.D. et al. Hand book of experimental immunology. Immunochemistry. Oxford: Blackwell 1/1973, chap. 18. - 6. Kosowicz, J. et al. Pol. Arch. Med. Wewn. 67 (1982), 225. - 7. Lacka, K. et al. Radiob. Radioth. 25 (1984), 729. Discussion Benker: Did your patients have other clinical signs of rheumatic diseases? Lacka: No, they have no signs, only we have observed the elbowcyst without motor-limitation, without pain. And they have no recourse of rheunatoid disease. And we have aspirated the synovial fluid and have given to this patients steroids, 100 mg

22 of h y d r o c o r t i s o n a n d a f t e r w a r d s till for w e e k s we h a v e n o served

ob-

cysts.

B e n k e r : D i d y o u h a v e the c h a n c e to s t u d y a s p i r a t e s of vial fluid from patients with rheumatoid

syno-

arthritis?

L a c k a ; A c c o r d i n g our k n o w l e d g e w e h a v e no p a t i e n t s w i t h roiditis disease and elevated antithyroglobuline microsomal antibodies

anti-

in s y n o v i a l f l u i d . B u t t h e r e is o n e

per a b o u t the o c c u r r e n c e of a n t i t h y r o g l o b u l i n e somal antibodies

and

thy-

and

pa-

antimicro-

in s y n o v i a l f l u i d a s p i r a t e d f r o m the n e e s

in p a t i e n t s w i t h r h e u m a t o i d d i s e a s e s , n o t w i t h t h y r o i d

di-

s e a s e s . A n d t h e r e are no p r o b l e m s to d e t e c t a n t i t h y r o i d b o d i e s in s y n o v i a l f l u i d . It is the same

anti-

method.

Gembicki: We did not investigate that rheumatoid cases,

we

k n o w o n l y the i n f o r m a t i o n f r o m the l i t e r a t u r e t h a t some

cases

w e r e i n v e s t i g a t e d . But w e c o u l d n o t f i n d any

information

a b o u t the t h y r o i d i t i s a n d any k i n d of c y s t i n v e s t i g a t e d this

for

antibodies.

L a c k a : W e h a v e m e a s u r e d the c y t o s i s c o m p a r e n c e

in the

v i a l f l u i d , a s p i r a t e d f r o m t h i s p a t i e n t a n d in f i r s t

synocase

t h e r e w e r e a b o u t 4 5 0 0 c e l l s per one m i l l i l i t e r . A n d in t h e s e c o n d p a t i e n t t h e r e w e r e 5200 c e l l s per m l . It m e a n s it w a s i n f l a m m a t o r y

f l u i d . But w e h a v e n o t m e a s u r e d

L e o v e y : D i d y o u c h e c k the l y m p h o c y t e s in s y n o v i a l

that

viscosis.

fluids?

L a c k a : W e h a v e m e a s u r e d o n l y the c e l l s in the s y n o v i a l

fluid,

w e h a v e n o t m e a s u r e d p o p u l a t i o n of l y m p h o c y t e s . B u t I t h i n k it s h o u l d be the r e s u l t of the p r o d u c t i o n of t h e r e in the s y n o v i a l

subpopulation

fluid.

Leovey: May be, that these locally produced antibodies a n i m p o r t a n t r o l e in the c e l l - m e d i a t e d c y t o t o x i c

play

immunity?

23 Immunological and genetical aspects in Tß-predominant Graves' disease Sabine Gerlach, H.F.Deckart, Eva Deckart and Annemarie Blottner Klinik für Innere Medizin Universität Leipzig, Klinik für Nuklearmedizin und Endokrinologie im Klinikum Berlin-Buch, Germany Nowadays it is undisputed that the special entity or biochemical feature termed T3~predominant hyperthyroidism may appear in association with toxic multinodular goiter, toxic adenoma, but also Graves' disease /l/. T3~predominant hyperthyroidism may be a short-time state in the course of a thyrotoxicosis or in some cases the forerunner of the usual form of thyrotoxicosis in which both T 3 and T4 production are increased, whereas in other patients it may persist as such /2,3/. The aim of our study was to find out, if there is any special immunologic or genetic background in patients with T3-predominant Graves' disease. Patients and methods We investigated 106 patients with Graves' disease (11 males, 95 females, mean age 46 years) in the first onset or in relapse of the disease - minimum three months and maximum one year after cessation of drug treatment. They were compared with a control group (n = 40, 22 males, 18 females, mean age 40 years). The differentiation between immunogenic and non immunogenic hyperthyroidism was carried out in the usual clinical way and by determination of thyroid antibodies /4/ and ultrasound investigation. We used a RIA for the determination of TAb, the passive haemagglutination method for determination of MAb (Wellcome) and a radioligand receptor assay (Henning) for TRAb measurement. HLA antigens were estimated by a microlymphocytetoxicity-test. Results 22.6 % of our patients were suffering from a T3~predominant disease (table 1). The real and exact prevalence of T3-toxicosis found by the most other authors is uncertain, but may be as high as 10 percents or even a little higher in areas of iodine deficiency without selection of autoimmune disease /!/.

24 It w a s v e r y s u r p r i s i n g for us, t h a t 71.1 % of our p a t i e n t s T3~predominant Graves' disease showed relapses, whereas p o r t i o n w a s o n l y 29.2 % in p a t i e n t s w i t h c o m b i n e d thyroidism

(table

T3/T4~hyper-

1).

T a b l e 1: T 3 - p r e d o m i n a n t and T 3 / T 4 ~ c o m b i n e d and relapses

patients

hyperthyroidism

T3~predominant G.d.

T3/T4

combined G.d.

n

24

82

%

22.6

77 .4

71.1

29. 2

relapses

%

W e o b s e r v e d the f o l l o w i n g i n t e r e s t i n g r e s u l t s in the of T A b and M A b in T 3 ~ p r e d o m i n a n t a n d c o m b i n e d disease

with

this

distribution

T3/T4~Graves' T3~hyperthyroidism

(table 2): The p a t i e n t s w i t h s e l e c t i v e

s h o w e d p o s i t i v e T A b in n e a r l y 50 % a n d p o s i t i v e M A b in 100 % c o n t r a r y to p o s i t i v e T A b in 17 % a n d p o s i t i v e M A b in 83 % of our patients with combined T3/T4~hyperthyroidism.

N e a r l y 50 % of

the

patients with T3~predominant hyperthyroidism showed both TAb

and

M A b , w h e r e a s t h i s a n t i b o d y p a t t e r n w a s f o u n d only in 16 % of

the

patients with combined T3/T4~hyperthyroidism

(table

2).

T a b l e 3 d e m o n s t r a t e s a c o m p a r i s o n of h i g h e r and lower

antibody

levels, a m e t h o d u s e d b y m a n y o t h e r a u t h o r s , too. We

summarized

t h r e e t i t e r or c o n c e n t r a t i o n s t e p s into one g r o u p at

least

b e c a u s e of p o s s i b l e d i f f e r e n c e s

in the a n t i b o d y s e c r e t i o n

rate

of the t h y r o i d . P a t i e n t s w i t h T 3 ~ h y p e r t h y r o i d i s m w e r e f o u n d h a v e s i g n i f i c a n t h i g h e r l e v e l s of M A b in 75 % in c o n t r a s t 37 % of the p a t i e n t s w i t h T 3 / T 4 ~ h y p e r t h y r o i d i s m The p a t i e n t s w i t h G r a v e s ' d i s e a s e (table

4).

3).

(total g r o u p ) s h o w e d a s i g n i -

f i c a n t l y h i g h e r d i s t r i b u t i o n of H L A B 8 the c o n t r o l g r o u p

(table

to

to

(31 % ) in c o m p a r i s o n

with

25 Table 2: Distribution of autoantibodies Graves' disease (n = 106)

antibodies TAb, MAb, TRAb

T _

3 hyperthyroidism % n

T 3 /T 4 -hyperthyroidism signifi

%

ca c

l%

TAb positive MAb pos. and negative

11

46

14

17

0.01

MAb positive TAb pos. and negative

24

100

68

83

0.05

11

46

13

16

0.01

24

100

69

84

0.05

TAb negative MAb negative

0

0

13

16

0.05

TAb positive MAb negative

0

0

1

1

n.s.

22

92

72

88

n.s.

TAb positive MAb positive at least 1 antibody pos. MAb or TAb

TRAb positive

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A


1 •p I« 0 01 >1 T4 > T 3 Tissue:

Liver, kidney, thyroid, pituitary,CNS

Inhibitors: PTU, ipanoic acid Decreased:

Hypothyroidism,

Increased:

Hyperthyroidism

I0W-T3

syndrome

Biological function: rT3 elimination. T3 production for export Type II

Only 5'-deiodination (outer ring) t

4 —> T3, rT3 —to 3.3'-T2 Substrate preference: T4 > rT3 Tissue:

CNS, pituitary, BAT, placenta

Inhibitors: Ipanoic acid (not PTU); Decreased:

Hyperthyroidism

Increased:

Hypothyroidism, low T 3 syndrome

Biological function: Local T 3 neogenesis (auto supply in brain, cold adaptation ) Type III

Only 5-deiodination (inner ring) T 3 —* 3.3'-T2, T4 —i rT3 (and sulfates) Substrate preference: T 3 > T4 Tissue:

Fetal membranes, various other tissues

Biological function: T 3 prevention and degradation

placenta, deiodinates exclusively the 5'-iodine position and is therefore primarily responsible for the conversion of T4 to T 3 in tissues with central functions. In contrast to type I, it is inhibited by PTU, decreased in hyperthyroidism and increased in hypothyroidism. - The type III isoenzyme

61 d e i o d i n a t e s the inner r i n g o n l y a n d c a t a l y z e s the v a t i n g p a t h w a y of T3 a n d T 4 d e g r a d a t i o n to t h e i r

bio-inactiinactive

m e t a b o l i t e s 3 . 3 ' - T 3 and rT3 w h i c h is of s p e c i a l i m p o r t a n c e fetal

in

tissues.

The hitherto recogniced physiological

f u n c t i o n s of the

iso-

e n z y m e s m a y be s u m m a r i z e d as f o l l o w s : T y p e I d e i o d i n a s e r e s p o n s i b l e for the s y s t e m i c T 3 s u p p l y and, by T 4 produces approximately

is

conversion,

70 % of the T 3 f o u n d in the

circula-

t i o n . T h u s , t y p e I s u p p o r t s the t h y r o i d g l a n d in p r o v i d i n g s u f f i c i e n t h o r m o n a l l y a c t i v e T 3 for its d i v e r s e a c t i o n s

in

the b o d y . - P r o d u c e d f r o m c i r c u l a t i n g T 4 type II is a local s o u r c e of T 3 for o r g a n s r e q u i r i n g t h e i r o w n s u p p l y to m a i n t a i n e s s e n t i a l p h y s i o l o g i c a l f u n c t i o n s like the p i t u i t a r y b r a i n ; for e x a m p l e ,

it is n e e d e d to m a i n t a i n a e u t h y r o i d

t r a c e l l u l a r b r a i n s t a t u s in p a t i e n t s w i t h i n c i p i e n t r o i d i s m or the I 0 W - T 3 s y n d r o m e .

hypothy-

In b r o w n a d i p o s e t i s s u e ,

II s e r v e s as a l o c a l s o u r c e for t h e r m o g e n i c T 3 to

and intype

protect

a g a i n s t c o l d - i n c l u d e d h y p o t h e r m i a . - T y p e III, f i n a l l y ,

may

p r e v e n t the i n a p p r o p r i a t e a c c u m u l a t i o n of

energy-providing

T 3 by its r a p i d 5 - d e i o d i n a t i o n to 3 . 3 ' - T 2

d u r i n g fetal

v e l o p m e n t and

de-

maturation.

F r o m the r e s u l t s of v a r i o u s t u r n o v e r s t u d i e s on the

metabolic

fate of T 4 in the w h o l e b o d y , it c a n be e s t i m a t e d that, e u t h y r o i d s u b j e c t s , r o u g h l y 75 % of the T 4 s e c r e t e d by t h y r o i d g l a n d is m e t a b o l i z e d to T 3 and rT3 by

in the

monodeiodina-

t i o n is the p r e d o m i n a n t p a t h w a y of T 4 d i s p o s a l , b u t 25 % of the T 4 s e c r e t e d is m e t a b o l i z e d by o t h e r r o u t e s . T h i s

percent-

age of n o n d e i o d i n a t i n g T 4 d i s p o s a l m a y be i n c r e a s e d in p a t h o p h y s i o l o g i c a l s i t u a t i o n s and, as e m p h a s i z e d by C h o p r a et al. (1983),

"we are left w i t h the c o n c l u s i o n t h a t r o u t e s of

T4

m e t a b o l i s m , o t h e r t h a n t h r o u g h T 3 and r T 3 , c o n s t i t u t e a m a j o r p a t h w a y of T 4 d i s p o s a l

in n o n t h y r o i d a l

illness".

W i t h t h i s q u o t a t i o n let us p r o c e e d f r o m m o n o d e i o d i n a t i o n

to

e t h e r - l i n k c l e a v a g e , a T 4 ~ d e g r a d i n g p a t h w a y w h i c h s e e m s to be

62

/ C 7

\ V - C H

2

0 0 H

- C H \NH 2

HO-

// W

C O O H O H

Iodide

Hydroquinone? (unstable)

\ V c h

2

- c h

s

NH.

Diiodotyrosine (DIT)

Figure 3 Ether link c l e a v a g e of

HO-

/

T4

63 of some i m p o r t a n c e in s e v e r e i n f e c t i o n s and s e p s i s . i n v e s t i g a t i o n s by B u r g e r et al. (Schwander & Meinhold

(1983) a n d by

In v i t r o

ourselfes

1987) h a d s h o w n t h a t p h a g o c y t o s i n g

hu-

m a n l e u k o c y t e s r a p i d l y d e g r a d e T4 by c l e a v a g e of its e t h e r b r i d g e b e t w e e n the two a r o m a t i c r i n g s . T h i s p a t h w a y , p l a y s a m i n o r role u n d e r p h y s i o l o g i c a l c o n d i t i o n s l e a d s to the f o r m a t i o n of d i i o d o t h y r o s i n e , stable hydroquinone compound

in v i v o ,

i o d i d e and an u n -

(figure 3). The T 4 b r e a k d o w n

D I T r e q u i r e s p h a g o c y t o s i s for T 4 u p t a k e into the

to

granulocyte

and is c a t a l y z e d by p e r o x i d a s e s d u r i n g the m e t a b o l i c r e a c t i o n of the

which

burst

cell.

A previously developed radioimmunoassay DIT in h u m a n s e r u m

for m e a s u r e m e n t

of

( M e i n h o l d et al. 1981) p r o v i d e d us w i t h

an a n a l y t i c a l t o o l for t e s t i n g the f o l l o w i n g h y p o t h e s i s : e t h e r link c l e a v a g e of T 4 by p h a g o c y t o s i n g l e u k o c y t e s

If

occurs

in v i v o w i t h c h a r a c t e r i s t i c s s i m i l a r to t h o s e o b s e r v e d

in

v i t r o , t h e n s e p s i s and o t h e r i n f e c t i o n s a s s o c i a t e d w i t h

in-

c r e a s e d p h a g o c y t o s i s of w h i t e b l o o d c e l l s s h o u l d e n h a n c e

the

m e t a b o l i c p r o d u c t i o n of D I T f r o m T 4 .

cel-

T h i s e n h a n c e m e n t of

lular DIT p r o d u c t i o n m a y be m a n i f e s t e d as a m e a s u r a b l e

in-

c r e a s e in the c o n c e n t r a t i o n of c i r c u l a t i n g D I T . S e r i a l

studies

w e r e p e r f o r m e d to e x a m i n e s e r u m D I T and o t h e r t h y r o i d

parame-

ters in c r i t i c a l l y

diseases

ill p a t i e n t s w i t h s e p s i s a n d o t h e r

w h o w e r e t r e a t e d at our O p e r a t i v e I n t e n s i v e C a r e U n i t . r e s u l t s of t h e s e s t u d i e s , w h i c h h a v e r e c e n t l y b e e n in d e t a i l

( M e i n h o l d et al. 1991a), are p r e s e n t e d

Some

published

in f i g u r e 4

and 5 and in t a b l e 5. The t i m e c o u r s e of D I T and i o d o t h y r o n i n e s e r u m l e v e l s in a p a t i e n t w h o d e v e l o p e d s e p s i s 7.5 d a y s a f t e r s e v e r e h e a d

in-

jury is s h o w n in f i g u r e 4. The o n s e t of s e p t i c s h o c k w a s c o m p a n i e d by a D I T and rT3 i n c r e a s e w h i c h r a p i d l y

ac-

reached

m a x i m u n l e v e l s some h o u r s b e f o r e the p a t i e n t d i e d , w h i l e a n d T 3 fell b e l o w the n o r m a l r a n g e . F i g u r e 5 s u m m a r i z e s r e s u l t s of D I T m e a s u r e m e n t s in the four p a t i e n t g r o u p s

T4 the

stu-

to o o csi Csi CD L ? I L J o OOOIÛNTCNIOOOIONICSIO E CNJ * ' * " * " * " * CD CD CD CD CD t S I I I I I I I I I I I o LT!

CD

>O

~o

ZD

U

M m -aip E-« 1W 73 .H mera m to -P •H ^ a) co Eh Q< TD .-H >1 01 r0 rH -o e U> O -rt fi -p u M 0) 0) Q. Ü 10 O (1) rH M •P (0 0) en -p Eh m tu e -P -a •HroG u ro m-H EH TJ EH MC M •H O 73 C ai c ü ® ¡c m 0) « -o

rH •

0 •w S* C O co -rt -P •P 10 10 c TJ •H -O (1) 0 fiCO -rf a> -H •o c -1Hi M £> 1 g e 3 O •H c-H •P 0) O a a)w •a en o m -a a m c m Ei -o IO a a a; dl •H -H 1-1 •P U (0 -H Ol a t-i •H a> a) fa ¡s -a

69

BrAc(125I]T^

75c /b Se

kDa

68 45

zm • mS.

29 20,5 12,4

Figure 7 A u t o r a d i o g r a m of S e - 7 5 - l a b e l l e d or B r A c (1-125) T4 a f f i n i t y - l a b e l l e d rat liver m i c r o s o m a l p r o t e i n s (Behne et al. 1990b)

70 digestion and cyanobromide cleavage of the double-labelled 27 kDa protein yielded identical distribution patterns and a constant activity ratio of the two radionuclides in each of the protein fragments. The results of these and additional experiments comparing the type I deiodinase and selenium content of the 27-kDa protein gave clear evidence that the active subunit of the type I enzyme contains selenium which might be chemically bound as a selenocystein. Our results were supported and extended by a very recent study (Berry et al. 1991) which demonstrated that selenium is indeed present at the active site of the type I deiodinase in the form of a selenocystenine. After glutathione peroxidase, a second selenoenzyme with important regulatory functions has been identified by these findings. The fact that type I iodothyronine 5'-deiodinase is responsible for most of the conversion of the prohormone thyroxine to the bioactive T3 in the body make evident the essential role of the trace element selenium in thyroid hormone metabolism and action. References 1. Beckett, G.J., S.E. Beddows, P.O. Morrice, F. Nicol, J.R. Arthur: Biochem J. 248 (1987), 443. - 2. Behne, D., S. Scheid, A. Kyriakopoulos, H. Hilmert: Biochem. Biophys. Acta 1033 (1990a), 219. - 3. Behne, D., A. Kyriakopoulos, H. Meinhold, J. Kohrle: Biochem. Biophys. Res. Comm. 173 (1990b), 1143. 4. Berry, M.J., L. Banu, P.R. Larsen: Nature 349

(1991),

438. - 5. Braverman, L.E., S.H. Ingbar, K. Sterling: J. Clin. Invest. 49 (1970), 855. - 6. Brown, B.L., R.P. Ekins, S.M. Ellis, W.S. Reith: In: In vitro procedures with radioisotopes in medicine, International Atomic Energy Agency, Vienna, 1970, p. 560. - 7. Burger, A.G., D. Engler, U. Buergi et al.: J. Clin. Invest. 71 (1983), 935. - 8. Chopra, I.J.: J. Clin. Invest. 54 (1974), 583. - 9. Chopra, I.J., U. Chopra, S.R.

71 Smith, M. Reza, D.H. Solomon: J. Clin. Endocrinol. Metab. 41 (1975), 1043. - 10. Chopra, I.J., J.M. Hershman, W.M. Partridge, J.T. Nicoloff: Ann. Intern. Med. 98 (1983), 946. 11. Gharib, H., W.E. Mayberry, R.J. Ryan: J. Clin. Endocrinol. Metab. 31 (1970), 707. - 12. Gross, J., R. Pitt-Rivers: Lancet I (1952), 439. - 13. Hesch, R.D., G. Brunner, H.D. Solling: Clin. Chim. Acta 59 (1975), 209. - 14. Köhrle, J., R.D. Hesch: In: Endokrinologie, R.D. Hesch (Hrsg.), Urban & Schwarenberg, München, 1989, S. 172. - 15. Köhrle, J., ü.B. Rasmussen, D.M. Ekenbarger et al.: J. Biol. Chem. 265

(1990),

6155. - 16. Meinhold, H., J.W. Dudenhausen, K.W. Wenzel, E. Saling: Clin. Endocrinol. 10 (1979), 355. - 17. Meinhold, H., A. Beckert, K.W. Wenzel: J. Clin. Endocrinol. Metab. 53 (1981), 1171. - 18. Meinhold, H., H.J. Gramm, W. Meissner et al.: J. Clin. Endocrinol. Metab. 72 (1991a), 945. 19. Meinhold, H., G. Böhm, U. Haselbach, R. Giencke, H. Gessner, D. Behne: Effects of selenium deficiency on thyroid hormone synthesis and metabolism. Abstractbook, 10th International Thyroid Conference, The Hague, 1991b, p. 187. 20. Schwander, J., H. Meinhold: Acta Endocrinol. 114 (Suppl. 283) (1987), 11. - 21. Silva, J.E., P.R. Larsen: J. Clin. Invest. 61 (1978), 1247. - 22. Visser, T.J., i. Van der DoesTobe, R. Docter, G. Hennemann: Biochem. J. 150 (1975), 489.23. Visser, T.J., J.A. Mol, M.H. Otten: Endocrinology

112

(1983), 1547. - 24. Vagenakis, A.G., A. Burger, G.I. Portnay et al.: J. Clin. Endocrinol. Metab. 41 (1975), 191. 25. Wenzel, K.W., H. Meinhold: Lancet II (1975), 413. Discussion Leövey: We found with my coworker Dr. Biro in 1983 that the human leukocytes are able in cell culture to produce monoiodine - thyrosine (MIT) and DIT too. We also found that cultured human leukocytes have TSH.they produce MIT and DIT. We do not know the exact explanation of this phenomenon. Meinhold: Before we came to the clinical studies we performed

72 for

one o r e t w o y e a r s

in v i t r o

studies

with

leukocytes.

we w e r e n o t a b l e t o f o u n d DIT i n r e s t i n g l e u k o c y t e s . , t t o s t i m u l a t e them t o p h a g o c y t o s i s , and i t s e s s e n t i a l uptake of

T4 t o t h e c e l l

and a l s o

c y t e s make t h e m e t a b o l i c

worst

establish

system.

Leovey:

this

oxidizing

In o u r

stimulated Benker:

investigations

b y TSH and a f t e r

At t h e Hague,

Leiden reported inhibit

the group of

kinds

of

clinical

As I showed i n t h a t

pituitary

deiodinase

local

T3 p r o d u c t i o n

type-2

from c i r c u l a t i n g

the p i t u i t a r y

is

able

to produce

deiodination. can't

So i t

is

possible

whithin the c e l l s say anything

w i t h t h e new

drug.

about

And i n a

central

the p o s s i b i l i t i e s

a

for

situation

in the

cir-

normal,

than

cells

to maintain

with that

from

and

used

own T3 b y u s i n g

the p i t u i t a r y

DIT.

speculate

the brain

are quite

its

were

substances?

especially T4.

to

differentially

when t h e T4 l e v e l

d e c r e a s e w h e r e a s T3 l e v e l s

T4 f r o m t h e p l a s m a w h i t h i n status

table

enzyme i s

beginning hypothyroidism,

culation

small

such

the

leuko-

van der Heide

Would y o u of

the

leukocytes

Prof,

deiodinases.

for

they produced

drugs which

applications

Meinhold:

of

of

that

We had

with oxidizing

t h e normal

stimulation

on a new c l a s s

various

about p o s s i b l e

essential

reaction

But

by

this

type-2

euthyroid

function, that

are

but given

I

73 Value of the estimation of peripheral serui T3 and rT3 for prognosis assessment in patients vith liver cirrhosis - a prospective study Chr. Rink 1 ), U. Siersleben 2 ), J. Haerting 3 ), T. Mende 2 ), R. Nilius 1 ) Department of Internal Medicine*), Department of Radiology 2 ) and Institute for Biostatistics and Medical Informatics 3 ) of the Martin-Luther-Universitat Halle-Wittenberg, Germany In the last decade it was established that serum triiodothyronine ( T 3 )

level reflects the severity both of acute and

chronic liver diseases /3,4,8,14,19/. In particular, in patients with liver cirrhosis the so-called

low-T3-syndrome

/3,12-14/. Therefore, it has been suggested that the estimation of peripheral serum thyroid hormone levels may provide an early prediction of the prognosis of patients with liver cirrhosis /6,19/. In view of modern therapeutic possibilities available also in hepatology, e.g. immunosuppression and liver transplantation, it is a very important task for hepatologists to predict more precisely the prognosis of patients with liver cirrhosis. So the search for new and more reliable prognostic parameters is being continued. It is the aim of our study to prove whether the development of low T3 serum levels is associated with a poor prognosis and whether the T 3 serum concentration can be used as a predictive parameter regarding the fate

of patients with liver

cirrhosis. For this purpose we used a Prognostic Index (PI) reliable for prognosis assessment in cirrhotics which was recently developed by us /I5,16/. By means of this statistical model it is possible to prove other

parameters

than that used in the index with regard

to their predictive value.

