Porphyrias in Japan. Epidemiological Statistics of Porphyrias

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1 Porphyrias in Japan Masao Kondo,a Yuzo Yanob "Department of Nutrition and Biochemistry, The Institute of Public Health, Tokyo, Japan; btokyo Metropolitan Toshima General Hospital, Tokyo, Japan Key Words. History of porphyria (in Japan) Incidence of porphyria Geographical distribution of porphyria Porphyria Abstract. Porphyrias are a clinically diverse group of diseases due to inherited deficiencies of enzymes in the heme biosynthetic pathway. Much progress has been made in the analysis of porphyrin metabolism, and the molecular biology of the enzymes in heme biosynthesis and their mutations in the porphyrias are now actively investigated. These diseases are classified into two types: erythropoietic and hepatic, depending on the major site of the clinical expression of the enzyme defect. They are further classified into eight subtypes according to the porphyrin metabolites that are overproduced and according to the causative enzyme defects. These diseases are all inherited as autosoma dominant traits, except for congenital erythropoietic porphyria (CEP) and aminolevulinic acid dehydratase (ALAD) deficiency porphyria (ADP), which are recessive. In addition, a few homozygous forms of the dominantly inherited porphyrias have also been recognized, which are presumably due to mutations with a milder enzymatic defect. The main clinical manifestations of the porphyrias are neurologic syndromes and skin photosensitivity. Introduction In this chapter, I shall describe the results of the most recent statistical analyses of epidemiological and clinical data from all cases of porphyria reported in Japan from to January. Porphyrias are a clinically diverse group of diseases due to inherited deficiencies of enzymes in the heme biosynthetic pathway. Depending on the clinical expression of the Correspondence: Dr. Masao Kondo, Department of Nutrition and Biochemistry, The Institute of Public Health, Shirokanedai, Minatoku, Tokyo, Japan. OAlphaMed Press ISBN X enzyme defect, porphyrias are classified as either erythropoietic or hepatic. They are further classified into eight subtypes, summarized in Table I according to causative enzyme defect, clinical presentation and overproduced substrate. Except for congenital erythropoietic porphyria (CEP) and aminolevulinic acid dehydratase deficiency porphyria (ADP), which are recessive, all hereditary forms of porphyria are transmitted as autosomal dominant traits. Epidemiological Statistics of Porphyrias Table I shows the number of patients with porphyria reported in Japan from to January. A total of cases have been reported, and they have been classified according to type and year reported. Prior to, the details of heme biosynthesis were poorly understood. In the years to, the porphyrin biosynthetic pathways were elucidated and the enzymological diagnosis of porphyria became available. In the following decade, to, the current classification of porphyrias has become possible based on the accurate measurement of enzymes in heme biosynthesis. Biochemical studies have provided much information about the pathogenesis of porphyrias. Moreover, recent progress in molecular biology has contributed greatly to the field of diagnosis of porphyrias [l]. Of particular interest are the cases of CEP. There have been cases of CEP reportedtto date, and of these were known by. In contrast, Butuni [] recently reported that there were only recognized CEP cases in the world by the same time. Since an accurate diagnosis hinges on assaying the enzyme uroporphyrinogen cosynthetase (URO I CoS), the disparity in

