DISORDERS OF PORPHYRIN METABOLISM

TOPICS IN HEMATOLOGY Series Editor: Maxwell M. Wintrobe, M.D.

University of Utah, Salt Lake City

DISORDERS OF PORPHYRIN METABOLISM Michael R. Moore, Ph.D., Kenneth E. L. McColl, M.D., Claude Rimington, Ph.D., and Sir Abraham Goldberg, M.D.

HEMOL YTIC ANEMIA IN DISORDERS OF RED CELL METABOLISM Ernest Beutler, M.D.

THE RESPIRATORY FUNCTIONS OF BLOOD Lars Garby, M.D., and Jerry Meldon, M.D.

TRACE ELEMENTS AND IRON IN HUMAN METABOLISM Ananda S. Prasad, M.D.

DISORDERS OF PORPHYRIN METABOLISM Michael R. Moare, s.sc.. rh.o.

and

Kenneth E. L. McColl, M.D., M.R.C.P.

Western bzfirmary Universily of Glasgow Glasgow, Scotlmzd

Claude Rimington, Ph.D., D.Sc., Hon. F.R.C.P., F.R.S.

N01wegimz Radium Hospital mzd Norsk Hydro Institute Oslo, Norway

and

Sir Abraham Goldberg, K.B., M.D., o.sc., F.R.C.P., F.R.S.E.

Westerrz Irzfimzary Universily of Glasgow Glasgow, Scotland

SPRINGER SCIENCE+BUSINESS MEDIA, LLC

Library of Congress Cataloging in Publication Data

Disorders of porphyrin metabolism.

(Topics in hematology) Dedicated to the memory of Maxwell M. Wintrobe. Includes bibliographies and index. 1. Porphyria. 1. Moare, Michael R. II. Wintrobe, Maxwell Myer, 1901-

[DNLM: 1. Porphyrins-metabolism. QU 110 0612] RC632.P6D57 1987 616.3'9

ISBN 978-1-4684-1279-6 ISBN 978-1-4684-1277-2 (eBook) DOI 10.1007/978-1-4684-1277-2

© 198 7 Springer Science+ Business Media New York

Originally published by Plenurn Publishing Corporation in 1987 Softcover re print of the hardcover 1 st edition 198 7

AII rights reserved

. III. Series.

87-14125

No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means. electronic. mechanical, photocopying, microfilming, recording, or otherwise, without written permission from the Publisher

MAXWELL M. WINTROBE

A Dedication

There are few in the field of medicine, and none in that of hematology, who do not know of Professor Max Wintrobe and of his great contribution to his specialty.

We were pleased when he approached us, in his capacity as series editor of Topics in Hematology, with a request that we write a book on the subject of the porphyrias. Circumstances militated against us and our efforts were somewhat tardy. Because of this, we had frequent transatlantic communica­tions from him, urging us to greater efforts. On one occasion, during the mam­moth International Congress of Hematology that he organized in Montreal, his gruff question, after the usual pleasantries, was, "Well-when will it be ready?" Max clearly had a great personal interest in the completion of our book. We were heartened by his complimentary responses to the manuscripts, as they were passed to him through the summer of 1986. Sadly, that was his last editing task. Before the book went to press, he died without having seen it in print. It is, however, gratifying that he saw its completion and was able to review it, if only in manuscript form.

We dedicate this volume, Disorders of Porphyrin Metabolism, to him because of his avid interest and great encouragement, which in no small measure ac­count for its very existence. We should also like to acknowledge his own per­sonal contribution to the science of hematology, of which porphyria is but one specialized topic.

M.R.M. K. E. L. McC. C. R. A. C.

A Biochemical Fantasy

I sometimes give my fancy wings

And eyes to see the souls of things . ..

Porphyrins red as a summer's rose

With feathered caps and silken hose,

Pigments of bile, ali burnished gold,

Striding their steeds like knights of old.

PBG like an eastern king

Wears purple robes mid a golden ring

But ALA is the risen sun

That telis of a new-bam day begun

Stenl DNA like II coiled-up spring

Speeds RNA 011 a messenger's wing

To knock 011 the door where the polysollles wait

To crack the code that spelis their fllte.