74 Material and methods To achieve our objectives we determined the peripheral thyroid hormone levels in 28 patients with liver cirrhosis. The diagnosis was established by laparoscopy and/or liver histology. The mean follow-up time of the 22 survivals was 13 months, the mean survival time of the 6 decreased patients was 4.3 months (control on April 30, 1991). Seventeen of the patients were males and 11 were females, for prognosis assessment of the liver disease we calculated the Prognostic Index (PI) in all of the patients on the basis of the COX regression model /22/: PI( Z o) = B'zo =

B

l z l 4 ... + BpZ 0 p,

where 6 is the coefficient of the variable z in the COX model. Calculating this index for each patient we used 11 parameters as recently described /16/ (table 1). Table 1: Variables and their coefficients necessary for calculation the Prognostic Index

variables

coefficients B

covariables z

diagnosis

0.9699

1 (micromodular)

encephalopathy

0.5572

0 (no PSE)

2 (other types) 1 (PSE) spider naevi

+ 0.9635

0 (no spiders) 1 (spiders)

PCV

+ 4 8837

platelets

-

0 0158

) )

Quick's value

-

0 0206

)

absolute

albumin

-

0 1164

)

values

-

of variables

0 4183

)

if-GT

+ 0 0001

IgA

+ 0 0948

potassium

+

) ) )

cholesterol

1 2792

75 The

index calculated by

d i c t i o n of According patients

these variables

the prognosis to the v a l u e

into

of c i r r h o s i s

of

three risk

risk group A:

permits

t h e PI w e c l a s s i f i e d

prognosis prognosis

B:

index

> - 4 to - 2 = m e a n

C:

index

- 6 to - 4 = g o o d

routine

(T3-RIA)1),

tri-iodothyronine

thyroxine

and basal as well

Statistical the Centre

in p e r i p h e r a l

analysis was performed of O r g a n i z a t i o n

Universitat

the Karl-WeierstraB-Institut BMDP

of

hormone

of

on the computer

of

the PI

as

blood.

of t h e

of t h e A c a d e m y

Berlin GmbH,

2) R I A of t h e A c a d e m y

venous

with statistical

in the v e r s i o n s

1) R I A of H e n n i n g

parameters

(RIA)2),

T3

reverse

and Calculation

Halle-Wittenberg

and by using

the

prognosis.

thyroid-stimulating

as the laboratory

determinations

pre-

groups: > - 2 t o +2 = p o o r

risk group

(TSH-RIA)1)

a l l of

index

risk group We measured

a precise

/15,16/.

ES

1040

Martin-Luther-

software both

of S c i e n c e s

1979 an

of

1985

by

Berlin

/2,15/.

FRG

Sciences

Berlin,

FRG

Results O u t of

the total

of

the

28 p a t i e n t s

classified

into

risk group

C. The d i f f e r e n c e s

respect dency p r

to the m e a n

of

= 0.54)

values

r i s k g r o u p A,

significance (figure

on T3

= 0.4;

serum T3

differences p = 0.0025;

that

the serum T3

thesis parameters

B/C:

prognostic

correlation

ten-

index

(y = - 1 . 8

-0.7x;

2). the regression

of

PI o n

(y = - 2 . 0 1 - 0 . 7 2 x ; r = 0 . 5 4 ;

between

A/C:

an inverse

into

with B/C:

one was expected

TSH were highly

groups

were 9

(A/B: p = 0.06; A / C : p = 0.04;

t h e s l o p e of

although a positive The

the risk

B, a n d

in a

(figure

hand,

7 patients

resulted

demonstrated

TSH was also negative

basal

between

concentrations

1). T h e r e g r e s s i o n of t h e

p = 0.03)

On the other

examined

12 i n t o r i s k g r o u p

(figure

the risk groups

significant p = 0.43)

4).

concentration

correlates

of t h e

e.g.

liver,

0.0028),

3).

A and B or C

(A/B: p =

(figure

p =

basal

regarding

0.004; It is

noteworthy

well with such

serum albumin,

syn-

cholesterol,

76

» tn"T>

• (n*ta)

S

Prognostic Groups Figure 1 Serum concentrations of T3 in the three risk groups of the PI (multiple box and whisker plot). (Wilcoxon: A/B: p = 0.06, A/C: p = 0.04, B/C: p = 0.54)

Figure 2 Regression of PI on T3 (with 95 % confidence interval), (y = -1.8 -0.7x; r = 0.4, p = 0.03)

77

Figure 3 R e g r e s s i o n of PI o n basal TSH (with 95 % c o n f i d e n c e interval). (y = -2.01 - 0 . 7 2 x ; r = 0.54, p = 0.0028) •o/i •

m

x

0) I-

Prognostic Groups Figure 4 Serum c o n c e n t r a t i o n s of basal TSH in the three risk groups of the PI (multiple b o x and w h i s k e r (Wilcoxon: A/B: p = 0.004, A/C: p = 0.0025, B/C: p = 0.43)

plot).

78 Quick's value, and IgA, whereas no other thyroid hormone did so (table 2). Table 2: Correlation matrix (extract of significant correlations, p < 0.05) of thyroid hormone and laboratory liver parameters

TSHb T 3 T 4 rT3

PCV thrombo chol. alb. Quick

K

PI

TSHb

1

-

-

-

-

-

-

-

-

+

+

T3

-

1

+

-

+

-

+

+

+

-

+

T4

-

+

1

+

-

-

-

-

-

-

-

rT 3

-

-

+

1

-

+

-

-

-

-

-

PCV

-

+

-

-

1

-

+

+

-

-

thrombo

-

-

-

+

-

1

-

-

-

-

chol.

-

+

-

-

+

-

1

-

-

-

alb.

-

+

-

-

+

-

+

1

+

-

Quick

-

+

-

-

-

-

-

+

1

-

K

+

-

-

-

-

-

-

-

-

1

PI

+

+

-

-

Moreover, the mean serum T3 concentration differed significantly between surviving and deceased patients p = 0.00076) (figure 5).

(Wilcoxon-Test,

79

deceased

Figure

suruiving

5

S e r u m c o n c e n t r a t i o n s of T 3 i n d e c e a s e d a n d s u r v i v i n g patients with liver cirrhosis (multiple box and whisker plot) (Wilcoxon: Discussion The

liver

and

13,14/.

liver

decrease for

it is a s s u m e d

in our

correlation

expressed

the basal

to b e an e n z y m a t i c

cannot

Index /15,16/,

TSH levels

TSH.

that

be the only

But

there

of

/14/.

and serum T3

On the c o n t r a r y ,

are significantly

lower

serum

/3,12, shift reserve this for

As between

is a s t r o n g

cirrhotic

serum concentrations

in

reason

find any correlation

cirrhotic patients.

in the b a s a l

of T 4 y i e l d i n g

hormone metabolism

between the prognosis

the low T3

that

develops

it c o u l d be d e m o n s t r a t e d

we could not

as P r o g n o s t i c

Interestingly, increase

/14/,

conversion

the T3

in c i r r h o s i s ,

deiodination

of t h e p e r i p h e r a l

observed

T3 and rT3 verse

But

surprising

low T 3 - s y n d r o m e

to the r T 3 p r o d u c t i o n

the d e v i a t i o n earlier

it is n o t

in p a r t i c u l a r and the

to n o n p h e n o l i c

(rT3) / 7 , 1 0 , 1 2 , 1 7 / .

switch over

s i t e of t h e p e r i p h e r a l

Therefore,

diseases,

The reason

from phenolic T3

important

/5,6,17/.

concentrations

0.00076)

conclusions

is t h e m o s t

of T 4 t o T 3 chronic

p =

in-

patients, (figure

do not

2).

induce

an

in the r i s k g r o u p than

in g r o u p s

B

A

80 and C. S i n c e t h e r e is no c o r r e l a t i o n b e t w e e n b a s a l T S H a n d r T 3 it seems to be m o r e i m p r o b a b l e that rT3 c o m p e n s a t e the l a c k i n g and w i l l b l o c k up the t r i - i o d o t h y r o n i n e r e c e p t o r s of the gland /18/.

I n s t e a d of t h i s h y p o t h e s i s t h e r e are a r g u m e n t s

g i v e c a u s e for the a s s u m p t i o n that in p a t i e n t s w i t h

T3

pituitary that

liver

c i r r h o s i s t o x i c s u b s t a n c e s f r o m the g u t r e a c h the b r a i n

by-passing

the liver by h e p a t o f u g a l c o l l a t e r a l s and m a y be r e s p o n s i b l e for a derangement

in n e u r o t r a n s m i t t e r m e t a b o l i s m a s s o c i a t e d w i t h a l -

t e r a t i o n s of the p i t u i t a r y r e c e p t o r s for T R H on T S H

secretion

/ l l / so as to p r e v e n t i n c r e a s e s of T S H s e c r e t i o n in r e s p o n s e decreased serum T3 concentration Nevertheless,

to

/20/.

the d e v e l o p m e n t of low T 3 s e r u m c o n c e n t r a t i o n s

p a t i e n t s w i t h liver c i r r h o s i s i n d i c a t e s p o o r p r o g n o s i s for

in

them.

If the T 3 v a l u e s do n o t i n c r e a s e to n o r m a l r a n g e s by m e a n s of t h e r a p y , the c o u r s e of the d i s e a s e w i l l t u r n out to be (see f i g u r e

fatal

5).

It seems to be true that low s e r u m T 3 l e v e l s are a v e r y parameter

sensitive

for p r o g n o s i s p r e d i c t i o n in p a t i e n t s w i t h l i v e r

cirrho-

sis . References 1. Cox, D . R . : J. R. S t a t i s t . Soc.

(B) 34

(1972),

187. - 2. D i x o n ,

W . J . , M . B . B r o w n , L. E n g e l m a n , J.W. F r a n e , M.A. H i l l ,

R.I.

J e n n r i c h , J.D. T o p o r e k : B e r k e l y , U n i v e r s i t y of C a l i f o r n i a

Press,

1983. - 3. H a m p e l , R., W. M e n g , A. W e b e r , R. M i c h a e l : Dt.

Ge-

s u n d h . - W e s e n 37 (1982),

1563. - 4. H a m p e l , R., A. W e b e r , B.

W. M e n g : Dt. G e s u n d h . - W e s e n 39 (1984),

S. A p p e l t : Dt. G e s u n d h . - W e s e n 36 (1981), 425. - 6 . H e p n e r , I.J. C h o p r a : A r c h .

Intern. M e d .

Dt. m e d . W o c h e n s c h r .

139 (1979),

1117. - 7.

G.,

G.W.,

Hesch,R.D.:

106 (1981), 971. - 8 . Itoh, S., Y. Y a m a t a ,

Oda, K. K a w a g o e : Am. J. G a s t r o e n t e r o l .

81

(1986), 444. - 9.

T., T. K o j i m a , T. T a k a h a s h i , Y. M u t o : G a s t r o e n t e r o l . (1987),

Jäger,

1755. - 5. H e l l t h a l e r ,

Japan.

344. - 10. L 1 Age, M . , H. W e i n h o l d , K.W. W e n z e l ,

S c h l e u s e n e r : J. E n d o c r i n o l . M., P.P. R o v a s i o , A. M a s a l a ,

I n v e s t . 4 (1980), S. A l a g n a ,

A. D e p l a n e , G. M a d e d d u , L. C h i a n d u s s i :

379. - 11.

S. R a s s u , A. Ital. J.

T.

Kano, 22

H. Langer,

Solinas,

Gastroenterol.

17 (1985), 69. - 12. R i n k , Chr., U. S i e r s l e b e n , J. H a e r t i n g ,

M.

81 Klaua, E. Mertens: Radiol, diagn. 23(1982), 88. - 13. Rink, Chr., U. Siersleben, H. Haerting, M. Klaua, E. Mertens: Z. ges. inn. Med. 37 (1982), 532. - 14. Rink, Chr., U. Siersleben, E. Meyer, Th. Zeisler, E. Mertens, M. Klaua, J. Haerting, W. Teichmann, R. Nilius: Radiol. Iugosl. 23 (1989), 45. - 15. Rink, Chr., J. Haerting: Martin-Luther-Universität Halle-Wittenberg, Wissenschaftliche Beiträge 1990/21 (R 118), Halle (Saale) 1990. 16. Rink, Chr., J. Haerting, R. Nilius: Z. Gastroenterol. (Suppl• 2) 29 (1991), 163. -17. Salata, R., J. Klein, G.S. Levey: Sem. Liver Dis. 5 (1985), 29. -18. Schlienger, J.L.: Z. Gastroenterol. 17 (1979), 452. - 19. Seitz, H.K., P. Czygan, F. Weber, R. Götz, B. Kommereil: L. Chiandussi, I.J. Chopra, I. Martini (eds.): Academic press London and New York 1982, p. 471. 20. Utiger, R.D.: The thyroid. In: Felig, Ph., J.D. Baxter, A.E. Broadus, L.A. Frohman (eds.): Endocrinology and metabolism 2nd edition. McGraw - Hill Book Comp. New York, 1987, p. 389.

Discussion Peschel: Did you find some differences of your results concerning the different etiology of your cases of liver cirrhosis whether they are of alcoholic, viral or autoimmune origin, because these various kinds have a different prognosis per se? Rink: No, we could not demonstrate such differences because the seguels of a cirrhosis are the same, nevertheless the etiology. You can find a collateralisation and we have arguments for such hypothesis that the collateralisation in the liver is a very important reason for the development ot I0W-T3 syndrome. These collaterals develop in every cirrhosis in a final state of the disease. We could not demonstrate differences in etiology statistically . Limanova: We did some examination in myocardial infarction with T3-I0W

syndroma. We found the same as you, that patients with

very low T3 level died and that patients that had T3 lower and after seven days the T3 improved

survived.

I would like to ask, did you examine T3 total or T3 free? Additionally, I remember a paper, seven or eight years old, the author tried to treat patients with 1 iver cirrhosis f

with PTU

(Propylthiouracil). They had very good results, but since that

82 we never red those articles - the other authors did not have success. Rink: We determined total T3 and our study is going on and we will also measure the free T3~fraction. We know the papers from the Toronto-group and as I know they are the only group that described such a positive effect of PTUtreatment in cirrhotic patients. We did not use such a treatment in our patients because we are not sure that there results a benefit for our patients. Meinhold: May I make a short comment to your findings regarding rT3 - this was not a parameter which could be used as a survival parameter. I think it is not surprising. In a paper this year they found that the rT3~production is not changed in all of that situations with the low T3 syndrome. One can't speak from a swich to higher rT3-production and so it's not surprising regarding the T3 that's a clear decrease. rT3 remains in it's production stable or constant and its elimination is inhibited. And so rT3 is not a good parameter in your system.

83 Thyroid hormones and TSH in acute myocardial infarction Pechin, J., I. Vereb, J. Murin Department of Nuclear Medicine of 1st Medical Clinic, Faculty of Medicine, Comenius University, Bratislava, CSFR The acute and chronic nonthyroidal diseases are often accompanied with abnormal changes of thyroid hormones (TH) metabolism and functional defects of axis hypothalamus-hypophysis-thyroid

gland

/l/. The acute myocardial infarction (AMI) occupies among these diseases an important place for the well-known influence of TH on myocardial oxygen consumption and thereby for the possibility to influence the course of the disease. Therefore, the serum level changes of TH and thyroid-stimulating hormone (TSH) are in the

foreground

of the interest of many authors. However, con-

flicting reports have been published /2-4/. The aim of our study was to investigate the dynamics of TH and TSH changes during AMI on bigger set of patients and to try to find the differences in the behaviour of TH in patients who died within 96 hours from the onset of illness in comparison with patients who survived longer than 3 weeks. Second aspect was to determine the diagnostic value of serum TH and TSH levels on thyroid function evaluation during the course of AMI. Patients and methods The study was performed in 88 patients with AMI. No patient showed clinical symptoms of functional changes of thyroid gland. Patients treated with corticosteroids or anticoagulants were exclude. The parameters were evaluated on the 1st day in 72 patients who survived more than 21 days and in 16 patients who died 96 hours from admission. In 58 patients the blood samples were taken in addition to the 1st day on the 3rd and the 7th day. The following commercial kits were used: total serum thyroxine (T4) was evaluated by R I A - T 4 ,

total serum triiodothyronine

(T3)

84 by

RIA-T3

(ETR)

by

(both from Thyro-KT

Mallinckrodt)•

The

commendations

of

The

medians

the

statistical

Friedman ranks

(Feinchemie

effective

Sebnitz) were

and

thyroxine

TSH by

always

made

ratio

Riamat

TSH

according

(Byk

to

re-

producer.

95 % c o n f i d e n c e analyses

two way

test

CSFR),

measurements the

and

KoSice,

intervals

non parametrical

analysis

of

and Mann-Whitney

variance, U

were

established.

methods

Wilcoxon's

were

In

used:

paired

signed-

test.

Results The values in those

of

who

investigated died

are

T4 nmol/l

parameters

compared

in s u r v i v e d

in f i g u r e

T3 nmol/l

TSH m/E/l

170-

315-

150

30

5.0

130

25-

4.0-

110-

20-

30-

90-

1.5-

2.0-

70

1.0-

1.0-

patients

and

1.

ETR >p 50 n m o l / 1 :

Triiodothyronine was determined values are shown on figure

over

100 / u U / m l

In t h e o t h e r

in 37 p a t i e n t s

15

levels. mild,

the

f r o m 6 to

1). is

presented

2. It c a n b e s e e n h o w q u i c k a r e t h e c h a n g e s of T 4

The hyperthyreosis which appear without eye's phenomena.

laboratory

patients

patients,

in n o n e of

ranging

T h e f o l l o w u p of t h e p a t i e n t s d u r i n g t h e f i r s t m o n t h s on figure

in o n l y

was

In 2 p a t i e n t s t h e c l i n i c a l

and

in 1 - 1 . 5 m o n t h s .

a n d in

(normal T 4 ,

for 7 y e a r s a n d a f t e r tients remained

that,

others

Definitely hypothyroidism

l o p e d in 1 p a t i e n t a f t e r a r e m i s s i o n of 8 y e a r s a n d a hypothyroidism

serum

5 patients

signs c h a n g e d to slight h y p o t h y r o i d i s m

to e u t h y r o i d i s m

and

in 6 (40 % ) .

(74 % of a l l ) ,

All values were elevated, (figure

(36 % of a l l )

1. It w a s h i g h i n a l l 3 t e s t e d

it w a s l o w i n 9 (60 % ) a n d w i t h a n o r m a l v a l u e

hyperthyrotics.

%)

TSH)

in 18 p a t i e n t s

s i g n s of h y p e r t h y r o i d i s m .

TSH was determined

(80 % )

T4 = 50-60 nmol/1:

(all w i t h h i g h

with clinical

(5)

high TSH)

in a n o t h e r , w h i c h

a therapy was started.

deve-

latent persisted

The other

3 pa-

euthyrotic.

27 of t h e p a t i e n t s w i t h l o w or n o r m a l T 4 a n d h i g h T S H a t seeing could be examined monthly. v e r t e d to n o r m a l v a l u e s w i t h i n six patients w i t h long standing

In 21 of t h e m

1-10 months

first

(77.8 % ) , T 4

(m. 4 . 5 m . ) .

low t h y r o x i n level, 4

From

became

rethe

156 definitely hypothyrotic, c o v e r e d in

1 with latent hypothyroidism and 1 re-

euthyroidism.

A t h e r a p y w i t h t h y r o i d h o r m o n e s w a s a p p l i e d in the m o s t of

the

followed patients

in

hypothyrotics,

(in a b o u t 2/3), e i t h e r as a s u b s t i t u t i o n

or as a s u p p r e s s i o n of the t h y r o i d

enlargement.

For a n e v a l u a t i o n of the d e f i n i t e s t a t u s , the t h e r a p y h a s s t o p p e d for s e v e r a l m o n t h s and the t h y r o i d f u n c t i o n w a s It w a s f o u n d t h a t 23 p a t i e n t s o u t of 37 r e e v a l u a t e d (latent h y p o t h y r o t i c )

(13.5 % ) d e v e l o p e d d e f i n i t e l y

HOKTHS AFTER

evaluated.

(62.2 % ) w e r e

e u t h y r o i d , w i t h n o r m a l t h y r o i d t e s t s , 9 (24.3 % ) w e r e euthyroid but with high TSH

been

clinically

and only 5

hypothyroidism.

DELIVERY

Figure 2 T h y r o x i n e l e v e l s in 27 p a t i e n t s

(follow up)

F o l l o w u p of PPT in 14 p a t i e n t s i n c l u d e d the n e x t p r e g n a n c i e s : 12 the s e c o n d a n d in 2 the s e c o n d and t h i r d ones. R e l a p s e of d i s o r d e r - a n e w e p i s o d e of P P T d e v e l o p e d

in

the

in 6 p a t i e n t s a n d in 2

of t h e m r e p e a t e d a f t e r the t h i r d d e l i v e r y . Every r e l a p s e w a s a s s o c i a t e d w i t h low T4 and h i g h T S H with hyperthyrosis

( i n c l u d i n g that in a p a t i e n t

in the f i r s t a t t a c k of PPT) and s i g n s of m i l d

hypothyrosis. Ultimate outcome

of the r e l a p s e s is: 4 p a t i e n t s

157 with latent hypothyroidism and 2 euthyrotics. Most of those patients who had no relapses in the consecutive pregnancies had been treated with thyroid hormonal therapy during the pregnancy. Table 2: Follow up of the hyperthyrotic patients

Patient

1.

2.

3.

4. 5.

T4

T3

hyperthyroid. euthyroidism

187 112

5.1

I seeing aft. 1.5M 3 M 6 Y.

hyperthyroid. hypothyr.(mild) euthyroid

202 54 81

13.0

N

N

I seeing aft. 1.5M 8 Y.

hyperthyroid. hypothyr.(mild) hypothyroidism

49 71 low

5.2

I seeing aft. 1.5M " 10 Y.

hyperthyroid. euthyroidism

200 90

I seeing after 7Y.

hyperthyroid. euthyroidism

time of examin.

Clinical status

I seeing after 1M 2Y.

II

II

TSH

nmol/1 nmol/1 /uU/ml

N

2.6 N

-

-

_

0.5 22.0 < 5

0.01 20.0 > 6

-

-

-

-

N

low

109

3.8

N

_

< 5 < 5

> 6 -

; 5

M - Month; Y - Year; N - Normal value Discussion Study of the course of PPT in a relatively large series of patients and over a long period of time, proves the known facts that PPT is a benign, transitory disorder in most of the cases. Even during the acute phase - attacks of the disease, the clinical picture is much milder than could be expected by thy laboratory disorder of the thyroid tests. In more than 60 % of the patients the thyroid function returns to normal after a transitory disorder and in about a quarter of the rest it is normal under augmented pituitary stimulation (latent hypothyroidism). Only in less than 15 % of the cases develops a clinical hypothyroidism. As in other immunologic diseases, the disorder oscilate between episodes of activation-relapses and remissions. The specificity of PPT is that re-

158 l a p s e s are a s s o c i a t e d w i t h p r e g n a n c i e s and o c c u r in p o s t p a r t a l p e r i o d . V e r y i n d i c a t i v e e x a m p l e s are 2 p a t i e n t s w i t h

relapses

a f t e r e a c h of 3 d e l i v e r i e s , w h e n a s e v e r e h y p o t h y r o i d i s m , m y x o e d e m a d e v e l o p e d and t h e n , a full r e c o v e r y w i t h

even

euthyroidism

and r e d u c t i o n of the g l a n d to a n o r m a l size f o l l o w e d .

In o n e of

t h e m , e c h o g r a p h i c f i n d i n g r e t u r n e d to n o r m a l p a t t e r n , a l s o .

Still,

P P T m a y d e s t r o y the t h y r o i d to s u c h a d e g r e e t h a t its f u n c t i o n c o m e i n s u f f i c i e n t a n d l o n g l i f e t r e a t m e n t is n e c e s s a r y .

be-

It m a y

h a p p e n in the f i r s t a t t a c k of the d i s e a s e or a f t e r a p e r i o d of y e a r s . By our e x p e r i e n c e it is n o t p o s s i b l e to p r e d i c t the of t h i s d i s e a s e , n e i t h e r the u l t i m a t e o u t c o m e of

course

it.

A n i n t e r e s t i n g a s p e c t of P P T is its r e l a t i o n to H a s h i m o t o ' s r o i d i t i s . A l m o s t in all p a t i e n t s w i t h P P T it w a s f o u n d

thy-

lymphocytic

i n f i l t r a t i o n of the t h y r o i d a n d h i g h t i t e r s of A T A , by w h i c h it is undistinguishable

f r o m the f o r m e r . T h e r e are o t h e r t y p e s of

thy-

r o i d i t i s p u b l i s h e d by G l u c k et al. /6/, N i k o l a i et al. / I / a n d c a s e s w i t h a t r a n s i t o r y h y p o t h y r o s i s by Y a m a m o t o et al. / 8 / ,

that

r e s e m b l e P P T in some f e a t u r e s . By m o s t of its c h a r a c t e r i s t i c s is i d e n t i c a l to H a s h i m o t o ' s t h y r o i d i t i s , b u t the m a i n

PPT

difference

is the r e v e r s i b i l i t y of the t h y r o i d i m p a i r m e n t a n d the c h a n g e of the t h y r o i d d i s o r d e r in s h o r t i n t e r v a l s , d i s l i k e

Hashimoto's

T h y r o i d i t i s w h i c h is an i r r e v e r s i b l e t h y r o i d d a m a g e . So, it is an autoimmune thyroiditis occuring t i o n in p o s t p a r t u m

in a y o u n g w o m a n , w i t h o n

activa-

period.