2 Table I. Enzymes in the heme biosynthetic pathway and classification of the porphyrias [] h) o\ Type of Enzyme HGM Chromosomal Clinical porph yria defect symbol localization presentation Overproduction of i Erythropoietic CEP EPP Hepatic AIP VP HCP PCT ADP Mixed HEP UROgen synthase Ferrochelatase PBG deaminase PROTOgen oxidase COPROgen oxidase UROgen decarboxylase ALA dehydratase UROgen decarboxylase UROS FECH PBGD PPOX CPO UROD ALAD UROD q.q. q. llq.q.? lp qq lp Neurologic Neurologic Neurologic Neurologic URO, COPRO PROTO, ALA, PBG PROTO, COPRO, ALA, PBG COPRO, ALA, PBG URO, HEPTA, IsoCOPRO ALA. COPRO URO, HEPTA, COPRO I, IsoCOPRO, PROTO CEP = congenital erythropoietic porphyria; EPP = erythropoietic protoporphyria; AIP = acute intermittent porphyria; VP = variegate porphyria; HCP = hereditary coproporphyria; PCT = porphyria cutanea tarda; ADP = aminolevulinic acid dehydratase deficiency porphyria; HEP = hepatoerythropoietic porphyria; PBG = porphobilinogen; COPRO = coproporphyrin; PROTO = protoporphyrin; URO = uroporphyrin; HEPTA = hepatocarboxylate porphyrin Table. The number of cases reported in Japan from to January [] Type CEP EPP AIP VP HCP APb PCT HEP Total Year _..~ cases ( : )._ First ~ ~ Total cases report ( : ) O( : ) ( : ) O( : ) O( : ) ( : ) O( : ) O( : ) ( :) ( ) ( : ) ( :) ( : ) O( : ) ( : ) ( : ) O( : ) (:) ( : ) (: ) (: )a ( : ) ( : ) ( : ) (: ) I( : ) (:)a Unknown sex (the superscript shows the number of cases) bacute porphyria of unknown type because of deficient clinical data. ( : ) ( :ll) ( :) ( :ll) ( : ) ( : ) (: ) * ( : ) (:Y ( : ) (:) ( :) ( I: ) ( : ) ( : )al (: )a O( : ) (:) ( : ) ( : ) ( :Y ( : ) ( : )a w ( : ) s a (: )a D ( : ). (:)a _ b g ~..

3 Kondo/Y ano Table. Incidence of porphyrias classified by age of patients [] Age CEP SO + S s Total cases AIP = acute intermittent porphyria; VP = variegate porphyria; HCP = hereditary coproporphyria. "Acute porphyria of unknown type because of deficient clinical data. reported prevalence exemplifies the improved diagnostic precision afforded by more refined biochemical assays. All the porphyria cases described in Table I were summarized from the medical abstract journal Igaku Chuo Zasshi (a Japanese journal) and from our own unpublished cases. The actual incidence of porphyria in Japanincluding unreported, misdiagnosed and latent casesis no doubt higher. Table shows the incidence of porphyrias classified according to the age of the patient. CEP is frequently identified in infants, children and young adults, but there were also cases identified in patients over years of age. Eight patients appeared to have the disease before the age of five, whereas seven cases developed symptoms at years of age. Acute porphyrias are more common in females than in males and frequently occur at puberty and in middle age, while porphyria cutanea tarda (P'cr) is more common in males than females and occurs at years of age. The different incidence between males and females is likely due to some precipitating factors characterizing each sex, which may play an important role in the clinical manifestation of these disorders. Clinical Statistics of Porphyrias While porphyrias are generally divided into two types, erythropoietic and hepatic, they may also be classified into two groups according to symptoms: cutaneous porphyrias and acute hepatic porphyrias. The former includes CEP, erythropoietic protoporphyria (EPP), hepatoerythropoietic porphyria (HEP) and porphyria cutanea tarda (PCT); the latter includes acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP). Table IV shows the frequencies of individual symptoms observed in patients with cutaneous porphyrias. The intensity of manifestations of the cutaneous symptoms varies depending on the chemical structure and quantity of porphyrins accumulated in tissues; they are most intense in CEP, followed by PCT and then by EPP. In CEP, deformed nails, partial defects of nose, ear or fingers, erythrodontia and splenomegaly are particularly conspicuous beyond the characteristic cutaneous symptoms. Hepatic dysfunction and liver cirrhosis occur in almost all cases of PCT, and serum iron is usually elevated. Liver biopsy was performed in of the cases studied, and the diagnoses verified by liver biopsy are shown in Table V. Acute porphyrias are characterized by a variety of neurological disturbances with intermittent exacerbations and remissions. The subjective symptoms and objective findings in acute,parphyrias are summarized in Tables V and.vii, respectively. Gastrointestinal attacks, actually neurogenic in origin, often precede other neurological symptoms and are the most common