Proud A TP displays his might

And milii-mu is a shaft of light.

Oh! Many a time I have longed to see

The dancing plumes of 10,000 G!

Dmr words caressed by the soft grey wing

In my twilight world of imagining.

-CLAUDE RIMINGTON (1967)

PREFACE

Each of the four authors of this book has a particular interest in disorders of porphyrin metabolism and special experience in their management. Their individual involvement in the field varies from 12 to 52 years and, combined, represents more than a century of personal experience. Since it has been written by both basic scientists and practicing physicians, the book is intended to be of value to all those involved in porphyrin metab­olism and the porphyrias. It is hoped that the fascination of porphyrin metabolism and the clinical challenge of the porphyrias experienced by each of the authors will be conveyed to the readers.

Michael R. Moore Kenneth E. L. McColl Claude Rimington Abraham Goldberg

vii

CONTENTS

Color Plates ............................................ xvii

1. The History, Classification, and Incidence of the Porphyrias 1

1.1. History ........................................ 1 1.1.1. Early Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 1.1.2. Early Descriptions of Porphyria .............. 4 1.1.3. Biochemical Developments .................. 4 1.1.4. Acute Porphyria . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 1.1.5. A Complete Pathway ...................... 8

1.2. Classification of the Porphyrias . . . . . . . . . . . . . . . . . . . . . 9 1.2.1. The Current Classification. . . . . . . . . . . . . . . . . . . 12 1.2.2. Enzymic Consideration of Classification ....... 13

1.3. Geographical Distribution and Incidence of the Porphyrias ..................................... 17

1.4. Porphyrinurias .................................. 18 1.5. The Royal Malady ............................... 19 1.6. Werewolves .................................... 19

2. Porphyrins and Enzymes of the Heme Biosynthetic Pathway 21

2.1. Structure....................................... 21 2.2. Heme Synthesis ................................. 23

2.2.1. ALA Synthase (EC 2,3,1,37) Succinyl CoA: Glycine C-Succinyl Transferase .............. 23

2.2.2. ALA Dehydratase (EC 4,2,1,24) (Syn Porphobilinogen Synthase, ALA Hydrolase) 26

2.2.3. PBG Deaminase (EC 4,3,1,8) [Syns Uroporphyrinogen 1 Synthase,

ix

x CONTENTS

H ydroxymethylbilane Synthase, Porphobilinogen Ammonia Lyase (Polymerizing)), and Uroporphyrinogen 3 Cosynthase (EC 4,2,1,75) (Uroporphyrinogen 3 Synthase) .............. 28

2.2.4. Uroporphyrinogen Decarboxylase (EC 4,1,1,37). 30 2.2.5. Coproporphyrinogen Oxidase (EC 1,3,3,3) ..... 32 2.2.6. Protoporphyrinogen Oxidase (EC 1,3,3,4) ...... 33 2.2.7. Ferrochelatase (EC 4,99,1,1) (Syn Heme

Synthase, Protoheme-Ferrolyase) ............. 33 2.3. Heme Biodegradation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

2.3.1. Heme Oxygenase (EC 1,14,99,3) ............. 35 2.3.2. Biliverdin Reductase (EC 1,3,1,24) ............ 37

2.4. Control of Heme Biosynthesis ............... . . . . . . . 38 2.4.1. The Role of ALA Synthase .................. 38 2.4.2. Glycine.................................. 39 2.4.3. Control in Normal Subjects ................. 39 2.4.4. Porphyrias-Control of the Pathway: Role of

PBG Deaminase as a Secondary Control Step ... 40 2.4.5. Control in Erythroid Cells .. '.' . . . . . . . . . . . . . . . 41 2.4.6. Other Factors ............................. 42

2.5. Neurobiochemistry of the Acute Attack .............. 44 2.5.1. The Role of 5-Aminolevulinate .............. 44 2.5.2. Pyridoxal Phosphate ....................... 45 2.5.3. Heme Deficiency .......................... 45