W h a t is the i n c i d e n c e of PPT, t h e r e are no d a t a for our

country.

A m i n o / 9 / e s t i m a t e it to be a b o u t 5.5 % of the w o m e n in J a p a n . the i n c i d e n c e is so h i g h e v e r y w h e r e , a n d b e c a u s e the disorder

is m i l d and t r a n s i t o r y and p o s s i b l y

ly in m a n y p a t i e n t s , many hypothyroidism

If

clinical

it p a s s e s

inapperent-

it m a y be p r e s u m e d that it is the c a u s e of in m e d i a e v a l w o m e n ,

p r o b a b l y h a d P P T in t h e i r y o u n g

i.e. t h e s e w o m e n v e r y

years.

C o n c e r n i n g the t h e r a p y of P P T , it is s y m p t o m a t i c as in o t h e r i m m u n o l o g i c a l d i s e a s e s : s u b s t i t u t i o n of the t h y r o i d h o r m o n e s t h e y are d e f i c i e n t .

H y p e r t h y r o i d i s m u s u a l l y h a s n o t be

treated.

T h e r e are no d a t a for e v e n t u a l y p r e v e n t i n g of the r e l a p s e s b y t r e a t m e n t . But, by our e x p e r i e n c e , o n c e s t a r t e d t h e r a p y t h y r o i d h o r m o n e s , s h o u l d be r e v i s e d in e v e r y p a t i e n t ,

where

with

for

any

159 avoidance of unnecessary, longlife treatment, at least in some patients. Conclusions 1. Clinical manifestations of PPT are mostly mild and shortlasting.

Hyperthyroidism appear in less than 10 % and hypothy-

roidism in about 20 % of the cases. Less than 20 % of the patients need a substitution therapy during the first attack of PPT. 2. Thyroid tests in PPT are disordered in much greater degree than clinical state. 3. For the diagnosis of PPT very often it is necessary to monitor the thyroid function many times, in the beginning monthly and later 1-2 times in the year. 4. At the end of follow up period of 37 patients of our series, clinical hypothyroidism was found in 13.5 % and latent hypothyroidism in 24.3 % of the patients. 5. Hypothyreosis may develop in the patients who recovered from PPT after many years and that's why longlife controls are recommended . References 1. Amino, N., K. Miyai, T. Onishi et al.: J. Clin. Endocrinol. Metab. 42 (1976), 296. - 2. Ginsberg, J., P.G. Walfish: Lancet 1 (1977), 1125. - 3. Hoffbrand, B.I., S.C. Webb: Postgrad. Med. J. 54 (1978), 793. - 4. Schleusener, H. et al.: J. Clin. Endocrinol. Metab. 56 (1983), 791. -5. Compact Review, New Compact 16 (1985), 107. - 6. Gluck, F.B. et al.: N. Engl. J. Med. 293 (1975), 624. 7. Nikolai, T.F. et al.: Arch. Intern. Med. 140 (1980), 478. 8. Yamamoto, T., H. Sakamoto: Ann. Intern. Med. 88 (1978), 808. 9. Amino, N. et al.: N. Engl. J. Med. 306 (1982), 849. Discussion Hehrmann: Did you see any linkage or connection to the breast feeding of the mothers? Last year we had a number of young patients who had subacute thyroiditis after they stopped breast feeding.

160 S i m o v a : No, we h a v e no r e s u l t s . But I h a v e to s u m o t h e r t h a t a b o u t 12 % of our p a t i e n t s h a d g o i t e r or some o t h e r d i s e a s e in the

data, thyroid

family.

Limanova: You mentioned, that thyroids were enlarged. May I ask y o u if the o r g a n s in u l t r a s o u n d w e r e r e a l l y e n l a r g e d ? W e h a v e e x p e r i e n c e t h a t in y o u n g w o m e n t h a t are r e a l l y s l i m , w e

the

thought

t h a t the t h y r o i d is e n l a r g e d , a f t e r u l t r a s o u n d the size is q u i t e normal. S i m o v a : At f i r s t w e m a d e p a l p a t i o n a n d r e c e n t l y a w a s m a d e by u l t r a s o u n d

investigation

also.

H n i l i c a : We d i d n ' t o b s e r v e any c a s e of s u b a c u t e t h y r o i d i t i s post partal

S i m o v a : W e h a d n o t c l i n i c a l d i a g n o s e d the t h r e e c a s e s as thyroiditis,

in

period. subacute

it w a s o n l y c y t o l o g i c a l f i n d i n g . T h e r e w a s no

pain,

no t e m p e r a t u r e , no s e d i m e n t a t i o n r a t e . B u t in c y t o l o g y it w a s typical Hashimoto when we repeated h i g h t i t e r s of

antibodies.

it in one c a s e . The o t h e r

had

161 Riedel's thyroiditis - positive therapeutic response to glucocorticoids M. Ventz, G. Knappe. D. Zieglitz I Internal Clinic of University Hospital, Charité Berlin, Germany Riedel's thyroiditis (struma) is a very rare chronic inflammatory disease of the thyroid gland. Bernhard Riedel first described a chronic sclerosing thyroiditis in 1896. Synonyms of the disease are: invasive fibrous thyroiditis or invasive sclerosing thyroiditis. Woolner et al. reported an operative incidence of 0.04 % that means 1 per 2000 thyroidectomies. The overall incidence of outpatients in this series of the Mayo Clinic was 1.06 per 100000 /2,6/. Although the condition is rare, benign and in most cases selflimiting, its importance lies in its ability to clinically mimic carcinoma almost completely. In this paper we report on a case of Riedel's thyroiditis recently seen in our clinic and discuss our experience with steroid treatment. Case report A 45 years old female patient first noticed a nonpainful swelling on the left side of the neck. This nodule grew in size progressively to the middle and right of the thyroid. She complained of pressure and dyspnea. Physical examination revealed a nontender, firm, stonyhard mass on the left side of the thyroid and in the region of the isthmus. Lymphnodes were not palpable. The circumference of the neck was 43 cm. Thyroid scan with Tc-99 showed no uptake in the left lobe, isthmus and lower part of the right lobe. Normal uptake was seen in the upper region of the right lobe. Thyroid sonography revealed an enlargement of the whole thyroid gland. Hypoechoic

areas were observed in the left region, isth-

mus and lower part of the right lobe.

162 F N B and C y t o l o g y : C y t o l o g y w a s s u s p e c t for m a l i g n a n t Fibrous tissue and inflammation cells were also Laboratory

cells.

found.

findings:

T h e f i r s t e s t i m a t i o n of t h y r o i d h o r m o n e s s h o w e d a n s i t u a t i o n a n d later a h y p o t h y r o i d

euthyroid

stage.

ESR w a s h i g h . G a m m a - g l o b u l i n s w e r e a l s o

elevated.

W e d g e r e s e c t i o n of the i s t h m u s w a s p e r f o r m e d . H i s t o l o g y

revealed

a fibrous invasive thyroiditis. Despite surgery patient

continued

to c o m p l a i n of d y s p n e a , a n d p r e s s u r e in the n e c k . T h e r e f o r e s t a r t e d w i t h the a d m i n i s t r a t i o n of 50 m g p r e d n i s o l o n e . T h e

we dose

was subsequently tapered down and discontinued after 4 months. the same time w e s u b s t i t u t e d L - t h y r o x i n e 1 0 0 - 1 5 0

T h e c i r c u m f e r e n c e of the n e c k d e c r e a s e d f r o m 43 c m to 39 cm. t h y r o i d v o l u m e fell a l s o f r o m 45 m l to 13 ml in 1 y e a r . l o g i c a l l y the t r a c h e a is no m o r e

At

/ug/day. The

Radio-

stenosed.

Discussion The e t i o l o g y of R i e d e l ' s t h y r o i d i t i s r e m a i n s u n k n o w n ,

although

several theories have been advanced. Two theories should be

men-

t i o n e d . It h a s b e e n s u g g e s t e d t h a t R i e d e l ' s t h y r o i d i t i s m a y b e a c o l l a g e n v a s c u l a r d i s o r d e r b e c a u s e of the p r e s e n c e of

vasculitis

o n p a t h o l o g i c e x a m i n a t i o n . V a s c u l i t i s m a y be p r o m i n e n t ,

particu-

larly in the e x t r a c e r v i c a l m a n i f e s t a t i o n s of this d i s o r d e r .

How-

ever, the f o c a l n a t u r e of the v a s c u l i t i s a r g u e s a g a i n s t a p r i m a r y p a t h o g e n e t i c r o l e in t h i s d i s e a s e / 3 , 4 / . T h e s e c o n d t h e o r y b a s e d o n the f i n d i n g of a n t i t h y r o i d a n t i b o d i e s in a

is

significant

p e r c e n t a g e of p a t i e n t s s u g g e s t i n g the p o s s i b i l i t y of a n

autoimmune

d i s o r d e r , a l t h o u g h t h e s e a n t i b o d i e s c o u l d also be s e c o n d a r y a n t i g e n r e l e a s e by d e s t r u c t i o n of t h y r o i d t i s s u e . T h e f e a t u r e of c e l l u l a r

infiltration with lymphocytes, plasma

and h i s t o c y t e s , w h i l e n o t s p e c i f i c , response.

is t y p i c a l of an

cells,

autoimmune

C r o s s - r e a c t i v e a n t i g e n s in s e v e r a l t i s s u e s c o u l d

p l a i n s i m i l a r p a t h o l o g i c p r o c e s s in m u l t i p l e a n a t o m i c However, normal serum complement levels and normal

ex-

sites.

lymphocyte

subpopulations speak against a immunologic mechanism /3/. a s s o c i a t i o n of R i e d e l ' s t h y r o i d i t i s w i t h o t h e r

to

pathologic

The

fibrosclerotic

163 l e s i o n s w a s f i r s t s u g g e s t e d in 1958 b y B a r r e t t He n o t e d a s i m i l a r i t y

/l/.

in the p a t h o l o g i c a p p e a r a n c e of

Riedel's

t h y r o i d i t i s and o t h e r f i b r o s i n g l e s i o n s . S u b s e q u e n t l y ,

examples

of R i e d e l ' s t h y r o i d i t i s w e r e r e p o r t e d in a s s o c i a t i o n w i t h a v a r i e t y of o t h e r f i b r o s c l e r o s i n g l e s i o n s , i n c l u d i n g cholangitis, retroperitoneal bital pseudotumor,

sclerosing

fibrosis, mediastinal fibrosis,

localized pulmonary fibrosis and fibrous

orpar-

otitis. T h e c l i n i c a l f e a t u r e of R i e d e l ' s s t r u m a is n o n s p e c i f i c and p r o c e s s is f r e q u e n t l y m i s t a k e n for n e o p l a s m . The a v e r a g e p r e s e n t s in the f o u r t h to f i f t h d e c a d e , and w o m e n are t h r e e to five t i m e s m o r e c o m m o n l y t h a n are m e n . M o s t

the

patient

effected patients

present with nonpainful thyroid mass that may produce

pressure

s y m p t o m s s u c h as d y s p n e a and d y s p h a g i a . G r o w t h of the m a s s m a y be r a p i d or g r a d u a l over s e v e r a l y e a r s . H o a r s n e s s of v o i c e w i t h v o c a l c o r d p a r a l y s i s h a s b e e n r e p o r t e d to o c c u r in this c o n d i t i o n creats confusion with carcinoma. Cervical lymphadenopathy

and

is n o t

p r e s e n t . The m a j o r i t y of p a t i e n t s are e u t h y r o i d , w h i l e some

are

h y p o t h y r o i d . The s t a t u s of t h y r o i d f u n c t i o n a p p e a r s to d e p e n d the e x t e n t of r e p l a c e m e n t of the g l a n d by n o n f u n c t i o n i n g

on

fibrous

tissue. L a b o r a t o r y f i n d i n g s in R i e d e l ' s t h y r o i d i t i s are a l s o

nonspecific.

ESR is f r e q u e n t l y e l e v a t e d . A n t i t h y r o i d a n t i b o d i e s m a y or m a y n o t be p r e s e n t . S o n o g r a p h y r e v e a l e s a h y p o c h e o i c s t r u c t u r e . g r a p h y s h o w s no u p t a k e in the i n v o l v e d

region.

S u r g i c a l t r e a t m e n t of R i e d e l ' s T h y r o i d i t i s l i s h an a c c u r a t e d i a g n o s i s .

Scinti-

is n e c e s s a r y to

estab-

In a d d i t i o n it m a y be n e e d e d to r e -

lieve from significant tracheal

compression.

The o n l y m e d i c a l t r e a t m e n t a d v o c a t e d is s t e r o i d t h e r a p y .

According

to l i t e r a t u r e and our o w n e x p e r i e n c e s t e r o i d t r e a t m e n t m a y be s u c c e s s f u l . H o w e v e r the d o s e m u s t be h i g h and the d u r a t i o n of t r e a t m e n t long

(about 3 m o n t h s ) / 3 - 5 / . T h e p r o g n o s i s for

with Riedel's thyroiditis

is g o o d , and it is g e n e r a l l y

patients

considered

to be a s e l f - l i m i t i n g d i s e a s e . S o m e i n v e s t i g a t o r s h a v e n o t e d disease progression. However, spontaneous regression has been

reported.

E x t r a c e r v i c a l m a n i f e s t a t i o n of the f i b r o s i s m a y a l t e r prognosis.

the

also

slow

164 Conclusions - Riedel's thyroiditis - The o r i g i n r e m a i n s

is a v e r y r a r e

disease.

unknown.

- D i a g n o s i s s h o u l d be h i s t o l o g i c a l l y

proved.

- In the d i f f e r e n t i a l d i a g n o s i s t h y r o i d c a n c e r , f i b r o s i n g

va-

r i a n t s of H a s h i m o t o ' s d i s e a s e a n d s u b a c u t e g r a n u l o m a t o u s r o i d i t i s s h o u l d be

- W e d g e r e s e c t i o n of i s t h m u s is n e c e s s a r y . c a n be

thy-

considered. Steroid

administration

successful.

In g e n e r a l the p r o g n o s i s is g o o d . In s o m e c a s e s the

prognosis

d e p e n d s o n the p r e s e n c e of a s s o c i a t e d d i s e a s e s s u c h as retroperitonitis,

sclerosing cholangitis, fibrous

fibrous

mediastinitis

and so on. References 1. B a r r e t t , N . R . : Brit. J. S u r y 46 (1958), 207. - 2 . H a y , M a y o C l i n . P r o c . 60 (1985),

J.D.:

836. - 3. M a l a t t e , M . J . , G . D .

Chin-

tich, C . W . Z u p p a n : A r c h . O t o l a r y n g o l . H e a d N e c k Surg. 117

(1991),

214. - 4. S c h w a e g e r l e , S . M . , T . W . B a u e r , C.B. E s s e l s t y n : A m . J. Clin. Pathol. W chenschr.

(1988), 715. - 5. W e s t h o f f , M : Dt. m o d .

113 (1988), 337. - W o o l n e r , L . B . , W . M .

O.H. B e a h r s : J. C l i n . E n d o c r i n o l .

17 (1957),

Wo-

McConahey,

201.

Discussion Z a m r a z i l : I a g r e e w i t h c o n c l u s i o n s a b o u t g o o d e f f e c t of

pred-

n i s o n e t r e a t m e n t . W e h a v e o b s e r v e d s a t i s f a c t o r y e f f e c t of n i s o n e in our p a t i e n t s too. U n f o r t u n a t e l y w e l o s t one e i g h t y e a r s later for r e n a l f a i l u r e due to

pred-

patient

retroperitoneal

f i b r o s i s . So p r o g n o s i s of the d i s e a s e is n o t g o o d in all

cases.

V e n t z : It is d i s c u s s e d a l s o in the l i t e r a t u r e , b u t I t h i n k t i m e s the d o s e w a s to low a n d it w a s a d m i n i s t e r e d in a to p e r i o d . B u t y o u k n o w the o r i g i n , the c o u r s e is u n k n o w n a n d fore we don't have a very good

treatment.

Bergant: Did you perform frozen section V e n t z : I c a n ' t say a n y t h i n g a b o u t

it.

histology?

someshort there-

165 Management of chronic lymphocytic thyroiditis in children and adolescents 0. Hniková, J. Zikmund and M. Finková Clinic of Children and Adolescents, 3rd Medical Faculty of Charles University, Prague, Czechoslovakia Juvenile autoimmune thyroiditis (chronic lymphocytic goitrous thyroiditis, Hashimoto's disease) has been reported in the last decade as quite a common cause of nonendemic goiter also in children and adolescents /2-5/. In our outpatient ward of the Pediatric Clinic in Prague 10, we have been following 28 patients with lymphocytic thyroiditis for 1-4 years. Material and methods There were 27 girls and only one boy with this diagnosis. Twenty of them were referred to our endocrinological ambulance by district physicians for evaluation of enlarged thyroid gland not responding to thyroglobulin therapy and only two for a small firm thyroid gland. The remaining six girls were found during an epidemiological study of goiter prevalence among school children in Prague 10 in 1988. 6020 school children aged 7-14 years were examined by palpation according to WHO goiter criteria (this means grade 0, IA - B, II, III) by school pediatricians. The children who had goiter grade IB and more were sent to endocrinological examination, including hormonal levels (total T 4 ,

TSH)

and ultrasound of the thyroid gland. For RIA determination of total T4 Kosice (Slovakia) kits and for RIA TSH Henning's kits were used. In those who had irregular echotexture findings antimicrosomal antibodies by RIA kits from Henning (positive result from 500 IU/ml) and antithyroglobulin antibodies by RIA kits from Serono (positive results more than 50 IU/ml) were performed. Results Out of 22 patients who were sent to us by district physicians, as was mentioned above, subclinical hypothyroidism in 4 girls was revealed and in two girls with small firm thyroid glands overt hypothyroidism was diagnosed. One girl had slight hyperfunction by laboratory tests. Adequate TSH-TRH response in

166 s u b c l i n i c a l h y p o t h y r o i d i s m and h y p e r t h y r o i d i s m w a s p r e s e n t . s o u n d f i n d i n g s w e r e t y p i c a l for the d i a g n o s i s , w h i c h w a s

Ultra-

confirmed

with cytological observations from fine-needle aspiration.

Eigh-

t e e n out of 22 c a s e s , i.e. 82 %, h a d a p o s i t i v e e l e v a t i o n of t i m i c r o s o m a l a n t i b o d i e s a n d 13 c a s e s , i.e. 60 %, a l s o globulin antibodies.

In the g r o u p of 6020 s c h o o l c h i l d r e n

10, g o i t e r w a s r e v e a l e d in 286 c h i l d r e n , Out of t h e s e c a s e s

i.e. in 4.1 %

in P r a g u e

(figure

(figure 2) 221 c h i l d r e n h a d g o i t r e s of

IA, i.e. 77.3 %, g r a d e IB w a s f o u n d in 52 c h i l d r e n , 18.2 % a n d g r a d e II in 13 c h i l d r e n ,

PALPATION

THYROID

CHILDREN

(age

goiter

i.e.

1).

grade in

i.e. in 4 . 5 %.

EXAMINATION

7 - 14 y e a r s ) ,

revealed in 4.1 %

an-

antithyro-

IN

PRAGUE

= 286

SCHOOL 10

children

Figure 1 Palpation thyroid examination study f r o m P r a g u e 10)

The sex r a t i o

(girls:boys)

in g o i t e r

(epidemiological

IA w a s 4:1, in g r a d e IB 3:1

and 10:1 in g r a d e II. G r a d e III w a s n o t e n c o u n t e r e d . M o s t (figure 3) w e r e b e t w e e n the age of 10-14 y e a r s in b o t h

cases

sexes.

E u t h y r o i d i s m w a s d i a g n o s e d on the b a s i s of n o r m a l s e r u m t o t a l and T S H v a l u e s in all c h i l d r e n w i t h g o i t e r g r a d e IB - II. s t r u c t u r e in 55 p a t i e n t s w a s n o r m a l , b u t in 6 g i r l s w a s w i t h h y p o e c h o g e n i c and u n e c h o g e n i c loci. F i n e - n e e d l e

T4

Echo-

irregular

aspiration

167 GOITER

GRADE ( W H O ) IN FROM PRAGUE

286 10

CHILDREN

Figure 2 Goiter grade in 286 school children study from Prague 10)

GOITERS

IN

S C H OO L

(epidemiological

C H I LDREN • P R A C UE 1«. I M S

( n = 65)

•

. B grade ( W H O )

m

1.

-.JiJL.1 1 li 7

«

? 8

4

s ? 9

»$

10

Figure 3 Goiters in school children (according to sex and age)

âj

ss

11

12

$

- •• -

a^

g g

1)

14

years

168 in t h e s e six p a t i e n t s e x h i b i t e d a t y p i c a l c y t o l o g i c a l p i c t u r e of l y m p h o c y t i c t h y r o i d i t i s . A l l of t h e m w e r e g i r l s 12.8 y e a r s

old

on the a v e r a g e . A l l h a d s i g n i f i c a n t l y e l e v a t e d a n t i m i c r o s o m a l tibody t i t e r s a n d 4 of t h e m also a n t i t h y r o g l o b u l i n a n t i b o d y

an-

ti-

ters . Discussion In c h i l d r e n and a d o l e s c e n t s , c h r o n i c a u t o i m m u n e t h y r o i d i t i s

may

r e s u l t in e i t h e r g o i t r o u s H a s h i m o t o ' s t h y r o i d i t i s , w h i c h is v e r y o f t e n r e p o r t e d or a t r o p h i c t h y r o i d i t i s , w h i c h is q u i t e r a r e children.

In our g r o u p of j u v e n i l e l y m p h o c y t i c t h y r o i d i t i s

in it w a s

p r e s e n t o n l y in two g i r l s o u t of 28 p a t i e n t s . G o i t e r in j u v e n i l e l y m p h o c y t i c t h y r o i d i t i s in m o s t c a s e s d o e s n o t d i f f e r at the b e g i n n i n g f r o m s i m p l e j u v e n i l e g o i t e r by p a l p a t i o n a n d is o f t e n a s y m p t o m a t i c . U l t r a s o u n d of the t h y r o i d g l a n d as a s c r e e n i n g

me-

t h o d s h o u l d be r e c o m m e n d e d in e n l a r g e m e n t s of the t h y r o i d

gland

(grade IB and m o r e ) .

four

In our e p i d e m i o l o g i c a l g o i t e r s t u d y ,

g i r l s h a d t e n d e r g o i t e r of g r a d e IB a n d t w o of g r a d e II at the time of the d i a g n o s i s . A l l six g i r l s w e r e t r e a t e d w i t h L - t h y r o x i n e 0 . 0 5 m g / d a y b e c a u s e of t h y r o i d e n l a r g e m e n t . g i r l s , a l t e r n a t e day p r e d n i s o n t r e a t m e n t w a s also

In t h e s e 6 introduced

w i t h a 5 m g d o s e / e v e r y o t h e r day a f t e r i n i t i a l 5 d a y s ' w i t h 15 m g / d a y . A l t e r n a t e day p r e d n i s o n t h e r a p y w a s

period

terminated

after 12 m o n t h s . T h e r e w e r e no side e f f e c t s of t h i s t h e r a p y . e v a l u a t i o n of u l t r a s o u n d been discontinued, ture in 5 g i r l s

findings', a f t e r p r e d n i s o n t h e r a p y

showed remarkable improvement

in

echostruc-

(figure 4a, b and 5a, b). In one g i r l the

r o i d e c h o s t r u c t u r e d i d n o t c h a n g e at all. S e r o l o g i c a l

thy-

findings,

h o r m o n a l l e v e l s a n d c y t o l o g i c a l c o n t r o l s in the c o u r s e of y e a r ' s t r e a t m e n t w e r e the same, b u t t h y r o i d v o l u m e s

one

diminished

(-6 m l o n the a v e r a g e ) . In the g r o u p of 22 p a t i e n t s w h o w e r e r e c e i v i n g p r e d n i s o n b u t o n l y L - t h y r o x i n e , the

The

had

not

echostructure

i m p r o v e d o n l y in 7 c a s e s , w h i l e the r e s t w e r e w i t h o u t c h a n g e . c a n be c o n c l u d e d t h a t the e a r l y d i a g n o s i s of the j u v e n i l e cytic thyroiditis

It

lympho-

is p o s s i b l e w i t h u l t r a s o u n d e x a m i n a t i o n as the

b e s t s c r e e n i n g m e t h o d w i t h f i n e - n e e d l e a s p i r a t i o n of tissue under ultrasound control

thyroid

in s u s p e c t e d c a s e s . The

patients

s h o u l d be r e g u l a r l y f o l l o w e d and t r e a t e d w i t h t h y r o x i n e in all

169

F i g u r e 4a H y p o - and u n e c h o g e n i c loci of i r r e g u l a r e c h o s t r u c t u r e in a p a t i e n t w i t h l y m p h o c y t i c t h y r o i d i t i s

Figure

4b

M i l d l y h y p o e c h o g e n i c loci and s l i g h t l y i r r e g u l a r e c h o s t r u c t u r e - same p a t i e n t as in f i g u r e 4a after one y e a r ' s t r e a t m e n t w i t h L - T 4 and a l t e r n a t e day p r e d n i s o n

170

Figure 5a Unechogenic loci in a patient with lymphocytic thyroiditis

Figure 5b Unechogenic loci not present, echostructure is regular - same patient as in figure 5a after one year's treatment with L - T 4 and alterate day prednison

171 cases with overt or subclinical hypothyroidism. Alternate day prednison therapy with small doses is still controversial and would require a long-term follow up. Although it has been reported in the literature /1,4,5,7/ that some cases can recover spontaneously after several years, we only encountered one case in a four-year follow up. We would like to express our thanks to Dr. Limanovâ for her participation in the cytological examinations and valuable advice in this matter. References 1. Frey, H.: Acta Endocrinol. (Copenh.) 98 (1981), 210. 2. Chiovato, L., P. Vitti, F. Santini, G. Lopez, C. Mammoli, P. Bassi, L. Giusti, M. Tonacchera, G. Fenzi, A. Pinchera: J. Clin. Endocrinol. Metab. 71 (1990), 40. - 3. Inoue, M., N. Taketani, T. Sato, H. Nakajima: Endocrinol. Jpn. 22 (1975), 483. - 4. Maenpaa, J., M. Raatikka, J. Rasanen, E. Taskinen, 0. Wager: J. Pediatr. 107 (1985), 898. - 5. Rallison, M.L., B.M. Dobyns, R.R. Kaeting, J.E. Rail, F.H. Tyler: J. Pediatr. 86 (1975), 675. - 6. Yamada, T.: J. Clin. Endocrinol. 46 (1978), 784. - 7. Yamamoto, T., H. Sakamoto: Ann. Intern. Med. 88 (1978), 808.