4 ~ ~ Porphyrias in Japan Table IV. Signs and symptoms of cutaneous porphyrias [].~ ~ ~ ~ ~ Derrnatologic symptoms Photosensitivity Erythema Blisters, erosion Ulcer Crust Scars Hyperpigmentation Depigmentation Hyperplasia, Sclerodermalike scars Fragility Hypertrichosis, Bristle Alopecia Destruction of bone and cartilage (fingernails, nose, pinnas, phalanges) Erythrodontia Dark urine Anemia Splenomegal y Liver cirrhosis Liver dysfunction Hypergly cemia Others (gastrointestinal, neurological, etc.) CEP EPP PCT HEP Total ( cases) ( cases) ( cases) ( cases) ( cases).. ~. ~ ~. ~ finding in acute porphyria (Table VI). These attacks are occasionally followed by disturbances of consciousness or convulsions, and are often accompanied by complaints of insomnia, anxiety and low back pain. It should be noted that the urine is often colorless in acute porphyria; dark urine was observed in only of cases examined. Table VII shows objective findings in patients with acute porphyrias. Clinical manifestations in these disorders varied widely. Of these, the most frequent signs were abdominal and neurological symptoms. Abdominal signs included tenderness, vomiting, constipation and paralytic ileus. Among neurological signs, peripheral neuropathy, consciousness disturbance, bulbar palsy, ataxia, convulsion and autonomic neuropathy were commonly observed. In addition, mental manifestations, cardiovascular disorders, and metabolic and hormonal disturbances were seen. Most of these signs are thought to result from dysfunction of the autonomic nervous system (ANS). Other relatively infrequent ANS symptoms included abdominal muscle guarding, ataxia, hypotension and schizophrenialike symptoms. The acute attacks and exacerbations of acute porphyria are known to be precipitated by various drugs and other factors. Table VIII shows a list of precipitating factors for porphyria reported to date in Japan. Barbiturates, antipyretic agents and analgesics are especially hazardous, but all such Table V. Histological diagnosis of biopsied liver specimens from patients with PCT [] Liver cirrhosis Chronic Hepatitis Active Nonactive Alcoholic Others Hepatoma Fatty liver Unknown (diagnosis not described) Total (cases) ~

5 Kondo/Y ano Table VI. Subjective symptoms in acute porphyrias [] _.. _.~ AIP VP HCP AP Total ( cases) ( cases) ( cases) ( cases) ( cases) Gastrointestinal manifestations Abdominal pain Nausea, vomiting Constipation Diarrhea Neurological manifestations Weakness or paralysis Sensory disturbance in the extremities Speech disturbance D ysphagia Convulsions Consciousness disturbance Dermatologic symptoms Erythema Hyperpigmentation Dark urine factors should be avoided in porphyric patients or latent gene carriers at risk for the disease. In PCT, chronic or heavy drinking of alcohol was incriminated in of cases studied. Iron overload is also implicated in the development of PCT. Hepatic dysfunction due to these factors is probably involved in the pathogenesis of PCT. No precipitating factors have been recognized in the erythropoietic porphyrias. Misdiagnosis of Acute Porphyria A significant number of clinical errors were made, especially in the initial diagnosis (Table IX). This is partly because porphyria is a rare disease and its diagnosis requires specific laboratory testing and/or enzyme assays. Common incorrect initial diagnoses included ileus, appendicitis, pancreatitis and acute abdominal pain suggesting lithiases. In fact, some patients were subjected to laparotom y because of incorrect diagnosis. Diagnostic clues for differentiating hyperemesis gravidarum, hysteria and GuillainBarr syndrome from acute porphyria must also be considered. Moreover, encephalitis, brain tumors, muscular atrophy, abdominal epilepsy and ulcerative colitis were occasionally confused with acute porphyria. In contrast, cutaneous porphyrias are rarely misdiagnosed. However, CEP and EPP can be initially misdiagnosed as dermatitis solaris, and PCT patients often suffer from liver dysfunction or cirrhosis. Treatment and Prognosis of Porphyrias The treatments undertaken in the cases of cutaneous porphyrias and in acute porphyrias are summarized in Tables X and X. In cutaneous porphyrias, along with protection of the skin against sunlight, the treatment was mainly topical medications in CEP; &carotene preparations in EPP; and phlebotomy, vitamin E and calcium ethylenediaminetretraacetate (Ca EDTA) in PCT, although therapeutic responses varied among the cases. In acute porphyrias, fluid infusion consisting of glucose, chlorpromazine, vitamins and corticosteroids was chiefly prescribed; the treatment was no more than symptomatic. Recently, administration of hemin, originally reported by Wada et al. [], has drawn attention because its mechanism of action is causal rather than symptomatic. However, this mode of treatment has not been used in Japan since the initial report by Wada et al. There is a single case of AIP in which hemodialysis or plasmapheresis was used with improvement of clinical symptoms. Hemodialysis and plasmapheresis may merit greater attention in the treatment of acute porphyrias.