2.6. Laboratory Investigation of the Porphyrias ........... 46 2.6.1. Porphyrias ............................... 46 2.6.2. Porphyrinurias............................ 46 2.6.3. The Properties of Porphyrins and

Porphobilinogen .......................... 47 2.6.4. Spectrophotometry and Spectrofluorimetry ..... 47 2.6.5. Initial Investigations ....................... 50 2.6.6. Enzymes of Heme Biosynthesis .............. 55 2.6.7. Quantitative Porphyrin Measurement ......... 57 2.6.8. Chromatographic Separation of Porphyrins .... 63 2.6.9. Other Techniques ......................... 66 2.6.10. Porphyrin Profiles. . . . . . . . . . . . . . . . . . . . . . . . . 68

3. The Acute Porphyrias ................................... 73

3.1. Introduction .................................... 73 3.2. Clinical Classification ........ . . . . . . . . . . . . . . . . . . . . . 73

CONTENTS xi

3.3. Biochemical Classification 73 3.4. Inheritance and Incidence ......................... 75

3.4.1. Acute Intermittent Porphyria ................ 76 3.4.2. Variegate Porphyria. . . . . . . . . . . . . . . . . . . . . . . . 76 3.4.3. Hereditary Coproporphyria ................. 77 3.4.4. Plumboporphyria.......................... 77

3.5. Acute Intermittent Porphyria . . . . . . . . . . . . . . . . . . . . . . . 77 3.5.1. Clinical Features .......................... 77 3.5.2. Gastrointestinal Manifestations .............. 81 3.5.3. Neurological Manifestations ................. 81 3.5.4. Cardiovascular Manifestations ............... 83 3.5.5. Renal Manifestations . . . . . . . . . . . . . . . . . . . . . . . 83 3.5.6. Psychiatric Aspects ........................ 84 3.5.7. Biochemistry ............................. 84 3.5.8. Other Laboratory Findings in Acute

Attack. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 3.6. Variegate Porphyria .............................. 91

3.6.1. Clinical Presentation ....................... 92 3.6.2. Concurrent Porphyria ...................... 94 3.6.3. Abnormal Enzyme Activity. . . . . . . . . . . . . . . . . . 94

3.7. Hereditary Coproporphyria ........................ 95 3.8. Plumboporphyria................................ 97 3.9. Differential Diagnosis of Acute Hepatic

Porphyrias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 3.10. Screening of Relatives ............................ 98

3.11. Precipitating Factors . . . . . . . . . . . . . . . . . . . . . . . . 98 3.11.1. Menstruation ............................ 99 3.11.2. Pregnancy .............................. 100

3.12. Management and Treatment. . . . . . . . . . . . . . . . . . . . . .. 101 3.12.1. Carbohydrate Loading .................... 103 3.12.2. Pain ................................... 105 3.12.3. Nausea and Vomiting ..................... 105 3.12.4. Tachycardia and Hypertension. . . . . . . . . . . . .. 106 3.12.5. fJ-Adrenoreceptor Blockers ................. 106 3.12.6. Convulsions............................. 106 3.12.7. Neuropathy ............................. 107 3.12.8. Fluid and Electrolyte Balance ............... 107 3.12.9. Hematin Therapy ........................ 108

3.13. Prevention of Attacks ............................ 114 3.14. Other Treatments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 116 3.15. Treatment of Photosensitivity ...................... 116

xii CONTENTS

4. Pathogenesis of the Neuropathy of Acute Porphyria ....... 119

4.1. Introduction .................................... 119 4.1.1. Neuropathological Features ................. 119 4.1.2. Electrodiagnostic Findings .................. 120

4.2. Hypotheses..................................... 121 4.2.1. Hypothesis 1 ............................. 121 4.2.2. Hypothesis 2 ............................. 126 4.2.3. Hypothesis 3 ............................. 128 4.2.4. Hypothesis 4 ............................. 132

4.3. Conclusion ..................................... 137

5. Drugs, Chemicals, and Porphyria ........................ 139

5.1. Allylisopropyl Acetamide ......................... 140 5.2. N-Alkylation of Heme by DDC . . . . . . . . . . . . . . . . . . . .. 141 5.3. Porphyrinogenesis by Halogenated Aromatic