172 Thyroiditis and thyroid hyperfunction V. Zamrazil, J. Nemec Institute of Endocrinology, Prague, Czechoslovakia Thyroiditis and hyperthyroidism are of particular interest of clinical endocrinologist for several reasons: 1. both diseases are common in population of many countries. In CSFR thyroiditis is the most frequent thyroid disease. 2. clinical picture and some laboratory findings are often similar; 3. interrelationships between thyroiditis and hyperthyroidism are complex and sometimes not yet fully elucidated. From this point of view one should take into account the following fact: both thyroiditis and hyperthyroidism are not defined diseases but complex of several entities with different etiopathogenetic factors, clinical course, laboratory findings and prognosis. The interrelationships of both diseases can be summarized in simplified form: 1. common autoimmune basis causes both Hashimoto's thyroiditis and Graves'-Basedow a form of hyperthyroidism; 2. hyperthyroidism is a manifestation (sometimes dominant) of thyroiditis (acute and subacute thyroiditis, postpartum thyroiditis, silent thyroiditis); 3. hyperthyroidism and thyroiditis is caused by destruction of the thyroid (actinotherapy, application od 1-131); 4. concurrent hyperthyroidism and thyroiditis are sometimes present in thyroid cancer; 5. iatrogenic hyperthyroidism develops during treatment of thyroiditis due to overdosage of thyroid hormones. Some important combinations are given in figure 1. From clinician's viewpoint, time relations in manifestations and clinical course of both diseases are important for diagnosis a treatment of patients suffering for thyroiditis and/or hyperthyroidism. For some combinations see figure 2.

INTERRELATION

AMONG

THYROID

INFLAMATION

AND

FUNCTION

Figure 1

DYNAMICS OF DEVELOPMENT O F THYREOTOXICOSIS A N D TITIS

THIS 1 1 1 1 TX

Figure 2

174 1. T h e c l i n i c a l m a n i f e s t a t i o n c a n be o b s e r v e d in the s a m e and b o t h d i s e a s e s e n d e d (figure

(are c u r e d ) at the same

time

2-1).

2. The time of c l i n i c a l m a n i f e s t a t i o n is i d e n t i c a l , b u t

after

s u c c e s s f u l t r e a t m e n t of the f i r s t d i s e a s e , the s e c o n d persists

time

(figure

one

2-II).

3. A f t e r h y p e r t h y r o i d i s m

is c u r e d , t h y r o i d i t i s o c c u r s

(figure

is c u r e d , h y p e r t h y r o i d i s m o c c u r s

(figure

2-III). 4. A f t e r t h y r o i d i t i s 2-IV). For the i l l u s t r a t i o n of some c o m b i n a t i o n s of t h y r o i d i t i s h y p e r t h y r o i d i s m a l l o w us to d e m o n s t r a t e t h r e e c a s e Case r e p o r t I

reports.

S i m u l t a n e o u s p r e s e n c e of G B TX a n d H a s h

f e m a l e , 28 y e a r s : m a n i f e s t h y p e r t h y r o i d i s m , orbitopathy painfull T4

: 250 n m o l / 1

endocrine

goiter

T3 6.8 n m o l / 1

TRH-TSH test suppressed

Treatment:

and

A R T 240 m s

antithyroglobulin

antibodies

(TgAtb) p o s . ,

antibodies

(MAtb) p o s . , T R A K p o s .

carbimazole, prednison, thyroidectomy

antimicrosomal subtotal

(STE)

Present status: therapy with T 4 ,

MATb still

pos.

Case r e p o r t II O c c u r r e n c e of H a s h d u r i n g t r e a t m e n t of G B TX f e m a l e , 24 y e a r s : m a n i f e s t h y p e r t h y r o i d i s m , m i n i m a l

orbito-

pathy T4 TgAtb

232 n m o l / 1 neg.

T3 MAtb

3.9 n m o l / 1

pos.

MAtb

pos.

P r e s e n t s t a t u s : small s o m e t i m e s p a i n f u l l treatment with T4

270 ms

neg.

4 m o n t h s a f t e r STE p a i n f u l l g o i t e r TgAtb

ART

TSH

goiter,

occured 7.8 m U / 1

175 C a s e r e p o r t III

O c c u r r e n c e of h y p e r t h y r o i d i s m t r e a t m e n t of h y p o t h y r o i d i s m by

caused

thyroiditis

f e m a l e , 42 y e a r s : c l i n i c a l h y p o t h y r o i d i s m , no T S H > 80.0 m U / 1 ART Treatment:

during

465 m s

T4

18.6

TgAtb

goiter

nmol/1

pos.

MAtb

pos.

T4

3 y e a r s later m a n i f e s t h y p e r t h y r o i d i s m , no T 4 > 250 n m o l / 1

T3

T S H ; 0.6

A R T 240 m s

mU/1

2 m o n t h s a f t e r c e s s a t i o n of T 4 T 4 > 250 n m o l / 1 ART

goiter

6.0 n m o l / 1 treatment:

T3

4.9 n m o l / 1

240 ms

a r e a c t i v i t y of T R H - T S H t e s t , TgATB

pos.

TRAK

Treatment: carbimazole,

MAtb

pos.

pos.

in p r e p a r a t i o n for

1-131

treatment As is o b v o u s f r o m p r e s e n t e d case r e p o r t s , c o m b i n a t i o n s of r o i d i t i s and h y p e r t h y r o i d i s m

thy-

involve various possibilities

at l e a s t some of t h e m are of c l i n i c a l i m p o r t a n c e .

Our

of t h i s p r o b l e m is s t i l l n o t g o o d . F u r t h e r s t u d i e s and

and

knowledge systema-

t i c e v a l u a t i o n of o b s e r v e d data s e e m s to be n e c e s s a r y . T h e

aim

of our p r e s e n t a t i o n is to call a t t e n t i o n to t h i s t o p i c . F r o m our m a t e r i a l a p r e l i m i n a r y c o n c l u s i o n s o n l y are

possible:

- s i m u l t a n e o u s p r e s e n c e of h y p e r t h y r o i d i s m and t h y r o i d i t i s relatively

is

frequent;

- m e c h a n i s m s of r e l a t i o n s h i p s are v a r i o u s , m o s t i m p o r t a n t to be c o m m o n a u t o i m m u n e - hyperthyroidism of t h y r o i d i t i s

seems

basis;

is d o m i n a n t in c l i n i c a l p i c t u r e of some (silent and p o s t p a r t u m

types

thyroiditis);

- d e v e l o p m e n t of t h y r o i d i t i s d u r i n g t r e a t m e n t of GB TX is m o s t important

combination;

- late o c c u r r e n c e of t h y r o i d i t i s d u r i n g and e v e n after

successful

t r e a t m e n t of G B TX is a strong a r g u m e n t for s y s t e m a t i c up of s u c h

patients.

follow-

176 References H a m b u r g e r J . I . : Ann. I n t e r n . M e d . 104 (1986), 219. - 2. A., S.H. I n g b a r , J.M. M c K e n z i e , G . F . F e n z i : P l e n u m P r e s s York, London),

1989. - 3. Z a m r a z i l , V. , J. N e m e c :

R a d i o t h e r . 26 (1985),

235.

Pinchers, (New

Radiobiol.

177 Clinical and laboratory evaluations of patients vith different types of thyroiditis I. Sztojka, Zs. Karanyi, A. Leovey First Department of Medicine, University Medical School, Debrecen, Hungary 171 patients (164 women (96 %) and 7 men (4 % ) aged 14-76 years) with thyroid diseases were studied. We reviewed the clinical data for all cases of thyroid disease in the outpatient clinic. Methods Thyroid function was measured with commercial available kits: T 4 , TSH by radioimmunoassay, T3~resin uptake, anti-thyroglobulin antibodies by tanned erythrocyte haemagglutination technique, antimicrosomal antibodies by complement fixation test. Radioactive iodine uptake (RAIU) with scan and fine needle aspiration cytology was performed without local anaesthetic using a 21 gauge needle on a 10 ml disposable syringe mounted in a syringe holder. The smears were stained using the May Griinwald Giemsa technique. Results 135 patients presented with Hashimoto's thyroiditis (132 women (97.8 %) and 3 men (2.2 %). Diagnosis of Hashimoto's thyroiditis was based on the positive tests for thyroid microsomal and thyroglobulin autoantibodies and cytological features by fine needle aspiration. De Quervain (subacute) thyroiditis was diagnosed in 6 patients (4 women (66.7 %) and 2 men (33.3 %)) by characteristic clinical features and fine needle biopsy. 8 patients (8 women) fit the criteria of "silent" thyroiditis with low RAIU and a nontender thyroid gland with hyperthyroidism, 20 patients presented with a clinically isolated nonneoplastic thyroid swelling (18 women (90 %) and 2 men (10 %)). Of the swellings 18 were solid on aspiration and 2 yielded fluid and were termed cystic. 2 patients with isolated swelling presented carcinoma (2 women) (figure 1). Average of patients were estimated when the diagnosis was discovered (figure 2). Hashimoto's thyroiditis: 33.5, subacute thyroiditis: 36.5,

"silent": 37.1 year. RAIU in Hashimoto's

178 thyroiditis was normal

(72 c a s e s

and elevated

(13 % ) ) . All p a t i e n t s w i t h s u b a c u t e

(17 c a s e s

(55.4 % ) low

(41 c a s e s

r o i d i t i s and "silent" t h y r o i d i t i s s h o w e d v e r y low

(2 % or

R A I U . It r e t u r n e d to n o r m a l in all p a t i e n t s in w h o m we in the

(31 % ) ) thyless)

repeated

recovery.

struma nodosa 12.8 %

Hashimoto 79 %

"silent" 4.7 % DeQuervain 3.5 %

Figure 1 D i a g n o s i s of

patients

We i n v e s t i g a t e d the s c a n in the p a t i e n t s w h e n it w a s

possible

(normal or e l e v a t e d R A I U ) . H a s h i m o t o ' s t h y r o i d i t i s u s u a l l y ed "scanty" scan

(91 c a s e s

(69.5 % ) ) or c o l d n o d u l e

(19 % ) ) , b u t s o m e t i m e s

"warm" n o d u l e

(7 c a s e s

thyroid gland

(3 % ) ) c a n be

seen.

(4 c a s e s

(25 c a s e s

(5.3 % ) ) , or

T h y r o i d m i c r o s o m a l and t h y r o g l o b u l i n a u t o a n t i b o d i e s w e r e ed at the d i s c o v e r y of d i s e a s e and a f t e r f o l l o w i n g the

disease

l e v e l . M e a n v a l u e w a s 98 U at the b e g i n n i n g

(normal

estimatelevated of

16 or l e s s ) , a f t e r the t r e a t m e n t d e c r e a s e d

15.6 U. P a t i e n t s w i t h s u b a c u t e t h y r o i d i t i s s h o w e d n o r m a l a n t i b o d y level

(12-6 U ) , and in c a s e s w i t h " s i l e n t "

normal

patients

(figure 3). H a s h i m o t o ' s t h y r o i d i t i s is c h a r a c t e r i z e d b y autoantibody

show-

to

auto-

thyroiditis

the m e a s u r e d w e r e e l e v a t e d a l i t t l e , a v e r a g e v a l u e w a s 36 U to 7.7 U. L a b o r a t o r y

f i n d i n g s of t h y r o i d f u n c t i o n at the t i m e of

179 Average (year]

39.6 39.1

38.8

40 39 38 37 36 35

Hashimoto

DeQuervain

'silent'

Different t y p e s of thyroiditis

Figure 2 A v e r a g e of p a t i e n t s w i t h d i f f e r e n t t y p e s of

thyroiditis

antibody level [U]

Hashimoto

DeQuervain

"silent'

Different t y p e s of thyroiditis Figure 3 T h y r o i d m i c r o s o m a l and t h y r o g l o b u l i n a u t o a n t i b o d y in d i f f e r e n t type of t h y r o i d i t i s

level

180 d i a g n o s i s in H a s h i m o t o ' s t h y r o i d i t i s : T 3 U w a s 0 . 9 4 , T 4 R I A w a s 105.7 n m o l / 1 . T S H - R I A w a s 4.1 m U / 1 . P a t i e n t s w i t h s u b a c u t e

thy-

r o i d i t i s p r e s e n t e d : T 3 U 1.2, T 4 R I A 178 n m o l / 1 , T S H - R I A 3.8 m U / 1 . C a s e s w i t h " s i l e n t " t h y r o i d i t i s s h o w e d : T 3 U 1.02, T 4 R I A nmol/1, TSH-RIA

D u r i n g the f o l l o w i n g e x a m i n a t i o n s s o m e t i m e s the p a t i e n t s altered thyroid functions both hyperthyroidism and (table

152

1.32 m U / 1 . showed

hypothyroidism

1).

Fine n e e d l e a s p i r a t i o n b i o p s y w a s p e r f o r m e d 171. The a s p i r a t e s w e r e c l a s s i f i e d

in 158 p a t i e n t s

into four c a t e g o r i e s :

from

features

of c h r o n i c l y m p h o c y t i c t h y r o i d i t i s , m o n o l a y e r e d s h e e t s w i t h flammation,

"possible neoplastic"

in-

increased cellularity and va-

r i a t i o n in n u c l e a r size, f e a t u r e s of i n f l a m m a t i o n w i t h g i a n t cells

(figure

4).

D u r i n g e v a l u a t i o n of the s m e a r s 68 w e r e c h r o n i c l y m p h o c y t i c r o i d i t i s , 72 s h o w e d c y t o l o g i c a l f e a t u r e s of i n f l a m m a t i o n , "possible neoplastic"

1 yielded fluid and were termed

and 1 w a s i n s u f f i c i e n t . giant

thy-

9 were

cystic,

7 s h o w e d f e a t u r e s of i n f l a m m a t i o n

with

cells.

T a b l e 1: C l i n i c a l s t a t e of t h y r o i d f u n c t i o n in d i f f e r e n t t y p e s of t h y r o i d i t i s T y p e s of thyroiditis

Thyroid

function

Transient Euthyr. Transient hyperthyr. hypothyr. Hashimoto 1 s

21

97

Subacute

5

1

"silent"

8

_

Hypothyr.

2

15

_

_

No of p t s 135 6 8

181 No.of patients

50

40 30 20 10

0

1 chronic lymphocytic thyroiditis

^

1 features of inflammation

^

1

^

1

'

possible inflammations with neoplastic with Giant cells

Evaluations of smears

Figure 4 Cytological evaluation of thyroid fine needle biopsy

Discussion Hashimoto's thyroiditis is the most common cause of hypothyroidism. It is believed to result from a derangement of immune system. Alterations of both cell-mediated immunity and humoral immunity have been proposed /1,13/. The most important characteristics of Hashimoto's thyroiditis are the lymphocytic infiltration of the gland. Fine needle aspiration cytology is used to exclude malignancy without excision and histologies examination. Extensive experience in Sweden /9/ and other centers suggests an accuracy of over 90 %. Thyroxin therapy is usually recommended for hypothyroid patients with Hashimoto's thyroiditis because the thyroid gland is progressively destroyed, with a permanent defect in thyroid hormonogenesis /2,3/. In our study 97 from 135 patients remained euthyroid and only 15 did not recover thyroid function, and need thyroxin therapy.

182 The main problem with Hashimoto's thyroiditis is the painful, enlarged thyroid gland. 125 patients from 171 received nonsteroid antiinflammatory drugs, and 43 patients need steroid therapy during some weeks to two months. Patients with subacute thyroiditis received antibiotic therapy during the febris and two patients were needed short time methimazol therapy against hyperthyroidism. An interesting problem is the "silent" thyroiditis. Several authors have noted the same or a similar disease recently and have suggested a number of names, including silent or atypical subacute thyroiditis /10, 12/, thyrotoxicosis with painless thyroiditis /14/, hyperthyroiditis as a diagnostic pitfall /8/, as well as a postpartum thyroiditis /5/. It need to emphasize that it occurs as a spontane resolving or transient hyperthyroidism with low RAIU and features of thyroiditis by cytological or histological or histologies examinations. It needs to be recognized and differentiated from other forms of hyperthyroidism, and need to be careful receiving definitive, ablative thyrostatic therapy /ll/. The relationship between this form and Hashimoto's thyroiditis is unknown, the low male-to-female ratio /4/, the relatively low family history of thyroid disease /6/, and the normal or a little elevated antithyroid antibody titer suggest differences from Hashimoto's thyroiditis. In our series we

could not describe about acute suppurative thyroiditis

and Riedel's thyroiditis /7/. Appearance of these is rare, during our investigation there was none of them. References 1. Brown, J., D.H. Solomon, G.N. Beall: Ann. Intern. Med. 88 (1978), 379. - 2. Buchanan, W.W.: Arch. Intern. Med. 115 (1965), 411. - 3. De Groot, L.J.: The thyroid and its disease. 4th ed. New York; Wiley (1975), 405. - 4. Furszyfer, J.: Metabolism 21 (1972), 197. - 5. Ginsburg, J.: Lancet 1 (1977), 1125. - 6. Heinman, P.: Acta Med. Scand. 179 (1966),

183 113. - 7. Al-Hilaly, M.A.: Acta Chir. Scand. 156 (1990), 237. - 8. Jackson, I.M.D.: N. Engl. J. Med. 293 (1975), 661. - 9. Lowhagen, T.: Surg. Clin. North Am. 59 (1979), 3. 10. Morrison, J., R.H. Caplan: Arch. Intern. Med. 138

(1977),

45. - 11. Nikolai, T.F.: Arch. Intern. Med. 140 (1980), 478.12. Papapetron, P.D., I.M.D. Jackson: Lancet 1 (1975), 361. 13. Volpe, R., M. Edmonds: Lamki Mayo Clin. Proc. 47 (1972), 824. - 14. Wool, P.D.: Am. J. Med. 60 (1976), 73.

184 Hashimoto-Thyroiditis with long-term negative auto-antibody determination: a case report Marie-Luise Weiss, A. Blottner, H.F.Deckart Klinik fiir Nuklearmedizin und Endokrinologie, Klinikum Berlin-Buch, Germany Introduction The incidence of Hashimoto-thyroiditis as a classical autoimmune disease of the thyroid has, as epidemiological studies have shown, considerably increased and it is more frequently diagnosed /8/. Pathogenetically the primary disturbance is based on a defect of the suppressor cell-T-lymphocytes, according to the hypothesis advanced by Volpe /IO/. Thus,clones originated through mutation cannot be eliminated by autoaggressive helper-T-lymphocytes

("forbidden clones"). They

initiate both humoral and cellular immune processes. Clinically, two courses of Hashimoto-thyroiditis have been observed: I. hypertrophic thyroiditis with occasionally rapidly growing goitre, functionally often euthyroid, a number of the cases was marked by hypothyroidism, occasionally a hyperthyroid stage is initially found. II. atrophic thyroiditis with absence of goitre, the patients have no complaints for long periods of time as long as symptoms of hypothyroidism appear. An important diagnostic procedure for Hashimoto-thyroiditis is the determination of auto-antibodies against thyroidbinding globulin (TAK) and thyroid microsomes (MAK) /I/. The simultaneous incidence of both antibodies with high titres has an important diagnostic value for Hashimoto-thyroiditis. Low-titrated or even absent thyroid auto-antibodies do not exclude autoimmunothyroiditis. The following case report demonstrates a phase-like progress of auto-antibody titres over an observation period of 11 years with an almost unchanged cytomorphological finding of florid Hashimoto-thyroiditis of the clinically hyperplastic form with an euthyroid course.

185 The p r e s e n t case r e p o r t is c o n s i d e r e d to be a

contribution

to the d i s c u s s i o n on p a t h o g e n e s i s and d i a g n o s t i c for

strategies

Hashimoto-thyroiditis.

M e t h o d s of

investigation

T h e t h y r o i d fine n e e d l e p u n c t u r e w a s p e r f o r m e d u s i n g

the

puncture-smear- and staining technique described earlier MAK-antibodies were determined using a commercial test Wellcome, passive haemagglutination)

/ll/.

(Fa.

semiquantitatively.

TAK-antibodies were quantitatively measured using a radioi m m u n o l o g i c a l m e t h o d /2/, c a l i b r a t e d a c c o r d i n g to

standard

A 6 5 / 9 3 of the M e d i c a l R e s e a r c h C o u n c i l , w h i c h c o n t a i n s

per

definitionem

exa-

1 m e g a u n i t per 1 litre

(MU/1). P r o g r e s s i v e

m i n a t i o n s of a u t o a n t i b o d i e s w e r e c a r r i e d out of the same boratory under identical

la-

conditions.

P a t i e n t data and r e s u l t s of the

study

The f e m a l e p a t i e n t St. H., b o r n on J a n u a r y

15, 1919 w a s

59

y e a r s old, w h e n she u n d e r w e n t h e r i n i t i a l e x a m i n a t i o n at our c l i n i c in 1978. T h y r o i d d i s e a s e s w e r e u n k n o w n in the

medical

h i s t o r y of h e r f a m i l y . The p a t i e n t r e t i r e d w i t h a p e n s i o n to m i t r a l s t e n o s i s of d e g r e e III w i t h a s l i g h t a o r t i c

due

insuf-

f i c i e n c y . For 3 m o n t h s the p a t i e n t h a d o b s e r v e d t h y r o i d

en-

l a r g e m e n t i n v o l v i n g a g l o b u s f e e l i n g , w h i c h g a v e r i s e to h e r v i s i t to the t h y r o i d o u t p a t i e n t - d e p a r t m e n t .

The p a t i e n t w a s

c l i n i c a l l y e u t h y r o i d at the initial e x a m i n a t i o n . B o t h

thyroid

l o b e s w e r e p a l p a t o r i l y e n l a r g e d , a b o v e the j u g u l u m a n d in the a r e a of the r i g h t t h y r o i d lobe t h e r e w e r e t o u g h n o d u l e s

pal-

p a b l e . The t h y r o i d s c i n t i g r a m of M a r c h 21, 1978

1)

(figure

revealed nodular goitre with inhomogeneous nuclide

distribu-

t i o n in b o t h l o b e s and a r e p r e s e n t a t i o n of c o l d n o d u l e s the i s t h m u s r e g i o n a n d of the r i g h t t h y r o i d lobe

centrally.

The fine n e e d l e p u n c t u r e of the i s t h m u s n o d u l e and the l o c a t e d in the r i g h t lobe, c a r r i e d out on M a r c h 31, yielded

(puncture-No.

134/78 A/B) the f o l l o w i n g

f i n d i n g s : The c y t o l o g i c s m e a r s o b t a i n e d f r o m

in nodule

1978,

cytologic

scintigraphically

186

Figure 1 T h y r o i d s c i n t i g r a m w i t h 37 M B q T c - 9 9 m enlarged, bilobular thyroid with inhomog e n e o u s s t o r a g e p a t t e r n , cold n o d u l e s in i s t h m u s r e g i o n a n d c e n t r a l l y l o c a t e d in t h e r i g h t t h y r o i d lobe cold n o d u l e s of the r i g h t t h y r o i d lobe and the i s t h m u s ,

re-

v e a l s i m i l a r p i c t u r e s . H o w e v e r , the p u n c t u a t e d s a m p l e of

the

i s t h m u s n o d u l e c o n t a i n s c o n s i d e r a b l y m o r e c e l l s . The

smears

are c h a r a c t e r i z e d by c o l o r f u l ,

cell

inflammable appearing

pictures with oncocytes, degeneratively altered

thyrocytes,

p y k n o t i c t h y r o c y t e s , c y t o l y s e s and a c o n s i d e r a b l e n u m b e r g r o u p - c e l l a n d s i n g l e cell n e c r o s e s , a p a r t f r o m t h i s , n o r m a l t h y r o c y t e s . T h e r e are l a r g e n u m b e r s of

of

also

lymphocytes

a n d l y m p h o b l a s t o m a s as w e l l as some p l a s m a - c e l l s - c y t o l o g i -

cally the typical picture consists of florid Hashimoto-thyroiditis - group II (figure 2).