6 Porphyrias in Japan Table VII. Objective findings in acute porphyrias [].._ AIP VP HCP AP Total ( cases) ( cases) ( cases) ( cases) ( cases).. _ Abdominal symptoms Tenderness Ileus Neurological signs. Peripheral motor palsy Sensory disturbance (superficial) Paresthesia Deep tendon reflexes Exaggeration Decreased or absent Abnormal reflexes Consciousness disturbance Convulsion, epilepsy Cranial nerve palsy Bulbar palsy Bladder and bowel dysfunction Muscle atrophy Disturbance of autonomic nervous system Mental manifestations Hallucination, delusion Hysteria Cardiovascular disturbance Hypertension Tachycardia Disturbance of metabolism and hormonal system Disturbance of electrolytes Hyperglycemia Thyroid dysfunction Dermatologic manifestation Erythema Hyperpigmentation Abnormality of fingernails, phalanges, etc. Others Liver dysfunction Dark urine

7 Kondo/Yano Table VIII. Precipitating factors in acute porphyrias [] Phenobarbital Antipyretics, Analgesics Pregnancy, Menstruation, Delivery Contraceptive pills Hypnotic Alcohol Hemodialy sis Others Unknown (not described) AIP VP HCP AP PCT Total ( cases) ( cases) ( cases) ( cases) ( cases) ( cases)... _.. Table IX. Incorrect initial diagnosis in acute hepatic porphyria []. AIP VP HCP AF Total ( cases) ( cases) ( cases) ( cases) ( cases).._ Abdominal symptoms Tenderness Ileus Acute abdomen Ileus Appendicitis Hysteria, Psychogenic disorders Hyperemesis gravidarum Pancreatitis Acute peptic ulcer Neuropathy GuillainBarrC syndrome Gallstone Subacute myeloopticoneuropathy (SMON) Epilepsy Renal, ureteral stone Ectopic pregnancy Myelopathy Ovarian volvulus Others Table X. Drugs and treatments used for cutaneous porphyrias []. _.. CEP EPP PCT HEP Total ( cases) ( cases) ( cases) ( cases) ( cases).... ~ Steroids Bcarotene Vitamins (mainly E) Epidermic liniment Phlebotomy Chloroquine CaEDTA,

8 Porphyrias in Japan Table X. Drugs used for treatment of acute porphyrias [] ~~~ AIP VP HCP AP Total ( cases) ( cases) ( cases) ( cases) ( cases) ~ ~~~ Fluid infusion (+glucose) Chlorpromazine AMP, ATP Steroids Vitamins (mainly B group) ACTH Vagostigmine Calcium Cytochrome C Plasmapheresis Table XI. Prognosis of porphyrias [] Improvement CEP EPP AIP VP HCP AP PCT HEP Total Table XI shows the prognosis of the porphyrias among Japanese patients. References Kappas A, Sassa S, Galbraith RA, Nordmann Y. The porphyrias. In: Scriver CR, Beaudet WS, Valle SD, eds. The Metabolic Basis of Inherited Diseases. New York: McGrawHill, :. Butani LK, Sood SK, Das PK, Deshpande SG, Mulay DN, Kandhari KC. Congenital erythropoietic porphyria, an autopsy report. Arch Derm ;:. Wada. Experimental and clinical studies on porphyria, some considerations on pathogenesis of hepatic porphyria. J Jap SOC Intern Med ;:. Kondo M, Yano Y, Urata G, Shirataka M. The porphyrias. In: Shima A, Ichihashi M, Fujiwara Y, Takebe H, eds. Frontiers of Photobiology. Amsterdam: Elsevier Science Publishers, :.