Hydrocarbons ................................... 142 5.4. Age ........................................... 143 5.5. Drugs and the Acute Porphyrias .................... 144

5.5.1. Identification of Unsafe Drugs ............... 145 5.5.2. Drug-Induced Neuropathy .................. 156 5.5.3. Steroids ................................. 157 5.5.4. Menstruation and Pregnancy ................ 159 5.5.5. Drug Categories: Specific Points . . . . . . . . . . . . .. 159

5.6. Conclusions .................................... 164

6. The Photochemistry, Photobiology, and Phototherapeutic Use of Porphyrins ...................................... 167

6.1. Introduction .................................... 167 6.2. Photochemistry ................................. 167 6.3. Photobiology ................................... 168 6.4. Phototherapy and Cancer ......................... 171

6.4.1. Light.................................... 174 6.4.2. Heat .................................... 174 6.4.3. Oxygen Requirement. . . . . . . . . . . . . . . . . . . . . .. 174 6.4.4. Biochemistry ............................. 175 6.4.5. Animal Tumors and Cells in Culture .......... 176 6.4.6. Human Studies ........................... 176

CONTENTS xiii

7. Cutaneous Hepatic Porphyria: Porphyria Cutanea Tarda and Symptomatic Porphyria ............................. 179

7.1. Classification.................................... 179 7.2. Pattern of Porphyrin Overproduction. . . . . . . . . . . . . . .. 180 7.3. Studies of Uroporphyrinogen Decarboxylase .......... 181 7.4. Cutaneous Manifestations ......................... 183 7.5. Liver Disease ................................... 186 7.6. Associated Conditions ............................ 187

7.6.1. Iron Overload ............................ 187 7.6.2. Drugs and Hormones ...................... 189 7.6.3. Alcohol.................................. 190 7.6.4. Chronic Renal Failure and Hemodialysis . . . . . .. 192 7.6.5. Hepatotoxins ............................. 193 7.6.6. Tumors and CHP . . . . . . . . . . . . . . . . . . . . . . . . .. 195 7.6.7. Immunological Disorders ................... 195

7.7. Management of CHP ............................. 196 7.8. Variants of CHP ................................. 198

7.8.1. Hepatoerythropoietic Porphyria .............. 198 7.8.2. Dual Porphyria ........................... 199

8. Erythropoietic Protoporphyria ........................... 201

8.1. Introduction .................................... 201 8.2. Inheritance ..................................... 201 8.3. Clinical Features ........................ . . . . . . . .. 202

8.3.1. Skin Changes ........... . . . . . . . . . . . . . . . . .. 202 8.3.2. Liver Features ............................ 204

8.4. Biochemistry.................................... 205 8.4.1. Skin Changes . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 207 8.4.2. Hepatic versus Erythropoietic Synthesis of

Protoporphyrin ........................... 207 8.5. Diagnosis ...................................... 208 8.6. Treatment ...................................... 209

8.6.1. Beta Carotene . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 209 8.6.2. Hepatic Features .......................... 210

9. Congenital Porphyria ................................... 213

9.1. History ........................................ 213 9.2. Heredity ....................................... 214 9.3. Biochemical Features ............................. 215

xiv CONTENTS

9.4. Clinical Features ........................... . . . . .. 218 9.4.1. Onset ................................... 218 9.4.2. Skin Manifestations. . . . . . . . . . . . . . . . . . . . . . .. 219 9.4.3. Pathogenesis of Cutaneous Lesions ........... 220 9.4.4. Hematological Features ..................... 221 9.4.5. Splenomegaly ............................ 222 9.4.6. Bones and Teeth .......................... 222 9.4.7. Liver.................................... 223 9.4.8. The Eye ................................. 223

9.5. Differential Diagnosis. . . . . . . . . . . . . . . . . . . . . . . . . . . .. 224 9.6. Prognosis and Treatment. . . . . . . . . . . . . . . . . . . . . . . . .. 224