Figure 2 Cytological findings of fine needle punctuated sample of Hashimoto-thyroiditis 2a: Complex of oncocytes and cell necrotic focus

2b: Lymphocytes and lytic thyrocytes

188 The fine needle puncture was repeated twice during the observation period (table): 1983 the isthmus nodule was punctuated (puncture-No. 737/83) and in 1989 the isthmus nodule as well as a sonographically established echo-poor region in the left thyroid lobe was punctuated

(puncture-No. 434/89 A/B). The

cytological findings of the different localizations revealed the picture of florid Hashimoto-thyroiditis; compared to the initial examination of 1978 there was no change of the cytological picture.

Table: In vitro and cytological results in the follow up of 11 years (patient St. H.) Date

T3

nmol/1

TSH mU/1

11.07. 78 13.05. 80

Tg-AK

Ms-AK Titer

Cytology

IE

neg.

neg.

Hashimoto-th.

neg.

neg.

neg.

neg.

14.04. 81

1.1

13.10. 81

1.0

neg.

neg.

15.11. 82

1.7

neg.

1:25000

13.10. 83

2.6

29.04. 85

3.0 1.7

3000 14000

1:409600 1:409600

2.6

20000

1:25600

neg.

1:6.5Mi11.Hashimoto-th.

neg.

1:6.5Mill.

30.03. 87 01.02. 88

2.4

13.06. 89

2.9

03.10. 89

4.4

1.6

Hashimoto-th.

The cytological findings gave rise to the determination of TAK-antibodies and MAK-antibodies (table). Both results were negative and also the medical check-ups produced negative results in the following years until 1981. Only 4 years after cytological diagnosis of Hashimoto-thyroiditis MAK-antibodies occurred in the lower titre region, which remained constant in further annual medical check-ups, but were detectable

189 with variable titre levels. Lower TAK-values were present the f i r s t t i m e in the 7 t h y e a r a f t e r i n i t i a l d i a g n o s i s ; r o s e s o m e w h a t in the 9th and 10th y e a r , w h e r e a s the

for

they

TAK-value

b e c a m e n e g a t i v e a g a i n at the 11 t h y e a r . D u r i n g the o b s e r v a t i o n p e r i o d two t h y r o i d s o n o g r a m s of

the

p a t i e n t w e r e p e r f o r m e d : on M a y 13, 1980 - b o t h t h y r o i d

lobes

revealed a homogeneous reflex pattern,

in the i s t h m u s a solid

e c h o - r i c h n o d u l e w a s f o u n d ; on A p r i l 4, 1989 - e c h o - p o o r g i o n in the r i g h t t h y r o i d lobe, i n h o m o g e n e o u s ,

almost

re-

echo-

n o r m a l n o d u l e in the i s t h m u s , n o r m a l e c h o s t r u c t u r e in the l e f t t h y r o i d lobe

(figure 3). The p a t i e n t r e c e i v e d

thyroid

h o r m o n e s d u r i n g the w h o l e o b s e r v a t i o n p e r i o d . For t h i s a scintigraphical

progressive control was not

possible.

SD-I VER
- t f i i i

ill

i

III

I

i I U h U Î i U h ni l i l l l i i ) III il Hi ti I I

Ih I U l u l i l i „„ l l l i i u i r , I I ¡I n li illl u l l l l 11 llll a l l : i l i l l l ; i l linn I Uhi i l i li il i n , j|| I, ihih hi i m ii in111 ii m i m i È H M i f l i i I u Hi I imi i l i i I hi I

It ii

I m

n

il

mill

liliiil

u

n H u m

linilllntrtiHill

III

u

substitution.

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•

kihlpllHI

i i i i i i . ^ $ h i i i i Ê i é h i

l i i

iiiiimn

i

u n

u

n

ii nu I ii m. i m . u m i l i a m i m m m m u h n i i i 11 mini n m 'i i; n i l ii n u n i m m i i h u m m u m m m i i m m i 11 I M i u i i i m M i i i i i i m u i HHIHIMIIÌIIIII II H ii I 1ì

immillili NU limi) I T I IL MI IL I m i M È M J I I MIMI

h m 11 i n mi li l i i n u m i l i H i i i

0i ii I i n i unii 11 u r n tumulami imi i m i

Il

A mini M

l a w I M I H "H I mi m h mimili I a mi

n u n im imi in i iiiiiiiiiuiiiimnimiiiiii 1111

11

Figure 4 Scan extreme low p e r t e c h n e t a t e

uptake

200

O O f-H ß -H X o M >i fi E-i 1 hi

o in rH

S-l 0) fi (-i

ra

e* o

in

oo

o

o T

>1 0.

•o tH •H 0 1 0 •H O •p o> M \ o X o

r

r^

i-H 0 E-i E E-i ß

«

W m

0)

+>

ra

p

IO r-

•

i—i i—i

IO

CM VD f-H

in

lO •

•

I—1

CN O rH

E E

rH m

m

CM

en •

CM

\

in oo

03 m S in CN

\

\

o cri

o ai

o Ol

i—t o>

o l"H

o «—i

l-H

O

l-H O

n o

' •

in o

•

lO O

in CM

o rH

•

rH Ol

\

•o -rH O U •H 4-> VH O o

CM CM

O f-H

•

Figure

7a

Figure

7b

Figure 7 U l t r a s o u n d shows d i f f u s e e c h o p o o r p a t t e r n w i t h s m a l l n o d u l e at the b e g i n n i n g of the d i s e a s e (7a u n c h a n g e d after 6 m o n t h s (7b)

ase

II:

. Granulomateous cells

t h y r o i d i t i s w i t h epitlieloid

203

*

\

1

Mi Ü tiff, a. • Ä m

.

fjti

^feta.

* i«

v'r 1

® k

2. C o n c e n t r a t i o n of l y m p h o i d c e l l s and c e l l lysis represent chronic-lymphocytic thyroiditis Hashimoto

204

3. Control puncture one year after. Detritic cells and lymphoid cells representing thyroiditis Hashimoto. Cytologic parameter of thyroiditis de Quervain are not more visible Conclusion Presentation of rare cases of combined form of Hashimoto' and de Quervain's thyroiditis, cytological verified, lead to hypothyroidism. Reference 1. Lenng, A.K., K. Hegde: J. Adolese Health Care 9 (1988) 434.

205 Occurrence of goitre and diffuse lymphoid thyroiditis (DLT) in secondary school adolescents in Bratislava J. Podoba, P. Hnilica, M. Srbecky Postgraduate Medical Institute, Bratislava, CSFR Prophylaxis of endemic goitre by iodinated salt has been implemented in Czechoslovakia since 1947, resp. 1951. The original dose of KI was increased two times. Since 1965 common salt contains 25 mg Kl/kg. This prophylactic measure has yielded remarkably good results /1-3/, nevertheless some authors in our country have recently argued for a more intensive prophylactic programme /4,5/. Similarly as in several other countries with iodine prophylaxis of endemic goitre /6-8/, the incidence of DLT keeps increasing also in the CSFR. In light of these conditions we decided to establish the following parameters in adolescents aged 14.5. - 18 year in Bratislava: 1. occurrence rate of goitre by palpation and inspection; 2. mean thyroid volume ultrasonographically; 3. involvement rate of DLT in the occurrence of goitre. Subjects and methods Series 1: Subjects: 358 boys (B), 360 girls (G) from five secondary schools in Bratislava. Age: range 14.5 - 18 years, mean 16.1 y (B), 16.1 y (G), median 16.0 y (B), 16.0 y (G). Body weight: mean 65.4 kg (B), 56.0 kg (G), median 65.0 kg (B), 56.0 kg (G). Examination methods: inspection, palpation, ultrasonography. USG equipment used: real time grey scale scanners using 7, 7.5 and 10 MHz transducers. Series 2: Subjects: 13 boys and 44 girls - outpatients with Gr. I goitre.

206 A g e : same as in s e r i e s Examination methods:

1.

i n s p e c t i o n , p a l p a t i o n , fine

needle

biopsy. D e f i n i t i o n and c l a s s i f i c a t i o n of g o i t r e WHO 1960, m o d i f i e d a c c o r d i n g to D e l a n g e Gr.

(Perez et

al.,

/9/)>

0

- goitre

0a

- thyroid not

absent

Ob

- thyroid palpable, but lobes not exceeding

palpable the

size of the t e r m i n a l p h a l a n x of the t h u m b in the subject Gr.

I

examined

- g o i t r e p a l p a b l e , n o t v i s i b l e at n o r m a l

position

of the n e c k

Gr.

la

- n o t v i s i b l e at h y p e r e x t e n d e d

lb

- v i s i b l e at h y p e r e x t e n d e d

II III

neck

neck

- g o i t r e v i s i b l e at n o r m a l p o s i t i o n of the

neck

- v e r y l a r g e g o i t r e , v i s i b l e f r o m the d i s t a n c e

of

10 m

V o l u m e of the t h y r o i d w a s c a l c u l a t e d a c c o r d i n g to B r u n n et al. / 1 0 / . D L T d i a g n o s i s w a s e s t a b l i s h e d by m e a n s of tion cytodiagnostics

aspira-

( c r i t e r i a a c c o r d i n g to P e r s s o n ) .

Fine

n e e d l e b i o p s y w a s p e r f o r m e d o n l y in p a t i e n t s w i t h Gr. I goitre. Results Tables

la, lb g i v e the r e s u l t s of p r e v a l e n c e of g o i t r e

t h y r o i d v o l u m e p a r a m e t e r s in a d o l e s c e n t s ,

and

In b o y s g o i t r e

was

f o u n d in 2.0 %, p a l p a b l e t h y r o i d n o t m e e t i n g the c r i t e r i a be c l a s s i f i e d as g o i t r e in 21.5 %

(Gr. Ob). T h e m e a n

v o l u m e w a s 11.2 m l , the m e a n r e l a t i v e t h y r o i d 0.17 m l / k g . In g i r l s g o i t r e w a s i d e n t i f i e d

to

thyroid

volume

in 11.2 % of

the

s e r i e s 1, p a l p a b l e t h y r o i d n o t c l a s s i f i e d as g o i t r e in 26.5 % (Gr. 0b). T h e m e a n t h y r o i d v o l u m e w a s 8.4 ml, the m e a n tive t h y r o i d v o l u m e 0 . 1 5 m l / k g . The m e a n r e l a t i v e volume was statistically

significant higher

rela-

thyroid

in b o y s

compared

207 to g i r l s

(p < 0 . 0 0 1 ) . In b o t h s e x e s a p o s i t i v e

w a s e s t a b l i s h e d b e t w e e n t h y r o i d v o l u m e and b o d y

correlation weight.

T a b l e la: P r e v a l e n c e of g o i t r e and t h y r o i d v o l u m e in m a l e a d o l e s c e n t s Boys

n = 358

Diffuse goitre gr (palp.)

Occurrence rate (%)

thyroid volume (ml) median mean s

parameters

mean relative thyroid volume (ml/kg)

0a

76.5

10.7

11.0

0.2

0.17

0b

21.5

11.1

11.6

0.5

0.17

la

1.4)

13.3

13.1

1.7

0.19

17.1

17.1

0. 1

0.26

lb

0.6)

2

'°

m e a n t h y r o i d v o l u m e 11.2 + 0.2 ml m e a n r e l a t i v e t h y r o i d v o l u m e 0.17 +_ 0.02 m l / k g No c a s e of d i f f u s e g o i t r e gr II or III nor of n o d u l a r was detected.

T a b l e lb: P r e v a l e n c e of g o i t r e and t h y r o i d v o l u m e in f e m a l e a d o l e s c e n t s

goitre

parameters

Girls

n = 360

Diffuse goitre gr (palp)

Occurrence rate (%)

thyroid volume (ml) median mean s

0a

62.2

7.7

8.0

0.2

0.14

0b

26.6

8.2

8.6

0.3

0.16

mean relative thyroid volume (ml/kg)

la

6.4)

8.8

9.2

0.7

0. 17

lb

4.7)

9.6

11.4

1.0

0.21

m e a n t h y r o i d v o l u m e 8.4 +_ 0.1 ml m e a n r e l a t i v e t h y r o i d v o l u m e 0.15 +_ 0.02 m l / k g A s i n g l e case of d i f f u s e g o i t r e gr II w a s r e c o r d e r e d , c a s e of gr III or n o d u l a r g o i t r e w a s d e t e c t e d .

no

208 Fine n e e d l e b i o p s y and c y t o l o g i c e x a m i n a t i o n w a s in 57 o u t p a t i e n t s goitre

performed

(aged 14.5 - 18 y) w i t h gr. I d i f f u s e

(table 2). Of the 13 b o y s e x a m i n e d DLT w a s

established

in 5 (38 %) and of the 44 g i r l s in 25 (56.8 % ) . F r o m the v a l e n c e of gr. I g o i t r e in s e r i e s 1 and f r o m the D L T

pre-

ratio

in s e r i e s 2 the m i n i m a l o c c u r r e n c e r a t e of D L T in the

popula-

t i o n of a d o l e s c e n t s a g e d 14.5. - 18 y e a r s w a s c a l c u l a t e d

to

be 0.8 % in b o y s and 6.3 % in g i r l s . D i s c u s s i o n and

conclusion

In the p e r i o d of l a s t 20 y e a r s of iodine p r o p h y l a x i s

only

sporadic locally orientated epidemiologic studies were r i e d out a s s e s s i n g the p r e v a l e n c e of g o i t r e in

adolescents

in C S F R / 4 , 5 / . T h e a u t h o r s r e p o r t e d a 24 - 40.7 % of gr. I g o i t r e in c h i l d r e n and a d o l e s c e n t s

car-

prevalence

in o r i g i n a l

m i c a r e a s and a r g u e d for a m o r e i n t e n s i v e p r o p h y l a c t i c

endepro-

g r a m m e . On u s i n g the c l a s s i f i c a t i o n a c c o r d i n g to P e r e z et al. (WHO 1960), our r e s u l t s p r o v e d to be m o r e o p t i m i s t i c .

While

in a d o l e s c e n t g i r l s the p r e v a l e n c e of g o i t r e w a s s t i l l to be c l a s s i f i e d as e n d e m i c , b o y s e x h i b i t e d o n l y m i n i m a l rate. The f i n d i n g of a s t a t i s t i c a l l y

occurrence

significant higher

r e l a t i v e t h y r o i d v o l u m e in b o y s c o m p a r e d to g i r l s w a s s u r p r i s i n g . On c o n s i d e r i n g the h i g h e r f o o d i n t a k e haps relatively

i n c r e a s e d iodine s u p p l y )

mean

however

(and p e r -

in b o y s this

finding

m i g h t be a c c o u n t e d for by the p r e s e n c e of some new as y e t unknown nutritional goitrogens.

In a d o l e s c e n t g i r l s D L T

v e d to h a v e a h i g h o c c u r r e n c e : m i n i m a l l y 6.3 % of the s u b p o p u l a t i o n is a f f e c t e d . The i n v o l v e m e n t of b o t h and p o t e n t i a l e n v i r o n m e n t a l of D L T s h o u l d be

f a c t o r s in the

investigated.

pro-

given

genetic

ethiopathogenesis

T a b l e 2: R e s u l t s of fine n e e d l e b i o p s y a n d c y t o l o g i c e x a m i n a t i o n in s e r i e s 2 of 57 o u t p a t i e n t s w i t h d i f f u s e g o i t r e gr. I Boys

Girls

Total DLT

13 5 (38 % )

Total DLT

44 25

(56.8 % )

References 1. P o d o b a , J., R. ¿ t u k o v s k y : A c t a e n d o c r . p a n a m e r . 3 (1972) 1935. - 2. P o d o b a , J., R. R e i s e n a u e r :

In: S c h i l d d r ü s e

(Eds. S c r i b a , P . C . , K.H. R u d o r f f , B. W e i n h e i m e r ) ,

Stuttgart

Thieme Verlag,

1982, 239. - 3. G u t e k u n s t , R., P.C.

J. E n d o c r i n o l .

I n v e s t . 12 (1989), 209. - 4. F e l t , V.,

K r e m e n o v a , J. B e d n a r : Exp. C l i n . E n d o c r i n o l .

Scriba:

66 (1988),

6. J e n s c h , E. et al.: Dt. m e d . W o c h e n s c h r .

104 (1979),

857. - 8. M ä e n p ä ä , J. et al.: J. P e d i a t r .

749. 838.

126 (1985),

107 (1985),

9. T h i l l y , C.H. et al.: In: E n d e m i c G o i t e r a n d E n d e m i c tinism

J.

86 ( 1 9 8 5 ) , 2 0 7 .

5. T a j t ä k o v ä , M. et a l . : K l i n . W o c h e n s c h r .

7. S t u b b e , P. et al.: M ü n c h . M e d . W o c h e n s c h r .

1981

869. Cre-

(Eds. S t a n b u r y , J.B., B.S. H e t z e l ) , NY, J. W i l e y ,

1980, 155. - 10. B r u n n , J. et al.: Dt. m e d . W o c h e n s c h r . 106 (1981),

1338.

210 Spontaneous course of Graves' Basedov's disease into hypothyroidism (case report) Eva Deckart Klinikum Berlin-Buch, Clinic for Nuclear Medicine and Endocrinology A 50 years old woman suffered from an acute virus-infection in July 1989. After reconvalescence symptoms as tachycardia, tremor, arthralgia persisted. Clinical examination: At her first visit in our outpatient department she demonstrated typical symptoms of severe thyrotoxicosis with general weakness, loss of concentration ability. No signs of endocrine-immunogenic orbito- or dermatopathy. The diagnosis of an immunogenic hyperthyroidism was verified by high pertechnetate uptake in normally sized thyroid gland, a diffuse echopoor pattern in thyroid ultrasound, an increase of TRAK and pathologic hormone parameters (table, figure 1). The patient was treated with low doses of Methimazole (15 mg/d at onset, rapidly decreased to 2.5 mg/d). 10 weeks later recurrence of hyperthyroidism occured, treated symptomatically with 6-blocking agent. Signs of beginning cardial decompensation initiated again Methimazole treatment beginning with 5 mg/d reduced to 2.5 mg/d. Further selftreatment without physician's consultation up to November, 1990. Again she visited the outpatient department in a state of severe hypothyroidism: At that time scintigraphy control showed no pertechnetate thyroid uptake at all. In ultrasound the diffuse echopoor pattern at onset had changed into homogeneous echonormal tissue characterization without loss of thyroid size (figure 2).

211

rH

O z N n) = E •H ß •P = = ai s Ol 01 OI E E E in • in in CS

a. m u a)

•C

m < rH « \ H 3 •H N

«

< Ol H E

•rH


1 • a. OO m i-H M a)

ai -H • -P a) c . aj -o g co -h H u f £ M SC C ra ai è m f í o U O M M ra •rt M -P - a) ra m- -p ë i ra 53 -"H rH -p

i o o -rf o m a)

en >i co

M

S

e 8-5 dl B H

îï ¿

•h ra N -g ai -h l(

B w m 3

^ m m 4J S

M

g..

I

n a

Ü-S

»

231

Sporadic MTC Primary tumor size and occurrence of LNM (n = 47) 25 I no LNM V)

20H

c

15-

o

1 J

I with LNM

aCO 1 0 -

5H

H r

>

J§ •+•> c — 0) 3 •-< •P v) e 0) Cu w « r o « * Bin —< O g g

3 "O V

Cancer

c intigraphy

ü u o e. I-J O.

£

ja

o W

—

0 - M VI fS3 01 c •H

5 2 •p v — CD TSE


E 0) 0) 1 o 1-

3

?

«

1 S

.2 5 «•»•> .ü g — t* « a> u -•-> —)

2000

>2000

41

sister

150

204

>2000

>2000

—

sister

146

>2000

>2000

>2000

4

brother

180

>2000

>2000

>2000

105

basal

Calcitonin (ng/1) stim.5 min stim.10 min

CEA (/ug/1)

—

Although DMSA scintigraphy of the neck was normal in the case of the 2 sisters, higher concentration of DMSA were detected in the liver. We found lesions in the thyroid on Tc-

328 scintigraphy. Both were found to have MTC, once in the stage T215. Significantly high DMSA concentrations were detected in 2 regions of the brothers thyroid, which were obvious as defects on scintigraphy with Tc. He was also found to be suffering from MTC (T3 b ) (figure 3).

Figure 3 Positive DMSA scintigraphy in cold lesions of thyroid by Tc-scintigraphy and MTC 5 of 6 nieces and nephews had abnormal calcitonin levels. DMSA scintigram, however, showed no evidence of possible pathological changes.

329 Our r e s u l t s s u p p o r t the n e c e s s i t y of f a m i l y s c r e e n i n g in M T C . The e x c l u s i o n of g e n e t i c a f f e c t i o n by g e n e m a p p i n g c o u l d fine the n u m b e r of b l o o d r e l a t i v e s , w h i c h w e h a v e to

con-

screen

b y c a l c i t o n i n . T h e o t h e r s we w o u l d save f r o m l i f e - l o n g

inse-

c u r i t y and w o r r y . Reference P o n d e r , B . A . J . : J. of the R o y a l S o c i e t y of M e d i c i n e 77 585.

(1984),

330 Results of therapy in patients vith «edullary carcinoma of thyroid gland (Poster) D. Gottschild, Gabriele Zinner, Carmen Luck, N.M. Granzow Nuklearmedizinische Abteilung der Klinik fiir Radiologie, Friedrich-Schiller-Universitat Jena, Germany Medullary carcinoma of thyroid gland is a very rare tumor. In Jena we treated from 1958 to 1985 367 patients with carcinoma of thyroid gland (table 1). 31 of them (9 %) had a medullary carcinoma. Age and sex of all patients and of patients with medullary carcinoma are shown in figure 1 a and 1 b. We found nearly the same distribution in age groups and a prevailing of female sex. In 2 patients (mother and daughter) the medullary carcinoma was part of an syndrome of Multiple Endocrine Neoplasia. In more than 50 % of the patients we found metastatic formations in regional lymphatic nodules and in distant organs (see table 2) at the time of diagnosis. The treatment included operation, external radiation therapy, therapy with radioiodine, and application of thyroid hormones. The following combinations were used: Operation and external

in 17 patients

radiation therapy Operation and therapy

in

2 patients

with radioiodine Operation, external radiation

in 10 patients

therapy, and radioiodine therapy External radiation therapy

in

1 patient

No therapy

in

1 patient

For all patients we prescribed thyroid hormones to suppress the secretion of TSH. The radioiodine therapy was applied in 8 patients to eleminate functioning thyroid tissue and in 4 patients with a minimal accumulation in metastatic formations.

331 Table 1: Frequency of medullary carcinoma in relation to other histological types Type of histology folliculary carcinoma

%

patients 101

30

papillary carcinoma

98

29

differentiated carcinoma without classification

43

13

anaplastical carcinoma

48

14

medullary carcinoma

31

9

oncocytoma

10

3

sarcoma

7

2

carcinomasarcoma

1

0.3

metastatic eosinophile adenoma

2

0.6

Table 2: Frequency and localization of metastatic formations in patients with medullary carcinoma

Lymphatic nodules of neck distant localizations:

6 patients

19

13 patients

42

lung

7 patients

bone

6 patients

liver

3 patients

other localizations

2 patients

The long-time follow up shows

the following results: From

all 31 patients with medullary carcinoma of thyroid gland were living 5 years after the beginning of therapy 16 (52 %). From 13 patients with distant metastatic formations were living 4 (31 %), and from 18 patients without distant metastatic formations were living 12 (66.7 %). In evaluation of our experiences we recommand the following therapeutic regime:

332 1. Operation with removing of the primary tumor and subtile examination of the lymphatic nodules 2. External radiation therapy 3. Long-term follow up with control of thyroid hormones, TSH, calcitonin, and administration of thyroid hormones.

333 The place of ultrasonography in the evaluation of medullary thyroid cancer P. Vldek, M. Neradilovci, J. N^mec, J. Bednai, Z. Novak Institute of Endocrinology and Dept. Nucl. Med. Faculty Hospital Prague-Motol, CSFR Medullary thyroid cancer arises from parafollicular C cells of the thyroid and produces a variety of biologically active compounds. One of them is calcitonin, which is used as a biochemical marker for presence of disease. Observation after surgery with determination levels of plasma calcitonin and ultrasound examination play important role in diagnosis of this disease. Materials and methods In our department were examined 49 patients with medullary thyroid carcinoma with high-frequency ultrasound. Neck and liver were imagined during 15 months (January 90 - March 91). The age of the 49 patients (20 men and 29 women) ranged from 17 to 78 years (mean 37.3 years). All patients had undergone previous thyroidectomy. The interval between surgery and ultrasonography ranged from 6 months to 8 years. In all patients plasma immunoreactive calcitonin levels were measured basally and after pentagastrin and calcium stimulation. Sonography of the neck and the liver were performed using diagnostic apparatus Hewlett Packard and Ultramark IV, Medata, equipped with ATL system. Sectorial probes with changeable frequencies were used, for neck evaluation with crystals with frequency 7.5 MHz and for liver examination with frequency 3 MHz. Very short focusation range 10-40 mm in 7.5 MHz frequency allowed the differentiation of superficially located structures also. Plasma calcitonin levels was measured with sets Diagnostic System Laboratories, Texas, USA. The upper level in this system is a 1000 ng/1. Normal levels are lower than 130 ng/1.