10. Porphyrins in Diseases Other than the Porphyrias ....... 227

10.1. Introduction .................................. 227 10.2. Heme Biosynthesis in Hemopoietic Disorders ....... 227

10.2.1. Iron Deficiency Anemia . . . . . . . . . . . . . . . . .. 227 10.2.2. Sideroblastic Anemia . . . . . . . . . . . . . . . . . . .. 229 10.2.3. Secondary Anemias ..................... 232 10.2.4. Hemolytic Anemia . . . . . . . . . . . . . . . . . . . . .. 233 10.2.5. Sickle Cell Anemia ..................... 233 10.2.6. {3-Thalassemia ......................... 233 10.2.7. Leukemias ............................ 234 10.2.8. Polycythemia .......................... 234

10.3. Lead Poisoning ................................ 234 10.4. Other Metals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 238 10.5. Alcohol and Heme Biosynthesis .................. 240 10.6. Abnormal Porphyrin Metabolism in Liver Disease ... 246

10.6.1. Cholestasis or Biliary Obstruction ......... 246 10.6.2. The Hereditary Hyperbilirubinemias ....... 247 10.6.3. Hepatic Tumors ........................ 249 10.6.4. Hereditary Tyrosinemia. . . . . . . . . . . . . . . . .. 251

10.7. Renal Disease ................................. 252 10.8. Miscellaneous Disorders ........................ 253

10.8.1. Malabsorption ......................... 253 10.8.2. Psychiatric Disorders .................... 253 10.8.3. Pregnancy ............................ 254 10.8.4. Schistosomiasis ........................ 254 10.8.5. Diabetes .............................. 254 10.8.6. Bronze-Baby Syndrome . . . . . . . . . . . . . . . . .. 254 10.8.7. Secondary Coproporphyrinuria ........... 255 10.8.8. Pseudoporphyria ....................... 255

CONTENTS xv

11. Porphyria in Animals 257

11.1. Squirrels ..................................... 258 11.2. The Harderian Gland ........................... 259

11.2.1. The Harderian Gland in the Golden Hamster 259 11.2.2. The Gland in Other Rodents . . . . . . . . . . . . .. 261

11.3. Acute Porphyria in Animals ..................... 262 11.4. Porphyria in Bovines ........................... 263

11.4.1. First Living Animal Cases ................ 264 11.4.2. Mode of Inheritance of Bovine Congenital

Porphyria ............................. 267 11.4.3. Breeding in South Africa ................. 267 11.4.4. Breeding in Other Countries .............. 268 11.4.5. The Carrier State ....................... 269 11.4.6. Quantitative Excretion of Porphyrins in

Bovine Congenital Porphyria ............. 271 11.5. Bovine Hereditary Protoporphyria ................ 272 11.6. Cutaneous Hepatic Porphyria in Bovines ........... 273 11.7. Mycosis Porphyria ............................. 273 11.8. Porphyria in Pigs .............................. 274

11.8.1. Breeding Experiments with Porphyric Pigs .. 274 11.8.2. Clinical Manifestations .................. 275 11.8.3. Urinary Porphyrins ..................... 276

11.9. Porphyria in Cats .............................. 276 11.10. Porphyrialike Condition in a Dog ................. 277

12. Perspective............................................ 279 Claude Rimington

13. References ............................................ 291

Index ................................................. 363

COLOR PLATES

Plate 1. Porphyrin fluorescence. (Top) A solution of protoporphyrin dimethyl ester illumi­nated in light of wavelength 410 nm, showing the typical red porphyrin fluorescence of wavelength 630 nm. (Bottom left) Urine from a patient with acute intermittent porphyria seen in daylight after illumination in sunlight for 4 hr. The figure shows the characteristic "port wine" appearance of the urine. (Bottom right) In ultraviolet light the red porphyrin fluorescence is somewhat quenched but may be more clearly seen at the meniscus.

Plate 2. Erythrodontia associated with congenital porphyria (Gunther's disease) in a 6-month-old female infant.

DISORDERS OF PORPHYRIN METABOLISM