334 Table 1: Sonographic findings and levels of plasma calcitonin in 49 patients with medullary thyroid carcinoma Sonographic findings

No. of patients

levels of plasma low high

Negative findings after TTE

22

15

7

Remainder of thyroid

12

10

2

Lymph nodes Lymph nodes and remainder of thyroid Calcified tissue in thyroid bed Hepatic metastases

6

1*

5

3

-

3

3

-

3

-

3 3

•Inflammatory node Results The table shows, that in 22 patients from 49 observed were not found thyroid tissue, lymph nodes or distant metastases in liver. In 15 cases the plasma calcitonin levels were low testifying this the eradication of tumor. In 7 cases, however, the ultrasound findings were negative and levels of calcitonin were enhanced. 3 patients had MEN lib syndrome and 1 patient was classified as non-MEN syndrome. In 12 patients remainders of thyroid were found. These patients had not undergone total thyroidectomy. Enhanced levels of calcitonin were detected in 2 cases. In 6 patients enlarged lymph nodes were seen, in 5 cases the levels of calcitonin were high. The size of cervical lymph nodes detected by ultrasound ranged from 5 to 22 mm. In 3 cases in these nodes calcifications were found. In 1 case hypoechogenic node 14 x 6 mm was evaluated as an inflammatory

335 one, as the level of c a l c i t o n i n w a s v e r y

low.

In 3 p a t i e n t s b o t h l y m p h n o d e s a n d r e m a i n d e r s of t h y r o i d w e r e f o u n d . The size of the l y m p h n o d e s w e r e a b o u t 8 - 2 8 m m ,

re-

m a i n d e r s of t h y r o i d a b o u t 10-25 m m . C a l c i f i c a t i o n s w e r e o n l y in 1 p a t i e n t . The l e v e l s of c a l c i t o n i n w e r e o v e r n g / 1 in all

seen

1000

cases.

In 3 p a t i e n t s c a l c i f i e d t i s s u e in t h y r o i d b e d w a s s e e n ,

in

all w e r e e x t r e m e l y h i g h p l a s m a c a l c i t o n i n l e v e l s . T h e s e

find-

ings w e e v a l u a t e d as p r i m a r y In 3 p a t i e n t s

tumor.

(6 %) w e r e d e t e c t e d h e p a t i c m e t a s t a s e s .

n o d e s in 2 of t h e s e s c a s e s w e r e a l s o p r e s e n t .

Lymph

1 patient

with

M E N lib s y n d r o m e h a d u n d e r g o n e t o t a l t h y r o i d e c t o m y w i t h n e g a tive u l t r a s o u n d of the n e c k , b u t w e f o u n d h e p a t i c with calcifications.

In all c a s e s the l e v e l s of

metastases

calcitonin

w e r e o v e r 1000 n g / 1 . Discussion The t r e a t m e n t of c h o i c e for m e d u l l a r y t h y r o i d c a n c e r tal b i l a t e r a l t h y r o i d e c t o m y and m o d i f i e d n e c k

S u r g e r y m a y be i n c o m p l e t e in some p a t i e n t s if the is n o t k n o w n at the t i m e of s u r g e r y .

is a t o -

dissection. diagnosis

In t h e s e p a t i e n t s

enhanc-

ed l e v e l s of c a l c i t o n i n m a y be e x p l a i n e d by s o n o g r a p h i c

de-

t e c t i o n of r e m a i n i n g t h y r o i d t u m o r s t i s s u e . S o n o g r a p h i c

find-

ings of h i g h e c h o g e n i c foci o f t e n a s s o c i a t e d w i t h

acustic

s h a d o w s w e r e f o u n d in our p a t i e n t s w i t h m a s s in t h y r o i d and w i t h l y m p h n o d e s . T h e s e c a l c i f i c a t i o n s w i t h i n t i s s u e are n o n s p e c i f i c .

In our g r o u p , h o w e v e r , e n h a n c e d

v e l s of c a l c i t o n i n w e r e found in all p a t i e n t s w i t h tions. P a t i e n t s w h o u n d e r w e n t total t h y r o i d e c t o m y

for

medul-

sent c l i n i c a l p r o b l e m . The p e r s i s t e n t h y p e r c a l c i t o n e m i a

preindi-

l o c a l i z a t i o n or

d i s t a n t m e t a s t a s e s . We saw w i t h u l t r a s o u n d d i s t a n t of the liver in 3 c a s e s

le-

calcifica-

lary c a n c e r and h a v e e l e v a t e d p l a s m a c a l c i t o n i n l e v e l s c a t e s r e s i d u a l s e c r e t i o n in e x t r a t h y r o i d a l

bed

thyroid

metastases

(6 % ) . The l e v e l s of c a l c i t o n i n

were

336 a l w a y s over

1000 n g / 1 . In our s t u d y w e h a d 5 p a t i e n t s

with

M E N II s y n d r o m e - o n l y in 1 p a t i e n t c a l c i t o n i n level w a s We h a v e p a t i e n t s w h e r e p a l p a b l e , s o n o g r a p h i c and

scintigra-

p h i c f i n d i n g s are n e g a t i v e a n d c a l c i t o n i n l e v e l s r e m a i n T h e s e p a t i e n t s n e e d to b e c a r e f u l l y f o l l o w e d Sonography

low.

high.

up.

is a m o d e r n n o n i n v a s i v e m e t h o d in the

evaluation

of f i n d i n g s of the n e c k a n d l i v e r , w h e r e p a l p a t i o n is e s p e c i a l l y d i f f i c u l t in the p r e s e n c e of p o s t o p e r a t i v e s c a r i n g after r a d i a t i o n t h e r a p y . U l t r a s o u n d w i t h m e a s u r e m e n t of plasma immunoreactive calcitonin levels rank among d i a g n o s t i c m e t h o d s in t h i s

or

the

basic

disease.

References 1. G o r m a n B. et a l . : R a d i o l o g y et a l . : Am. J. og R a d i o l o g y P r a k t . lek.

162 (1987),

11 (1990),

147. 2. V a n B e e r s

107. - 3. Rilzek e t a l . :

(Praha) 67 (1987), 835. - 4. T e l a n d e r , R . L .

al.: A r c h . S u r g . 124 (1989),

841.

et

337 Medullary thyroid carcinoma - results of some diagnostic procedures used at our institute D. Bergant, M. Auersperg, M. Us-Krasovec, F. Pompe, J. Petric, T. Movrin, Z. Zemva*, N. Besic The Institute of Oncology, Ljubljana, Yugoslavia/Slovenia •University Clinic of Nuclear Medicine, the University Clinic Center, Ljubljana, Yugoslavia/Slovenia Diagnostic procedures used in 42 patients with medullary thyroid carcinoma (MTC) diagnosed and/or treated at the Institute of Oncology in Ljubljana between 1978-1989 are reviewed. The value of routine procedures such as tumor marker assay (calcitonin (TC), CEA), fine needle biopsy (FNAB) and radionuclide tracers imaging (Tc-99m(V) DMSA, I-131-MIBG, In-lll-anti CEA) was assessed. The accuracy of the diagnostic methods was: TC assay 97.3 % (36/37 pts), FNAB 89.7 % (35/39 pts), Tc-99m(V) DMSA scintiscan 83.3 % (15/18 pts), CEA assay 82.1 % (23/28 pts), 1-131MIBG 27.2 % (3/11 pts) and In-lll-anti CEA scintiscan (2/3 pts). Medullary thyroid carcinoma (MTC) originates from calcitonin (TC) producing parafollicular cells (C-cells) /35/. Relatively few cases of MTC, great clinical /26,27,30/ and histological variability /15,28/32/ genetic aspects of MTC /21,24/ diagnostic and therapeutic problems with advanced MTC call for multivarious diagnostic workup for recognition of the disease and its extent /1,8,13/ prior to any treatment planning /3,22,26,27,36/. This report is intended to present the results of some diagnostic procedures for MTC used at our Institute, such as: tumor marker assays (TC and CEA), fine needle aspiration biopsy (FNAB), radionucleid tracers imaging (Tc-99m(V)-DMSA

(DMSA),

I-131-MIBG (MIBG), In-111-anti-CEA (anti-CEA) and screening programme.

338 Material (pts) w i t h t h y r o i d

carcinoma

w e r e d i a g n o s e d a n d / o r t r e a t e d at t h e I n s t i t u t e of

During

1 9 7 8 - 1 9 8 9 , 478 p a t i e n t s

Oncology,

L j u b l j a n a . M e d u l l a r y t h y r o i d c a r c i n o m a w a s d i a g n o s e d in 42 patients

(8.7 % ) , 20 m a l e s and 22 f e m a l e s , m e a n age

40.0

y e a r s , r a n g e 16-78. Out of 42 p t s t h i r t y - s i x h a d the v a r i e t y of M T C . M E N Ila w a s o b s e r v e d in 3/42 pts 34 y e a r s ) ; M E N lib in 1/42 p t s lib in 1/42 pts in 1/42 p t s

sporadic

(23.33

and

(17 y e a r s ) , n o n - f a m i l i a l

MEN

(16 y e a r s ) and n o n - M E N f a m i l i a l f o r m of M C T

(37 y e a r s ) . T h r e e f a m i l i e s

r e d i t a r y f o r m of M T C w e r e

(5 p a t i e n t s ) w i t h h e -

diagnosed.

A l l of our 42 p t s w i t h M T C h a d a p a l p a b l e n e c k t u m o r . m e t a s t a s e s w e r e p r e s e n t in 11/42 p t s on the f i r s t

admission.

T e n / 4 2 pts w e r e r e f e r r e d to this I n s t i t u t e f r o m o t h e r tals. E i g h t of t h e m w e r e m i s d i a g n o s e d and t r e a t e d

Distant hospi-

already.

M T C w a s d i a g n o s e d o n r e v i s i o n of the h i s t o l o g i c t i s s u e

spe-

cimens . Methods The c l i n i c a l r e c o r d s of 42 pts w i t h M T C w h o a t t e n d e d our

In-

s t i t u t e d u r i n g the r e f e r r a l p e r i o d w e r e s t u d i e d . F N A B w a s p e r f o r m e d by c o n v e n t i o n a l t e c h n i q u e . C y t o l o g i c s m e a r s

were

routinely stained by Giemsa, and Papanicolaou methods. m e l l i u s m e t h o d w a s u s e d for the d e t e r m i n a t i o n of

Gri-

neurosecre-

tory g r a n u l e s w h e r e a s and i m m u n o r e a c t i v e T C a n d CEA

cells

w e r e d e t e r m i n e d by the A B C m e t h o d a n d a n t i b o d i e s p r o d u c e d

by

DAKO-Denmark. Serum TC was measured by radioimmunoassay

for h u m a n T C . A

c o m m e r c i a l k i t R I A - m a t c a l c i t o n i n I p r o d u c e d by Diagnostica,

FRG w a s

BYK-Sangec

used.

S e r u m C E A w a s d e t e r m i n e d by e n z y m e i m m u n o a s s a y m e t h o d

using

a C E A - E I A - D u o m a b 60 "Roche" k i t . T h e D M S c o m p o u n d and

1-131-

M I B G w e r e p r o d u c e d by the B o r i s K i d r i c I n s t i t u t e , V i n c a , g o s l a v i a . A f t e r w a r d s D M S w a s l a b e l l e d in our l a b o r a t o r y T c - 9 9 m ( V ) at p H

8.0.

Yuwith

339 A n t i - C E A a n t i b o d i e s a n d In-Ill w e r e p r o v i d e d b y nal-CIS,

Internatio-

France.

Only s t a n d a r d s c i n t i g r a p h y w a s

performed.

Results 1. F N A B FNAB

(blind or U S c o n t r o l l e d ) w a s p e r f o r m e d

t i e n t s w i t h the f o l l o w i n g r e s u l t s

in 39/42

pa-

(table).

Table

FNAB diagnosis

n u m b e r of patients

M T C or s u s p e c t e d M T C Anaplastic thyroid carcinoma Poorly differentiated follicular carcinoma

35/39 2/39 2/39

Four c a s e s w e r e n o t r e c o g n i z e d as M T C s b e f o r e

treatment;

t h e r e w e r e no c l i n i c a l f e a t u r e s of M T C p r e s e n t , the r e s u l t s w e r e m i s l e a d i n g and tumor m a r k e r s

(TC, CEA) w e r e

n o t d e t e r m i n e d , so that M T C w a s d i a g n o s e d by 2. T u m o r m a r k e r

histology.

assays

Tumor marker assays were introduced

in the

diagnostic

w o r k u p as late as in 1978, and w e r e l i m i t e d to the m i n a t i o n of T C and CEA o w i n g to l a b o r a t o r y On a d m i s s i o n , T C w a s d e t e r m i n e d pathological

deter-

conditions.

in 37/42 p a t i e n t s and w a s

in all b u t one.

In our s e r i e s C E A w a s a n a l y s e d less r e g u l a r l y Pathological

FNAB

(33/42).

l e v e l s w e r e o b t a i n e d in 28/33 p a t i e n t s ,

d e r l i n e l e v e l s in 4 / 3 3 and n o r m a l l e v e l s in 1/33 In the l a t t e r case T C w a s s i g n i f i c a n t l y

elevated.

bor-

patients.

340 3. R a d i o n u c l i d e

tracers

Tc-99m(V)-DMSA

(DMSA), I - 1 3 1 - M I B G (MIBG) s c i n t i s c a n

b e e n u s e d f r o m 1986 o n a n d I n - 1 1 1 - a n t i - C E A

have

(anti-CEA)

s i n c e 1989, as a n a d d i t i o n a l d i a g n o s t i c m e t h o d s for ing p r i m a r y , r e s i d u a l , r e c u r r e n t or m e t a s t a t i c

imag-

MTC.

On a d m i s s i o n , D M S A s c i n t i s c a n w a s p e r f o r m e d in 18/42 t i e n t s . S p e c i f i c u p t a k e by M T C w a s d e m o n s t r a t e d pts

(thyroid t u m o r

in

pa-

15/18

11/15, s e v e r a l t u m o r s i t e s 4 / 1 5 ) .

In

2/18 c a s e s the r e s u l t s w e r e f a l s e n e g a t i v e and in o n e f a l s e p o s i t i v e . In l a t t e r c a s e D M S A s p e c i f i c was demonstrated

case

cumulation

in the t h y r o i d M T C and l i v e r

metastases,

whereas false positive cumulation was demonstrated

in a

b r a i n h a e m a n g i o m a later f o u n d o n a u t o p s y . M I B G w a s u s e d in 11/42 c a s e s . S p e c i f i c i m a g i n g of M T C w a s f o u n d in 3/11. F a l s e n e g a t i v e r e s u l t s w e r e o b t a i n e d 8/11 c a s e s ; t h e r e w e r e no f a l s e p o s i t i v e

I m m u n o s c i n t i g r a p h y w i t h a n t i - C E A w a s p e r f o r m e d by tional scintigraphy

in

results.

in 3 c a s e s . M T C w a s i m a g e d

conven-

twice.

All b u t one s i t e , w h e r e DMSA, M I B G , and a n t i - C E A

specific

u p t a k e w a s d e m o n s t r a t e d , w e r e c o n f i r m e d to be M T C by or 4.

FNAB

histology.

Screening S c r e e n i n g u s e d at our I n s t i t u t e s i n c e 1969 w a s

initially

l i m i t e d to p h y s i c a l e x a m i n a t i o n of the r e g i s t e r e d

family

m e m b e r s w h o w e r e i n f o r m e d a b o u t M T C and s c r e e n i n g .

Tumor

marker

(TC, CEA) d e t e r m i n a t i o n w a s n o t a v a i l a b l e at

time. T h e s e m e t h o d s w e r e a d d e d to our s c r e e n i n g l a t e r . S i n c e the b e g i n n i n g of 1990 our s c r e e n i n g me

that

programme program-

comprised:

- r e g i s t e r of a f f e c t e d

families

- c o n s u l t i n g of f a m i l y m e m b e r s a b o u t M T C a n d the of

screening

benefit

341 - physical

examination

- basal TC and CEA

assay

- p r o v o c a t i v e t e s t s w i t h p e n t a g a s t r i n and d e t e r m i n a t i o n TC serum levels after - follow

of

it.

up

A l t o g e t h e r t h r e e f a m i l i e s w i t h f a m i l i a l f o r m of M T C w e r e found. Discussion A l t h o u g h M T C r e p r e s e n t s o n l y 2 - 1 2 % of t h y r o i d c a n c e r s , s h o u l d a l w a y s be c o n s i d e r e d in the t h y r o i d p a t h o l o g y

it

/8,26,

2 7 , 3 6 / . In our s e r i e s the i n c i d e n c e w a s 8.7 % . T h e f a c t t h a t 8/10 c a s e s r e f e r r e d to our I n s t i t u t e f r o m e l s e w h e r e w e r e i n i t i a l l y m i s d i a g n o s e d , p r o b a b l y o w i n g to the n i c a l a n d the h i s t o l o g i c a l v a r i a b i l i t y of the t u m o r ,

e x p e r i e n c e of the d i a g n o s t i c i a n and c r a m p e d l a b o r a t o r y t i o n s d o e s i n d i c a t e t h a t M C T is still a d i a g n o s t i c

cli-

limited condi-

problem

/29/. T C / 8 , 9 , 1 1 , 1 5 / and F N A B / 8 , 1 6 , 1 8 , 2 6 / e n a b l e a r e l i a b l e o p e r a t i v e d i a g n o s i s of M T C . The r e s u l t s of t h e s e p r o c e d u r e s w e r e e q u a l l y r e l i a b l e in our s e r i e s as

pre-

diagnostic reported

/12,15,16,19,25/. T h e v a l u e of CEA a s s a y for d i a g n o s i s a n d f o l l o w u p in p a t i e n t s w i t h M T C is g r e a t , t h o u g h C E A is a l e s s s p e c i f i c and less s i t i v e t u m o r m a r k e r for M T C t h e n

sen-

/5,20,26,36/.

CEA is n o t u s e f u l in f a m i l i a l s c r e e n i n g b e c a u s e it is n o t e l e v a t e d in C - c e l l h y p e r p l a s i a

/4,5,20,29/.

F a v o u r a b l e r e s u l t s w e r e o b t a i n e d u s i n g D M S A for M T C They were possibly

imaging.

i n f l u e n c e d by r e l a t i v e l y g r e a t n u m b e r

patients with advanced MTC, though similar result were s e r v e d for r e s i d u a l , r e c u r r e n t a n d d i s s e m i n a t e d d i s e a s e T h e s e f i n d i n g s c o r r e s p o n d w e l l to the r e p o r t e d o n e s 23,31/.

of

obtoo.

/14,17,

342 Using MIBG for MTC visualisation we did not achieve as good results as those obtained with DMSA /6,17/. Nevertheless, MIBG whole body scintigraphy should be performed on admission. Possible coexisting pheochromocytoma can be demonstrated and, when a specific uptake by MTC is found, additional therapy with MIBG is possible /2,17/. Anti-CEA scintigraphy poses some immunological problems, the main being specificity and sensitivity of the method, sensibilisation and consequential allergic reactions /10/. Our experience with this method is very limited (3 cases) and no conclusions can be drawn. According to literature, the incidence of the familial form of MTC is 20-30 % /22,24,26,36/. Only in 5/42 (11.9 %) of our cases familial MTC was observed, possibly owing to incomplete familiar screening, also due to poor family members compliance . In general, the prognosis in patients with MTC depends above all on early diagnosis and an adequate therapy. Prior to any treatment planning, a multidisciplinary diagnostic workup is needed to identify MTC and possible coexisting MEN (especially pheochromocytoma). Family screening is mandatory for early MTC detection /I,IX, 24,33/. When subclinical MTC or even C-cell hyperplasia is diagnosed and is treated correctly, the best chances for cure are achieved /24,25,30/. References 1. Baulieu, J.L., D. Guilloteau, F. Bauilieu, J.C. Besnard, L. Pourcelot: Bull Cancer 71 (1984), 182. - 2. Baulieu, J.L., D. Guilloteau, M.J. Delisle et al.: Cancer 60 (1987), 2189. 3. Ben Mrad M.D., P. Gardet, A. Roche et al.: Cancer 63 (1989), 133. - 4. Busnardo, B., M.E. Girelli, N. Simioni, D. Nacamulli, E. Busetto: Cancer 53 (1984), 278. -

343 5. C a l m e t t e s , C., M . S . M o u k h t a r , G. M i l h a u d : C a n c e r I m m u n o t h e r . 4 (1978), 251. - 6. C l a r k e , S.E., C.R.

Immunol. Lazarus,

P. W r a i g h t , C. S a m p s o n , M . N . M a i s e y : J. N u c l . M e d . 29 (1988), 33. - 7. D e c k a r t , H., E. D e c k a r t , Ch. K o l o c et a l . : biol. Radiother.

Radio-

28 (1987), 714. - 8. Delisle., M . J . : A n n .

E n d o c r i n o l . 49 (1988), 51. - 9. Duh, Q . Y . , J . J . S a n c h o , G r e e n s p a n et a l . : A r c h . Surg. 124 (1989),

1206.

F.S.

-

10. E d i n g t o n , H . D . , C.G. W a t s o n , G. L e v i n e et a l . :

Surgery

104 (1988), 1004. - 11. E m m e r t s e n , K., H . E . N i e l s e n , L.

Mose-

k i l d e , H. H v i d H a n s e n : A c t a R a d i o l . O n c o l . 19 (1980), 85. 12. G a r c i a , A., F. M a r t i n , C.F. G a r c i a , F.J. C a v a n z o : P a t h o l . 3 (1990),

19. - 13. G o r m a n , B., J.w.

E.M. J a m e s et a l . : R a d i o l o g y 162 (1987),

Surg.

Charboneau,

147. - 14.

Guerra,

U., C. P i z z o c a r o , A. T e r z i , R. G i u b b i n i , M. B e s t a g n o :

J.

N u c l . M e d . A l l i e d Sci. 32 (1988), 242. - 15. G u l i a n a , E. M o d i g l i a n i : A n n . E n d o c r i n o l . 49 (1988), 34. - 16. D. B e l l i d o , C. B e r n a l et al.: C a n c e r 59 (1987),

J.M., Hawkins,

1206.

-

17. H o e f n a g e l , C.A., C.C. D e l p r a t , D. Z a n i n , J . B . v a n der S c h o o t : C l i n . N u c l . M e d . 13 (1988), 159. - 18. K o p a l d ,

K.H.,

L . J . L a y f i e l d , R. M o h r m a n n , L . J . F o s h a g , A . E . G i u l i a n o : Surg. 124 (1989), 1201. - 19. L o w h a g e n , T., J.S.

Arch.

Williems,

G. L u n d e l l , R. S u n d b l a d , P.O. G r a n b e r g : W o r l d J. Surg. 5 (1981), 61. - 20. M e n d e l s o h n , G., S.A. W e l l s , S.B.

Baylin:

C a n c e r 54 (1984), 657. - 21. N e l k i n , B . D . , A . C . de

Bustros,

M. M a r b y , S.B. B a y l i n : JAMA 261 (1989), 3130. - 22.

Neradilo28

và, M. J. N é m e c , V. N a h o d i l : R a d i o b i o l . R a d i o t h e r .

722. - 23. P a t e l , M . C . , R.B. P a t e l , P. R a m a n a t h a n , N.

(1987), Rama-

m o o r t h y : Eur. J. N u c l . M e d . 13 (1988), 507. - 24.

Ponder,

B.A., N. F i n e r , R. C o f f e y et al.: Int. J. R a d i a t .

Oncol.

Biol. P h y s . 9 (1983),

Ordonez,

161. - 26. S a a d , M . F . , N . G .

R.K. R a s h i d et al.: M e d i c i n e 63 8 1 9 8 4 ) , 319. - 27. G.W.: Semin. Oncol.

Sizemore,

14 (1987), 306. - 28. S o b o i , R . E . ,

M e m o l i , L . J . D e f t o s : Engl. J. M e d . 320 (1989), 444.

V.

-

29. T a k a m i , H., T. B e s s h o , T. K a m e y a et al.: W o r l d , J.

Surg.

12 (1988), 572. - 30. T e l a n d e r , R . L . , D. Z i m m e r m a n , J.A.

van

344 Heerden, G.W. Sizemore: J. Pediat. Surg. 21 (1986), 1190. 31. Udellsman, R., O.A. Mojiminiyi, N.D.W. Soper, I.D. Buley, B.J. Shepstone, N.E. Dudley: brit. J. Surg. 76 (1989), 1278. - 32. Uribe, M., C.M. Fenoglio-Preiser, M. Grimes, C. Feind: Am. J. Surg. Pathol. 9 (1985), 577. - 33. Wells, S.A., S.B. Baylin, W.M. Linehan, R.E. Farrell, E.B. Cox, C.W. Cooper: Ann. Surg. 188 (1978), 139. - 34. Wheeler, M.H.: Surgery 104 (1988), 1477. - 35. Williams, E.D.: J. Clin. Pathol. 19 (1966), 114. - 36. Williams, E.D.: In: Polak, J., S.R. Bloom eds. Endocrine Tumor: the pathobiology of regulatory peptide-producing tumors. Edinburgh: Churchill Livingstone (1985), 229.

345 FKEE PAPERS Tumor markers in thyroid diseases J. Bednar, J. Nibmec, M. Neradilova, M. Soutorova Institute of Endocrinology, Prague and Department of Nuclear Medicine, Faculty Hospital, Prague-Motol, Czechoslovakia In the last ten years' period two in vitro diagnostic parameters have been commonly considered as tumor markers: serum thyroglobulin (TG) concentration in the diagnosis of differentiated thyroid cancer, and serum immunoreactive calcitonin (iCT) concentration in the diagnosis of medullary thyroid carcinoma. Serum thyroglobulin determination has been performed in our laboratory since 1981 /l/. Up to the end of the last year (1990) we have made nearly 22 000 determinations in blood serum of patients investigated in our institute. In the last years, at about 3000 determinations have been made yearly on the average. Since the time we have begun to use our own new specific antiserum against TG (the working dilution 1:90000 i.e. the final dilution 1:270000 is used), the resulting TG values decreased to a certain degree. Nowadays, the TG concentration of 60 /ug/1 is regarded as the upper limit of "normal" values in healthy persons with an eufunctional thyroid gland. The distribution of results of the thyroglobulin determination in patients with differentiated thyroid carcinoma after total thyroid ablation (by surgical and radioiodine treatment) without proved residual tumors or metastatic lesions, and in patients with differentiated thyroid carcinoma with an active tumor or metastatic lesions and/or where the suspicion of them could not be excluded, is given on figure la and lb. In addition to the basic division at 100 /ug/1 intervals, another division is used depicting in detail the

346 d i s t r i b u t i o n b e t w e e n 0 a n d 100 / u g / 1 . In the s u b g r o u p metastases

(figure lb) n e a r l y h a l f of p a t i e n t s

with

(47.4 % )

had

l y m p h n o d e m e t a s t a s e s p r o v e d or s u s p e c t e d . O n l y a q u a r t e r patients

(24.6 %) h a d h i g h l y e l e v a t e d c o n c e n t r a t i o n of

globulin

(over 100 / u g / 1 ) . P a t i e n t s w i t h l y m p h n o d e

ses

( s u s p e c t e d or c o n f i r m e d ,

of

thyro-

metasta-

i s o l a t e d or in c o m b i n a t i o n

with

a r e s t of t u m o r , some of w h i c h a c c u m u l a t e d 1 - 1 3 1 ) h a d t h e T G c o n c e n t r a t i o n b e l o w the l i m i t 60 / u g / 1 or a b o v e The o p t i m a l r e s u l t of t r e a t m e n t

it.

is the d e c r e a s e of T G

concen-

t r a t i o n s to the v a l u e s c l o s e to z e r o . T h i s l i m i t d i f f e r s

ac-

c o r d i n g to the l a b o r a t o r y m e t h o d . Now, we r e g a r d the v a l u e 20 / u g / 1 as a l i m i t b e t w e e n n o r m a l and e n h a n c e d T G

concentra-

t i o n in our p a t i e n t s u n d e r t h y r o i d s u p p r e s s i v e t r e a t m e n t

and

35-40 / u g / 1 in p a t i e n t s a f t e r the w i t h d r a w a l of t h i s

treat-

m e n t in h y p o t h y r o i d i s m w i t h n e g a t i v e r e s u l t of w h o l e

body

scintigraphy. a b l y lower

Fully a t h y r o i d p a t i e n t s h a v e u s u a l l y

consider-

values.

In p a t i e n t w i t h d i s t a n t m e t a s t a s e s of d i f f e r e n t i a t e d

thyroid

c a n c e r , m o r e t h a n 95 % h a v e i n c r e a s e d or h i g h T G v a l u e s .

Also

in our g r o u p of p a t i e n t s w i t h d i s t a n t m e t a s t a s e s a n d w i t h n e g l i g i b l e u p t a k e of r a d i o i o d i n e w h o h a v e b e e n t r e a t e d by

ra-

d i o i o d i n e w i t h o u t d o s e m e a s u r e m e n t , m o r e t h a n 85 % h a d a n

in-

creased TG concentration.

In c o m p a r i s o n w i t h t h a t , o n l y

15 %

of p a t i e n t s w i t h local d i s s e m i n a t i o n on the n e c k in m e t a s t a t i c n o d u l e s a n d / o r w i t h the r e c u r r e n c e of p r i m a r y t u m o r , w i t h s u p p r e s s e d u p t a k e , h a d e n h a n c e d TG c o n c e n t r a t i o n .

and

In

spite of the fact t h a t t h i s g r o u p of p a t i e n t s is n o t w h o l y t y p i c a l , b e c a u s e it i n c l u d e s a l s o p a t i e n t s w i t h

dedifferen-

t i a t i o n of the o r i g i n a l t u m o r , t h e s e c i r c u m s t a n c e s

represent

a s t r o n g w a r n i n g a g a i n s t the o v e r e s t i m a t i o n of low

thyroglo-

bulin values.

In c a s e s , w h e r e the c o n c e n t r a t i o n of T G

in the l i m i t s of a t h y r o i d i s m , the w h o l e b o d y should be made each 5-7 years

scintigraphy

(see the s c h e m e of

of d i f f e r e n t i a t e d t h y r o i d c a r c i n o m a on this

lies

monitoring

symposium).

347

A

1. 1b .. K 2"

50-

40-

30-

20

S0-

10-

~T\ n so

100

Figure

—I— 300

—I— 500

ii i 100 uih

and /, more n % / \

la

T h y r o g l o b u l i n c o n c e n t r a t i o n in p a t i e n t s w i t h differentiated thyroid carcinoma after total t h y r o i d a b l a t i o n w i t h o u t t u m o r or m e t a s t a s e s

A

100-

1. ab ..K 2"

30-

20-

5010-

-lou. 50

100

Figure

300

500

100 10C

ug/l

more ug /1

lb

T h y r o g l o b u l i n c o n c e n t r a t i o n in p a t i e n t s w i t h differentiated thyroid carcinoma with metastases or t u m o r

349 T h e t e r m i n a t i o n of t h y r o g l o b u l i n h a s o n l y n e g l i g i b l e

value

for s c r e e n i n g of t h y r o i d c a r c i n o m a b e c a u s e in e v e r y c a s e of g o i t e r r e g a r d l e s s of its f u n c t i o n the T G c o n c e n t r a t i o n c a n be e n h a n c e d , o f t e n v e r y c o n s i d e r a b l y . By r e t a i n i n g the

thyroid

in s i t u the T G c o n c e n t r a t i o n c a n n o t be u s e d r e l i a b l y to the f o l l o w up of p a t i e n t s . O n l y in c a s e s , w h e r e we look for p r i m a r y s o u r c e of d i s t a n t m e t a s t a s e s h i g h T G v a l u e c a n to a n o b j e c t i v e d i a g n o s i s . T h i s m a y be e f f e c t i v e w h e r e the g l a n d is n o t e n l a r g e d as p r o v e d b y

the serve

especially

palpation.

Medullary thyroid carcinoma always produces enormous

quanti-

ties of c a l c i t o n i n . U p to 30 % of c a s e s w i t h M C T are the c a l l e d f a m i l i a r v a r i a n t c h a r a c t e r i z e d by an a u t o s o m a l t y p e of h e r e d i t y . In s u b c l i n i c a l p e r i o d c a l c i t o n i n in e n d a n g e r e d

so-

dominant

secretion

i n d i v i d u a l s c a n be e n h a n c e d o n the b a s i s of h y -

p e r p l a s i a of C - c e l l s . E n h a n c e d c a l c i t o n i n s e c r e t i o n in p e r s o n s f r o m t h o s e f a m i l i e s a p p e a r s as an i n d i c a t o r of the i l l n e s or a m e n a c e of it. It is s u f f i c i e n t to the e s t i m a t i o n of sis and e n a b l e s to i n d i c a t e s u r g e r y e v e n in the

diagno-

subclinical

s t a g e w h i c h i n f l u e n c e s v e r y p o s i t i v e l y the p r o g n o s i s of sease

( i m p o r t a n c e of the f a m i l i a r s c r e e n i n g ) .

di-

In a d d i t i o n ,

the c o n t r o l of the d y n a m i c s of iCT s e c r e t i o n d u r i n g the

treat-

m e n t and in the f o l l o w up of p a t i e n t s c a n s e r v e for

testing

the e f f e c t of t r e a t m e n t a n d i n d i c a t e s a l s o p o s s i b l e

recurren-

ce of the d i s e a s e

(i.e. r e c u r r e n c e of the p r i m a r y t u m o r or

the p r e s e n c e of d i s t a n t

metastases).

On f i g u r e 2 the r e s u l t s of s e r u m iCT d e t e r m i n a t i o n

in four

s u b g r o u p s f r o m our g r o u p of 410 p a t i e n t s i n v e s t i g a t e d , demonstrated

the m a n u f a c t u r e r , the u p p e r l i m i t of " n o r m a l " iCT t i o n s is 130 p g / m l . A n o r m a l

to

concentra-

(Gaussian) d i s t r i b u t i o n

cannot

be g e n e r a l l y p r o v e d , t h e r e f o r e the v a l u e of m e d i a n h a s c a l c u l a t e d . The u p p e r l i m i t of n o r m a l v a l u e s h a s b e e n pg/ml.

are

(RIA-mat C a l c i t o n i n II t e s t k i t ) . A c c o r d i n g

been 100

350

Figure 2 R e s u l t s of s e r u m iCT

determination

351 The i n d i v i d u a l s u b g r o u p s i n v o l v e : 1. P a t i e n t s e x a m i n e d the s u s p i c i o n of M C T , w h e r e the d i s e a s e h a s n o t b e e n

for

clini-

c a l l y or in o t h e r w a y s p r o v e d a n d / o r i n d i v i d u a l s e x a m i n e d another thyroid disease thyroidal disease.

for

(with e x c e p t i o n of M C T ) or for a n o n -

2. P a t i e n t s w i t h M C T a f t e r

a n d / o r e x t e r n a l i r r a d i a t i o n , a n d on h o r m o n a l

thyroidectomy substitution

w i t h o u t any c l i n i c a l s u s p i c i o n of the p r e s e n c e of an a c t i v e tumor or m e t a s t a s e s .

3. P a t i e n t s w i t h M C T as in p r e v i o u s

g r o u p , b u t s u s p e c t e d of m e t a s t a t i c l e s i o n s a n d / o r w i t h stases clinically proved

(lymph n o d e s , l i v e r , lung,

4. P a t i e n t s a f t e r c o m p l e t e a b l a t i o n of the t h y r o i d

meta-

bones). (i.e.

ter T T E a n d r a d i o i o d i n e t r e a t m e n t ) for d i f f e r e n t i a t e d

af-

thy-

r o i d c a r c i n o m a . A s u r v e y of the m o s t i m p o r t a n t r e s u l t s of r u m iCT d e t e r m i n a t i o n b e f o r e and 5 m i n a f t e r i.v. of c a l c i u m

(3-4 m g / k g ) and p e n t a g a s t r i n

/ u g / k g of b o d y w e i g h t )

(Peptavlon,

is p r e s e n t e d on t a b l e 1. T h e

ICI, 5 - 7 differen-

c e s b e t w e e n the c o n c e n t r a t i o n of iCT b e f o r e and a f t e r l a t i o n w e r e d i v e r s e . T h e d i f f e r e n c e of t h e i r m e a n s the s u b g r o u p w i t h and w i t h o u t m e t a s t a s e s w a s

se-

application

stimu-

between

statistically

significant. A s i m i l a r p i c t u r e h a s b e e n o b t a i n e d f r o m p a r a l l e l iCT

deter-

m i n a t i o n in the same g r o u p of p a t i e n t s by m e a n s of a p r o p r i e tary m e t h o d u s i n g our o w n s p e c i f i c a n t i s e r u m a g a i n s t iCT and l a b e l l e d iCT (1-125) w h i c h h a s b e e n p r e p a r e d in our

labora-

tory / 2 , 3 / . W i t h this m e t h o d , the c o n c e n t r a t i o n s of iCT w e r e g e n e r a l l y h i g h e r , and t h e r e f o r e the l i m i t of "normal" h a s b e e n r a i s e d up to 300 p g / m l . Our o w n s p e c i f i c a g a i n s t iCT s h o w s p r o b a b l y c r o s s - r e a c t i o n s w i t h

values

antiserum

circulating

r e l a t e d p e p t i d e s , w h o s e s p e c t r u m is o w i n g to the p r o c e s s of c a l c i t o n i n b i o s y n t h e s i s v e r y large and w h o s e s o u r c e m a y be o n l y in the

not

thyroid.

M u t u a l o v e r l a p p i n g of iCT c o n c e n t r a t i o n v a l u e s b e f o r e l a t i o n of c a l c i t o n i n s e c r e t i o n in p a t i e n t s w i t h a n d m e t a s t a s e s of M C T h a s b e e n m i l d

(about 10 % in the

stimu-

without test-kit

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a •** +* /-» ai M U

«

353 and 11-13 % in the proprietary method). It has been confirmed that iCT determination is very helpful tool for the differential diagnosis of MCT in the follow-up of patients with MCT. References 1. Bednair, J., D. Pichova, J. NSmec, S. Rohling, V. Stankov, J. HoluSova: fieskoslov. Farm. 30 (1981), 294. - 2. Bilek, R., M. Soutorova, J. Bednar, M. Pechova, M. Neradilova, J. Nemec, J. Havelka: ¿eskoslov. Farm., in press. - 3. Bednar, J., M. Neradilova, M. Soutorova, R. Bilek, J. Nemec, M. Pechova, J. Havelka: Czechoslovak Medicine, in press.

354 Effects of Propranolol enantiomers in hyperthyroidism (Poster) B. Obermayer-Pietsch, C. Stiegler, H. WarnkroB, G. Obermayer, S. Sager*, W. Lindner*, G. Leb Department of Internal Medicine, University of Graz, •Institute of Pharmaceutical Chemistry, University of Graz, Austria Racemic propranolol is known to inhibit the conversion of thyroxine ( T 4 ) to triiodothyronine ( T 3 ) with a simultaneous increase of reverse-triiodothyronine

(rT3). The levorotatory

(S-) enantiomer has 179 times more beta-blocking activity than R-propanolol. 22 hyperthyroid patients with recent onset of disease and nine euthyroid healthy controls received 40 mg R-prop. t. i.d. for 5 days; 10 patients and the euthyroids also s-prop. after a placebo-pause. We recorded cardiac parameters, peripheral thyroid parameters and serum-levels of the prop, enantiomers using HPLC. There was a wide range of individual propranolol values; Sprop. levels were about 40 % higher than R-prop. levels. T 3 and fT3 decreased significantly (p 0.01) in both groups, rT3 increased markedly (p 0.01; 50 %); the T3/T4~ratio decreased in both groups during R-prop. indicating lower conversion from T4 to T 3 . Since beta-blocking effects of R-prop. are negliable at the dosage used, we assume a stereospecific inhibition of 5 1 -deiodeinase in the conversion-step from T4 to T3 and the accumulation of rT3- We conclude that a benefit for hyperthyroid patients especially for those with contraindications for beta-blockers (congestive heart failure, obstructive airway disease etc.) is evident.

355 Thyroglobulin pattern in hyperthyroidism factitia (Case report) Eva Deckart Klinikum Berlin-Buch, Clinic for Nuclear Medicine and Endocrinology A female patient, 22 years of age, was transferred to our outpatient department with suspicion on hyperthyroidism. Her complaints: headache, nervousity, tachycardia

(115/min).

The clinical examination: no goiter, no vascular murmur, but hyperthyroid impression. No pertechnetate uptake of the thyroid gland (figure la) normal echopattern in thyroid sonography (figure 2). In vitro parameter: high T T 3 - and T T 4 serum level, no thyroid antibodies detectable, extreme low thyroglobulin concentration, normal TBG serum level despite estrogen pill intake (table 1). The patient was asked to take thyrostatic drug

(Methimazole),

but no treatment effect was seen during the following three months. The strong intervention on her bad compliance led her to consult a physician in Vienna, who confirmed the diagnosis of hyperthyroidism. The appelation to her common sense to stop the dangerous intake of high doses of thyroid hormone (as technician employed in a thyroid hormone tablets producing company she could get these tablets without recipe)

and the surveillance

during a stay on our ward finally normalized the situation: After withdrawal of tablets the thyroid hormone serum level began to normalize since December 1990 (table 1). The eumetabolic state can be observed by the increase of body weight (24 kg within 2 months), the change of sinustachycardia with a heart frequence of 115/min to normal frequence of 69/min and by normalization of bone metabolism (alkaline phosphatase was increased to 8.1/uMol/ml

(normal

range 1.4 - 2.8) during thyroid hormone abusus), and normal pertechnetate uptake in thyroid gland (figure lb).

356

•-I

\

•—i rH

IO

o o in

r-

Ol en s EH N

^ rH

(U

(a

ra

Stí




a< o 3 fi i a> 4-1 -H rd 0 J-> u 0) >1 a fi fi -p 0 aj fi

-p U o. s 3 3 O 1 lp Ol fi u a> ai a) P «H f-l -p (0 «H ^ -P 0) ai OJ O 00 t-H a. c i fi -o E o •H CL •P OL 3) O M en 14 -H -p 1-1 (U i ai fi u 0. ai fi e E-< >i a - p a) u >H fi i fi O e rH r-i Q. (U e -H fi •o a. > M +> (0 a) -H 3 ai O U -P M 0 W H S 3 M •• Ol >1 •• -H fi m fi rH i-H h

358

Figure 2 Thyroid ultrasound, transverse section (above), longitudinal section of left and right lobe (middle, lower fig). Normal echo pattern. Normal thyroid size

359 Thyroid function was suppressed by high doses of thyroid hormone (TSH 0.1 mU/1, thyroglobuline 6/ug/l). The high serum level of thyroglobuline (above 500/ug/l) after drug release indicated the reactivation of thyroid cell function followed by a normalization within six weeks. Conclusion Report on a psychopathic female patient who induced herself hyperthyroidism by thyroid hormone consumption in high doses keeping secret to the physician she consulted. Thyroglobulin- and TSH-serum level reflected the suppression of pituitary-thyroid axis. Thyroglobulin was the first parameter showing reagibility of thyroid cell system after withdrawal of thyroid hormone drugs. References 1. Alzawa, T., M. Ishihara, Y. Koizumi, K. Hashizume et al.: Amer. J. Med. 89 (1990), 175. - 2. Deckart, H., A. Blottner, W. Lobers, E. Deckart, W. Riichel: Thyroglobulin - a diagnostic parameter in Hyperthyroidism and in its followup. Radioaktive Isotope in Klinik und Forschung, Vol. 19 (Hrsg. H. Hofer, H. Bergmann, H. Sinzinger), Schattauerm Stuttgart, New York 1991, p. 514, Radiol, diagn. 26 (1985), 119.

360 Parameters of bone-metabolism in patients with hyperthyrosis (Poster) P. Dietel, H.J. Heberling, D. Lohmann City Hospital Leipzig, Germany The occurrence of hypercalcemia in a thyrotoxic patient may present an interesting problem. A moderate elevated serum calcium level may be noted during the course of hyperthyroidism in about 2.2 %. Excess of thyroid hormones is thought to produce hypercalcemia and hypercalcuria by activating osteoclastic bone resorption. Furthermore, thyroid hormone has been shown to increase the responsiveness of bone to administrated PTH, but whether endogenous PTH plays a role in the exaggerated osteoclastic activity of hyperthyroidism remains controversial, since PTH values have been reported to be elevated, diminished or normal. Primary hyperparathyroidism has also been reported in several hyperthyroid patients, but probably accounts for hypercalcemia in no more than 1 % of thyrotoxic patients. In such cases however it could be desirable to detect the parathyroid lesion before definitive therapy of hyperthyroidism is chosen. Parathyroid hormone levels, electrolytes, phosphatases and thyroid function were monitored during therapy with antithyroid medication in a group of patients with different forms of hyperthyroidism

(n = 36).

In average there was no significant change in serum calcium and AP after normalization of thyroid function, but a small significant increase of PTH-levels. However, in patients with elevated serum calcium levels at presentation, a significant decrease of serum calcium was found. That's why it may be, that the primary effect of thyrotoxicosis is the stimulation of osteoclastic bone resorption and that the resulting small increase in serum calcium tends to suppress PTH secretion. In contrast to reports in the literature we had no diagnostic

361 p r o b l e m s in the one p a t i e n t w i t h c o n f i r m e d p H P T . He c l e a r l y e l e v a t e d c a l c i u m - a n d P T H - v a l u e s e v e n in the of a c t i v e

hyperthyroidism.

revealed phase

362 PARATHYROID Clinical experience in parathyroid carcinoma G. Knappe, Helga Gerl, M. Ventz Clinic of Internal Medicine, Humboldt-University, Charité Berlin, Germany Primary hyperparathyroidism due to parathyroid carcinoma is a rare disease. According to McCance et al. (1987) about 120 cases have been reported in the literature during nearly 40 years since 1948. 2 to 5 % of all cases of primary hyperparathyroidism are estimated to be malignant, although the incidence found by various authors differed from 0.2 to 5.3 % (Gottswinder et al., 1984; Rapado et al., 1988). The most common presenting signs and symptoms are hypercalcemia, bone disease, renal stones and a palpable neck mass. Local recurrence or metastatic spread are to be expected in

30 % in

each case, and less than half of the patients die within 5 years (Schantz and Castleman, 1973). The following report is a retrospective evaluation of five cases we observed since 1973. Case reports Case 1 This young man suffered from multiple bone fractures beginning at the age of 18. 6 years later he presented a palpable mass on the right side of the neck which corresponded to local uptake of selen-methionin in the scintiscan. The total serum calcium was excessively elevated up to 4.8 mmol/1. The patient presented with typical clinical signs of primary hyperparathyroidism which was later proved by successful removal of a parathyroid adenoma and subsequent hypocalcemia. Two years later hypercalcemia recurred and the reoperation three tumors, one of which was a histologically proved carcinoma with invasion of thyroid gland tissue. Although three adenomas and one carcinoma had been removed serum calcium remained elevated. A new surgical exploration revealed

363 i n o p e r a b l e c o n d i t i o n s w i t h tumor i n v a s i o n of the e n t i r e

ven-

tral n e c k r e g i o n . The c l i n i c a l c o u r s e w a s c h a r a c t e r i z e d s e v e r e d i s e a s e d e t e r i o r a t i o n of o s t e o p a t h y and loss of

by nearly

all t e e t h due to the d e v e l o p m e n t of a l a r g e e p u l i s - l i k e

tumor

in the r i g h t m a x i l l a r r e g i o n . X - r a y i r r a d i a t i o n of the n e c k r e g i o n did n o t d e l a y the fatal c o u r s e .

It is n o t k n o w n if

only h y p e r c a l c e m i a and r e n a l f a i l u r e b u t also d i s t a n t ses c o n t r i b u t e d to the d e a t h in the f o l l o w i n g y e a r . nately, a u t o p s y w a s n o t c a r r i e d

metasta-

Unfortu-

out.

Case 2 The

second

p a t i e n t , a m a n of 20 y e a r s of age, p r e s e n t e d

excessively high serum calcium rathyroid hormone

with

(4.8 m m o l / 1 ) and e l e v a t e d

(880 / u m o l / 1 ) . A f i r m p a l p a b l e n o d u l e

the l e f t n e c k r e g i o n w a s e x t i r p a t e d ,

pafrom

and a f t e r d i a g n o s i n g

l i g n a n c y by f r o z e n s e c t i o n e x a m i n a t i o n the o p e r a t i o n

ma-

was

completed with total thyroidectomy. Additionally, a hyperp l a s t i c p a r a t h y r o i d g l a n d w a s f o u n d in the lower p o l e of r i g h t t h y r o i d lobe. The final tumor d i a g n o s i s w a s

anaplastic

p a r a t h y r o i d . A f t e r t r a n s i e n t h y p o c a l c e m i a the p a t i e n t f e e l i n g w e l l . He w a s t r e a t e d for p o s t o p e r a t i v e

the

was

hypothyroidism,

but a c o r r e c t i o n of s e r u m c a l c i u m w a s n o t f u r t h e r

needed.

20 m o n t h s later c a l c i u m and p a r a t h y r o i d h o r m o n e w e r e f o u n d to be in the n o r m a l r a n g e . Five y e a r s a f t e r s u r g e r y the was free of c o m p l a i n t s a n d in g o o d h e a l t h .

patient

Unfortunately,

f o l l o w up e x a m i n a t i o n s of s e r u m c a l c i u m , p a r a t h y r o i d

hormone

and n e c k u l t r a s o u n d w e r e n o t c a r r i e d o u t . T h i s p a t i e n t the o n l y case of c a r c i n o m a in a s e r i e s of 55 p a t i e n t s p r i m a r y h y p e r p a r a t h y r o i d i s m p u b l i s h e d by W e n d t and

was with

Geipel

(1989). Case 3 A s i m i l a r g o o d o u t c o m e w a s o b s e r v e d in a 37 y e a r s old presenting with typical primary hyperparathyroidism

woman

and a'

p a l p a b l e f i r m n o d u l e , n e a r l y 4 cm in d i a m e t e r , at the

level

of the left u p p e r t h y r o i d pole. S o n o g r a p h y s h o w e d a s o l i d

364 nodule with irregular echo structure. The serum calcium ranged between 3.25 and 3.75 mmol/1, and PTH was elevated to 580 pg/ml (C-terminal assay). After removal of the tumor and histologic diagnosis of a partly trabecular parathyroid carcinoma with multiple and in part atypical mitoses a second operation with total thyroidectomy was carried out. Four years later the patient was seen in good health and without any evidence of recurrence. Calcium and parathyroid hormone were found normal, and only thyroid hormone replacement was needed. 10 years after surgery the patient was free of complaints and normocalcemic. Case 4 A 51 years old woman suffered from nephrocalcinosis and severe cystic osteopathy with bone fractures. The serum PTH was elevated to 836 pmol/1 (midregional assay), and serum calcium ranged from 3.45 to 3.59 mmol/1. A nodular goitre was palpable and solid nodules were found on both sides on sonography. The Tc-99m-scintiscan showed the maximal uptake in the right nodule whereas a cold nodule was found in the left lobe. A fine needle biopsy of the cold nodule revealed oncocyte-like cells. After surgery this nodule was judged to be a parathyroid adenoma. Additionally in the right thyroid lobe a follicular thyroid carcinoma was diagnosed. After subsequent thyroidectomy no malignancy was found in the removed tissue. Because of thyroid carcinoma the treatment was completed with radioiodine irradiation. Nevertheless, the disease advanced, X-ray examinations revealed multiple osteolytic lesions and very small pulmonary nodules, and hypercalcemia persisted with values exceeding 3 mmol/1. An oral treatment with WR2721, an organic thiophosphate compound, normalized the serum calcium as well as the elevated magnesium levels and ameliorated the clinical condition. A clear-cut decrease of parathyroid hormone could not be observed.

365 No r e c u r r e n t g o i t r e or l y m p h n o d e s w e r e p a l p a b l e . A n of tumor l o c a l i z a t i o n w i t h t h a l l i u m s c i n t i s c a n w a s

attempt

negative

in the n e c k and c h e s t . Some t h a l l i u m u p t a k e in the l e f t t a r s a l b o n e s r e m a i n e d o b s c u r e . F i n a l l y , a long t e r m

meta-

treatment

w i t h W R - 2 7 2 1 w a s c a r r i e d out for s e v e r a l m o n t h s w h i c h a g a i n lowered serum calcium but without

normalization.

The p a t i e n t r e t u r n e d to her family and d i e d in h e r

regional

h o s p i t a l . At a u t o p s y s c a t t e r e d c l u s t e r s of p a r a t h y r o i d c i n o m a w e r e f o u n d in the p a r a t r a c h e a l scar t i s s u e

ca-

showing

f i b r o u s b a n d s , m i t o t i c f i g u r e s and c a p s u l a r and b l o o d i n v a s i o n . No t h y r o i d t i s s u e c o u l d be d e t e c t e d . No

vessel

systemic

m e t a s t a s e s w e r e f o u n d in the lungs and b o n e s , b u t b r o w n cell t u m o r s and o t h e r s i g n s of h y p e r p a r a t h y r o i d a l w e r e p r e s e n t in the

giant

osteopathy

skeleton.

Case 5 T h i s f e m a l e p a t i e n t , n o w 63 y e a r s of age, s e e m e d to be

cured

f r o m p r i m a r y h y p e r p a r a t h y r o i d i s m b y r e m o v a l of a chief

cell

a d e n o m a . D u r i n g a ten y e a r f o l l o w up c a l c i u m a n d

parathyroid

h o r m o n e r e m a i n e d n o r m a l but after t h a t h y p e r c a l c e m i a up to 3.0 m m o l / 1 r e a p p e a r e d . A n o d u l e of 12 m m in d i a m e t e r

was

found on s o n o g r a p h y and c o m p u t e d t o m o g r a p h y . A t f i r s t

the

p a t i e n t w a s t r e a t e d w i t h W R - 2 7 2 1 w h i c h n o r m a l i z e d the

serum

c a l c i u m . L a t e r the t u m o r and r i g h t t h y r o i d lobe w e r e

removed.

The h i s t o l o g i c

parathy-

i n v e s t i g a t i o n r e v e a l e d in p a r t n o r m a l

r o i d t i s s u e as w e l l as t u m o r t i s s u e w i t h i n v a s i o n of

surround-

ing s t r u c t u r e s and b l o o d v e s s e l s . T h e p a t i e n t is n o w in g o o d health but after transient normocalcemia increased again possibly

the s e r u m

indicating persisting

calcium

carcinoma.

Discussion It is w e l l k n o w n f r o m l i t e r a t u r e that the c l i n i c a l p i c t u r e patients with hormone secreting parathyroid carcinomas not differ substantially

f r o m the f i n d i n g s in b e n i g n

in

does

primary

366 hyperparathyroidism.

T h e r e are the same b i o c h e m i c a l

findings,

and the e x c e s s of p a r a t h y r o i d h o r m o n e c a u s e s the same manifestations

in k i d n e y s and b o n e s . N e v e r t h e l e s s ,

cial a s p e c t s w h i c h a g r e e w i t h o t h e r r e p o r t s are in our c a s e s

organ

some

remarkable

(table 1). C o r r e s p o n d i n g to o t h e r r e p o r t s

(Cohn

et al., 1985; W a h l et al., 1988) t h r e e of our p a t i e n t s y o u n g e r t h a n 40 y e a r s of age w h e r e a s p r i m a r y r o i d i s m due to a d e n o m a o c c u r s p r e d o m i n a n t l y Several authors

spe-

were

hyperparathyin o l d e r

people.

(McCance et al., 1987; G o t t e s w i n t e r et al.,

1984) r e f e r to r e l a t i v e l y h i g h s e r u m c a l c i u m in m a l i g n a n c y w h i c h w a s p r o v e d true in t h r e e of our p a t i e n t s w i t h l e v e l s e x c e e d i n g 4 m m o l / 1 . The e x p e r i e n c e w i t h

calcium

parathyroid

h o r m o n e l e v e l s and w i t h tumor m a r k e r s s e e m s too l i m i t e d to n o w to p e r m i t c o n c l u s i o n s a l t h o u g h some a u t h o r s striking high PTH values

up

noticed

(McCance et al., 1987; S h a p i r o

et

al., 1989; R a p a d o et al., 1988; W a h l et al., 1988). The c i n o m a s h a v e b e e n f o u n d p a l p a b l e in four of our

car-

patients

w h i c h c o n f i r m s the g e n e r a l e x p e r i e n c e of a h i g h f r e q u e n c y palpable tumors

(McCance et al., 1987; P o l l a c k et al.,

S c h a n t z and C a s t l e m a n ,

of

1961;

1973).

R e c u r r e n t h y p e r p a r a t h y r o i d i s m h a s b e e n d e s c r i b e d in b o t h g e n e t i c and s p o r a d i c f o r m s b u t p r e d o m i n a n t l y a d e n o m a s are

in-

v o l v e d in t h i s s i t u a t i o n . Two of our p a t i e n t s s e e m e d at

first

c u r e d b u t 2 to 10 y e a r s later r e l a p s e d w i t h a m a l i g n a n t

tu-

mor. A c c o r d i n g to M a z z u o l i et al.

(1987) r e c u r r e n t

t h y r o i d i s m is a v e r y r a r e e v e n t and in t h e i r case

hyperparareports

o n l y one of t h r e e p a t i e n t s h a d c a r c i n o m a . On the other hyperparathyroidism associated with differentiated

hand,

thyroid

c a r c i n o m a is f o u n d m o r e f r e q u e n t l y t h o u g h g e n e r a l l y the

co-

i n d i d e n t a l p a r a t h y r o i d t u m o r s are b e n i g n . N i e d e r l e et al. (1982) r e v i e w e d 151 c a s e s w h i c h w e r e 2.9 % in a s e r i e s of m o r e t h a n 5000 c a s e s of p r i m a r y

hyperparathyroidism.

The p r o g n o s i s of p a r a t h y r o i d c a r c i n o m a is r e l a t i v e l y

good

t h o u g h o n l y the i n i t i a l o p e r a t i o n r e p r e s e n t s the only of c u r e and c h e m o t h e r a p y and r a d i o t h e r a p y

f a i l e d to

chance

improve

367 survival (Cohn et al., 1985). Weather WR-2721 contributes to a more favourable course cannot be concluded from our two cases. Results of long-term treatment with WR-2721 have not been reported up to now whereas short time studies with intravenous application led to significant decrease of serum calcium (Glover et al., 1985; Morita et al., 1985).

Table 1: Remarkable findings in parathyroid carcinoma

Patient

1

2

3

4

5

age < 40

+

+

+

-

-

Ca > 4 mmol/1

+

+

+

-

-

osteopathy

+

+

+

+

+

tumor palpable

+

+

+

+

-

multiple tumors

+

-

-

+

+

first histology

ad

ca

ca

ad

ad

remission with first treatment

+

+

+

-

+

remission of hyperparathyroidism in years

2

5

10

0

10

Acknowledgement The parathyroid operations (case 1,3-5) were performed in the Clinic of Surgery, Humboldt-University/Charite

(Director:

Prof. Dr. Dr. h.c. H. Wolff); case 2 was operated on in the I. Clinic of Surgery, Klinikum Buch, Berlin (Director: Prof. Dr. F. Wendt). The autopsy of case 4 was carried out in the Institute of Pathology, Bezirkskrankenhaus Halle/Saale (Head: Dr. sc. med. Knolle).

368 References 1. Cohn, K., M. Silverman, J. Corrado, C. Sedgewick: Surgery 98 (1985), 1095. - 2. Glover, D.J., L. Shaw, J.H. Glick, E. Slatopolsky, C. Weiler, m. Attie, S. Goldfarb: Ann. Intern. Med. 103 (1985), 55. - 3. Gottswinter, J.M., R. Ziegler, H.J. Weise, K. Baczako, B. Heymer, Ch. Herfarth: Klin. Wochenschr. 62 (1984), 613. - 4. Mazzuoli, G., S. Minisola, A. Scarda, A. De Matteis, S. Tabolli, F. Bigi, C. Valtorta, E. D'Erasmo: Postgrad. Med. J. 63 (1987), 201. - 5. McCance, D.R., B.D. Kenny, J.M. Sloan, C.F.J. Rüssel, D.R. Hadden: J. Roy. Soc. Med. 80 (1987), 505. - 6. Morita, M., K. Higashi, J. Tajiri, T. Sato: Ann. Intern. Med. 103 (1985), 961. - 7. Niederle, B., R. Roka, K. Klaushofer, J. Kowarik: In: A. Fritsch und G. Geyer

(Hrsg.): Hyperparathyreoidismus, Urban & Schwarzenberg,

Wien-München-Baltimore,

1982, 76. - 8. Pollack, S., R.R.

Goldin, M. Cohen: Arch. Intern. Med. 108 (1961), 583. 9. Rapado, A., G. Renedo, J.M. San Román, H. Oliva, J.M. Castrillo, V. Soné, M. Velo, F. Rurrión: Rev. Clin. Esp. 182 (1988), 407. - 10. Schantz, A., B. Castleman: Cancer 31 (1973), 600. - 11. Shapiro, D.M., W. Recant, M. Hemmati, T. Mazzone, R.H. Evans: Surgery 106 (1989), 929. - 12. Wahl, R.A., M. König, H. Schmidt-Gayk, H.D. Roher: Wien. med. Wochenschr. 138 (1988), 461. - 13. Wendt, F., D. Geipel: Exp. Clin. Endocrinol. 94 (1989), 163. Discussion Gembicki: My congratulation for so excellent presentation may I ask you for some comments on two following

subjects:

1. I am sure you performed bone scintigraphy in majority of your cases. Does this method, which usually is demonstrating bone changes much earlier then X-ray method, help you in evaluation of cases pathology as well as to monitor the progress of the treatment? 2. You mentioned that you treated one patient with radioactive iodine - may I ask you what was the reason of such a

369 treatment? Knappe: Bone scintigraphy was not made in all patients, and only in the one who had first presented an adenoma and long term remission for ten years there was some evaluation of osteopathy. But now we look for before severe disease and I can not give an answer. To your second question - it was the treatment of the coincidence of follicular thyroid carcinoma. This patient two carcinomas - one thyroid carcinoma and parathyroid carcinoma . Peschel: Remarks to the difficulties in establishing the definitive diagnosis if you find solid trabecular patterns with mitosis but no vascular invasion as it has been demonstrated in case number three. Knappe: In all cases we have this extensively discussed with our pathologists and regularily they made the diagnosis of carcinoma when capsular and blood vessel invasion is found. In the problematic case (No. 3) they have only found clusters of irregular mitosis but no blood vessel invasion. Rink: Did you observe some ECG changes in this patients with hypercalcemia? Knappe: I don't remember exactly, but some ECG changes are related to hypercalcemia, may be.

370 Unusual course of primary hyperparathyroidism R. Hehrmann Medizinische Klinik, Abteilung I, Diakonissenkrankenhaus Stuttgart, Germany As an introduction into the subject of primary hyperparathyroidism (I.HPT) an unusual case is being reported, showing, that even today I. HPT can be mistaken for metastatic cancer. A 69 year old women came into our hospital by chance, when she visited her husband, who was treated as an inpatient because of a transitory ischemic attack in November 1990. She suffered severe pain in her back, her pelvis and her right leg, and she could only walk using two crutches. An X-ray of her pelvis and vertebral column was made showing a spontaneous fracture of the right pelvis and all signs of low bone mineral content. The patient became now hospitalized and the retrospective case history revealed the following: Hypertension and hyperlipidaemia were known since 1985 and peripheral arterial vessel disease was treated by catheter dilatation of the right superficial femoral artery. In 1988 cerebral ischemia with left hemiplegia was treated in another hospital with complete neurological recovery. Since January 1990 she suffered from increasing back pain and inconsistant pain in both legs. Multiple X-rays over the year and a bone scan in September 1990 led to the diagnosis of multiple osteolytic bone lesions. An extensive search for a primary tumor was without success. In September 1990 a bone biopsy was performed on one of the osteolytic lesions at the dorsal processus of the 7th cervical vertebra, but a definite histological diagnosis could not be made, however bone metastases could not be verified. In October 1990 palliative radiation of the osteolytic lesions of the spine and the right calcaneous was performed.

371 T h e r e w a s o n l y l i t t l e relief of p a i n , the use of remained

analgetics

high.

A f t e r the v i s i t of h e r h u s b a n d in our h o s p i t a l the p a t i e n t also h o s p i t a l i z e d and the r e l e v a n t l a b o r a t o r y s h o w e d the f o l l o w i n g

was

parameters

results:

C a l c i u m w a s r e p e a t e d l y n o r m a l w i t h 4.8 m V a l / 1 , P04 w a s

slight-

ly d e c r e a s e d to 1.8 m g / d l . K i d n e y f u n c t i o n w a s n o r m a l as w e l l as total p r o t e i n , a l b u m i n and e l e c t r o p h o r e s e s . U r i n a r y excretion was

calcium

normal.

A l k a l i n e p h o s p h a t a s e w a s e x t r e m e l y e l e v a t e d to 1 0 7 5 - 1 3 0 0 Parathyroid hormone

(PTH) w a s c l e a r l y

- P T H C - t e r m i n a l w a s 322 p M o l / 1

(normal

- PTH intact

(normal

was

22 p M o l / 1

10-55) 1-6 ).

B o n e d e n s i t y w a s as low as 48 % of y o u n g n o r m a l s femoral

(DPA of

left

neck).

U l t r a s o n o g r a p h y of the n e c k r e v e a l e d a s m a l l b i l a t e r a l goitre

U/l.

elevated:

(right lobe 24 ml, left lobe 15 m l ) and a s m a l l

p o o r n o d u l e in r i g h t i n f e r i o r p o s i t i o n m e a s u r i n g

nodular echo-

11 x 11 x 13

mm. The d i a g n o s i s of p r i m a r y h y p e r p a r a t h y r o i d i s m sufficiently

s e e m e d to be

safe.

On D e c e m b e r 7th, 1990 p a r a t h y r o i d e c t o m y w a s c a r r i e d o u t .

In

r i g h t i n f e r i o r p o s i t i o n a p a r a t h y r o i d a d e n o m a of 0.6 g w a s r e m o v e d as w e l l as one n o r m a l p a r a t h y r o i d

in r i g h t u p p e r

sition. A third, normal parathyroid was identified u p p e r p o s i t i o n , a f o u r t h g l a n d c o u l d n o t be

po-

in l e f t

found.

In a d d i t i o n n e a r l y total t h y r o i d e c t o m y of the r i g h t lobe w a s performed. Postoperatively

c a l c i u m fell to 3.7 m V a l / 1 w i t h o u t

symptoms

of t e t a n y . Oral c a l c i u m s u b s t i t u t i o n w a s i n i t i a t e d , the t i e n t d i s c h a r g e d f r o m the h o s p i t a l

1 week after

operation.

4 w e e k s later she r e p o r t e d d r a m a t i c i m p r o v e m e n t of

symptoms,

b a c k and j o i n t p a i n h a d a l m o s t v a n i s h e d , she c o u l d w a l k out

support.

pa-

with-

372

Calcium was now normal (4.4 mVal/1) as well as phosphate (2.8 mg/dl) but surprisingly, alkaline phosphatase was still markedly elevated (636 U/l). C-terminal PTH (105 pMol/1) and intact PTH (8.5 pMol/1) were clearly lower than preoperatively, but were not normalized. Oral calcium substitution was discontinued. 3 months after operation the patient felt very well, was practically without complaints. Calcium had further increased to 4.8 mVal/1, P04 was low (1.9 mg/dl), alkaline phosphatase was unchanged (641 U/l). PTH remained moderately elevated (PTH C-terminal 104 pMol/1, intact PTH 14 pMol/1). Despite dramatic clinical improvement after removal of a parathyroid adenoma the diagnosis of residual hyperparathyroidism due to "multiple gland disease" must be suspected. Computertomography and magnetic resonance tomography could not clearly demonstrate the site of a further parathyroid adenoma, ultrasound shows a small echopoor area parattracheally and dorsal to the residual left thyroid lobe. A second operation os planned. References 1. Hehrmann, R.:Plasma-Parathormon, Methodik, Pathophysiologic und Klinik. Urban & Schwarzenberg (1980). 2. Freyschmidt, J., R. Hehrmann: Rontgen-Bl. 31 (1978), 495.3. Hehrmann, R., E. Keck: Dt. Arztebl. 79/28 (1982), 42.

373 Long-term results of operated hyperparathyroidism U. Krause*, Ch. Jeziorowski*, Th. Olbricht** Abteilung für Allgemeine Chirurgie* und Abteilung für Klinische Endokrinologie** der Medizinischen Klinik der Medizinischen Einrichtungen der Universität, Gesamthochschule, Essen, Germany The natural history, diagnosis, treatment modalities and early post operative results of primary hyperparathyroidism (pHPT) are well described in the literature /l-4,6/. Also, the indication for surgical treatment as well as the operative procedure are generally accepted /1,7/. On the other hand, reports about long-term results after successful surgical treatment are rare. Rates of true recurrences are reported to be about 1 % /5/. From July 1990 till March 1991 we performed a retrospective study of all patients who were operated on for primary hyperparathyroidism at our institution from 1979 through 1989. There were 225 patients with the diagnosis of pHPT. The majority has been operated between 1985 and 1989. Mean age at time of operation was 60.4 years (range 21 to 85). Most of the patients were between 51 and 70 years old (135 or 60 %) (see figure 1). The sex ratio was 3:1 in favour of the females . Thirty patients had no symptoms of their disease (13.3 %), whereas the rest of 195 patients were symptomatic. Of these, 57 % had nephrolithiasis, 29 % had bone disease, 14 % had gastric or duodenal ulcer and 9 % had psychiatric disturbances. The total percentage is more than 100 because of multiple symptoms in about 1/3 of patients (table 1). Operative results 1. Localization diagnostics As a standard method of localization we performed ultrasound in all cases. In 123 patients we obtained a positive

374 preoperative image of the suspected adenoma, resulting in a sensitivity rate of 55 %. In 102 patients (45 %) ultrasound was negative. In these cases correct negative results are included, however (approximately 10 %). Computed tomography we did not use routinely. Most of the patients with CT-scans were referred to us after diagnosis elsewhere. Of 59 patients there were 36 with positive imaging (61 %). In 23 patients or 89 % CT-scan was negative. We do not recommend any localization diagnostics before initial surgery for pHPT, except ultrasound. Like most other active groups in this field we perform the first operation regardless of the result of preoperative localization diagnostics. 2. Intraoperative findings Enlarged glands could be detected in 214 patients (95 %). The localization was nearly equally distributed between the upper and lower position (43 versus 39 %). In 12 % of the patients adenomas were found in both positions, in only one patient a mediastinal adenoma was removed. Regarding pathology, in 11 patients only normal tissue was removed corresponding to a failure rate of 5 %. In 183 patients (81 %) one adenoma was found, in 17 patients (7.6 %) two adenomas were removed, three in eleven patients or 5 % and four in 3 patients or 1.3 %. For the purpose of this study we did not distinguish hyperplasia and multiple adenomas. The majority of patients with more than one adenoma had multiglandular disease, whereas true double adenomas were rare. 3. Perioperative morbidity Permanent recurrent nerve paralysis - the major complication of parathyroid surgery - occurred in 7 patients or 3.3 %. Five patients had unilateral lesions and two patients suffered from bilateral injury. One patient required

375 t r a c h e o s t o m y . T h i s r a t e of r e c u r r e n t n e r v e p a r a l y s i s p a r e s to o t h e r a u t h o r s , w h o r e p o r t r e c u r r e n t n e r v e in 0.5 to 10 % of c a s e s

injuries

/l/.

4. I m m e d i a t e p o s t o p e r a t i v e r e s u l t s

(table

2)

The s e r u m c a l c i u m l e v e l s w e r e n o r m a l i z e d at time of sion from hospital

com-

in 134 p a t i e n t s

dismis-

(95.5 % ) . 78 p a t i e n t s

w e r e h y p o c a l c e m i c , r e q u i r i n g o r a l s u b s t i t u t i o n of

calcium.

T h e s e two g r o u p s of p a t i e n t s a d d to a t o t a l n u m b e r of p a t i e n t s w h o c a n be r e g a r d e d as b e i n g s u c c e s s f u l l y (94.5 %) . T h i r t e e n p a t i e n t s

(5.5 % ) r e m a i n e d

hypercalcemic.

In t h e s e n u m b e r 4 p a t i e n t s w i t h r e o p e r a t i o n are

included,

as w e l l as two p a t i e n t s w h o h a d m a l i g n a n t d i s e a s e of t h y r o i d s , w h i c h w a s r e c o g n i z e d in f u r t h e r

Table

without -

para-

operations.

1: S y m p t o m s of 225 p a t i e n t s w i t h p H P T

Symptoms

with

212

operated

frequency symptoms

symptoms

nephrolithiasis

- bone - ulcer

disease disease

- psychiatric

disturbance

percent

30

13.3 %

195

86.7 %

129

57.3

%

65

28.9 %

30

13.3 %

20

8.9 %

n = 225

376 Table 2: Immediate postoperative results of 225 operated patients: Serum-calcium levels Serum calcium normal

frequency 134

hypo

78

hyper*

13

percent 59.5 %) =94.5 % 34.7 %) 5.8 %

(*n = 4 reoperations)

Results of follow up examination (table 3) In 1990 till March 1991 we could examine 129 of 225 operated (57 %) in our policlinic. Of additional 50 patients we received information by a questionnaire sent to the patients and their doctors. Mean follow up time was 4.8 years (minimum was 1.1 and maximum was 11.1 years). The majority of patients (57 % had a follow up time of 3 to 6 years. Among the 179 evaluable patients there was no symptomatic recurrence of hyperparathyroidism, except four patients with persisting hypercalcemia who could not be cured after initial and follow up surgery (s. chapter III, 4.). Of 129 patients who were reexamined we have exact laboratory data (see table 3). Three patients with biochemical recurrence of hyperparathyroidism were detected during re-evaluation 83, 8, 10 years after initial surgery). True recurrence was defined as elevated calcium level as well as elevated parathormone after originally achieved normocalcemia lasting at least one year after surgery. All of the three patients had no symptoms. One of these we have operated on again in the meantime, and found a local recurrence. Fourteen patients or 10.8 % were normocalcemic, without symptoms, but had elevated pTH-levels. In our opinion, these patients have a considerable risk of developing a recurrence later on. These patients will be carefully observed in the future.

377 T a b l e 3: R e s u l t s of f o l l o w up e x a m i n a t i o n (mean time 4.8 y e a r s ) : t h r e e p a t i e n t s d e v e l o p e d r e c u r r e n c e s n = 129 e x a m i n e d ) n = 50 by q u e s t i o n n a i r e )

recurrence

175

(cured a f t e r i n i t i a l n =

(Cai, P T H Î )

normocalcemic,

PTH 1

hypocalcemic normal PTH, normal

Ca

surgery) %

3

2.3

14

10.8

3

2.3

109

84.6

129

100 %

n = 129

T h r e e p a t i e n t s or 2.3 % w e r e h y p o c a l c e m i c , b u t w i t h o u t

symp-

toms . The r e s t of the p a t i e n t s , t h a t m e a n s

109

(85 %) h a d

normal

P T H a n d n o r m a l c a l c i u m l e v e l s . H o w e v e r , f i f t e e n of t h e s e or 11 % w e r e s u b s t i t u t e d w i t h oral

calcium.

A m o n g the 50 p a t i e n t s a s k e d by q u e s t i o n n a i r e t h e r e w a s no s y m p t o m a t i c r e c u r r e n c e . The l a b o r a t o r y d a t a r e f e r r e d to us d i d n o t r e v e a l any m o r e r e c u r r e n c e , t h e s e are

incomplete,

however. S u m m a r i z i n g the r e s u l t s of f o l l o w up e x a m i n a t i o n , we f o u n d 3 of 129 é v a l u a b l e p a t i e n t s w i t h r e c u r r e n t

hyperparathyroidism,

that m e a n s 2.3 %. R e g a r d i n g the t o t a l of 175 p a t i e n t s

éva-

l u a b l e , the r e c u r r e n c e r a t e w o u l d be 1.7 %. If we a s s u m e ,

the

same r e c u r r e n c e r a t e in the g r o u p of p a t i e n t s w h o are l o s t to f o l l o w up t h e r e m i g h t be one m o r e p a t i e n t w i t h

recurrent

disease. Most interesting elevated PTH

is a g r o u p of n o r m o c a l c e m i c p a t i e n t s

(14 or 10.8 % of é v a l u a b l e p a t i e n t s ) .

with

Theoreti-

c a l l y , t h e s e p a t i e n t s h a v e a n i n c r e a s e d risk to d e v e l o p current hyperparathyroidism

later

on.

re-

378

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as

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evi 0 ag> C O — C O

a î Co

m CD 03 01& n LI. co c 0 03 E

o,

O, M o

M-l

O