Porphyria Cutanea Tarda with Constrictive Pericarditis in a Family Susumu ADACHI,1 MD, Jun AMANO,2 MD, Hiroshi ITO,1 MD, Takashi YAJIMA,3 MD, Toshizumi SHIRAI,2 MD, Yasuhiro MIYAHARA,3 MD, Fumiaki MARUMO,1 MD, and Michiaki HIROE,1 MD SUMMARY Two cases of familial porphyria cutanea tarda (PCT) with constrictive pericarditis are described. A 50-year-old woman and her 48-year-old younger brother were admitted because of right ventricular heart failure. Constrictive pericarditis was diagnosed by RV pressure waveform and echocardiogram. The patients were diagnosed as PCT based on clinical symptoms, histologic findings and elevated urinary excretion levels of uroporphyrin. Even to this day, over 40% of the etiology of constrictive pericarditis remains unknown. There is a possibility of overlooking porphyria cutanea tarda in constrictive pericarditis patients. This report describes the first documented cases of familial PCT with constrictive pericarditis. (Jpn Heart J 1997; 38: 749-753) Key words: Right ventricular heart failure, Uroporphyrin, Coproporphyrin, Protoporphyrin. P ORPHYRIAS originate from hereditary or acquired enzymatic deficiencies of the biosynthetic pathway of heme, that result in the accumulation of the porphyria compounds in a variety of organs. Porphyrias are classified as either erythropoietic or hepatic, based on the site of over production of the heme precursors. Porphyria cutanea tarda (PCT), a hepatic porphyria, is caused by the decreases in uroporphyrinogen decarboxylase (UROD) activity. Deficiency in UROD, which catalyzes the conversion of uroporphyrinogen to coproporphyrinogen, results in decreased hepatic heme synthesis and can cause skin photosensitivity without neuropathy.1) However, there is no previous report of cardiac complications. This report describes the first documented cases of PCT with constrictive pericarditis in a family. From the 1Second Department of Internal Medicine, Tokyo Medical and Dental University, Tokyo,2 Department of Cardiovascular Surgery, and 3Department of Internal Medicine, Hokushin General Hospital, Nakanoshi, Nagano, Japan. Address for correspondence: Michiaki Hiroe, MD, Second Department of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113, Japan. Received for publication February 3, 1997. Accepted March 26, 1997. 749
750 ADACHI ET AL Jpn Heart J September 1997 CASE REPORTS Patient 1: A 50-year-old woman was admitted because of mild dyspnea which had gradually increased in the previous three months. Physical examination revealed venous dilatation and severe pretibial edema. Chest auscultation revealed a grade II/VI diastolic regurgitant murmur and a third heart sound. Electrocardiogram showed low voltage QRS complexes in the limb leads and in the left pericardial leads. Right ventricular pressure was 34/16mmHg and revealed a dip and plateau waveform. Two-dimensional echocardiogram showed an immobile and dense pericardium (Figure1A). Constrictive pericarditis was diagnosed by RV pressure waveform and echocardiogram. She had been treated with diuretics, and her symptoms improved slightly. On hospital day 20, she underwent pericardiectomy, and a firm white hypertrophic pericardium was obtained. The pericardium was white, tight and tylotic (Figure2A). Microscopic examination revealed non-specific inflammation and tylosis (Figure2B). After pericardiectomy, the symptoms of right sided heart failure disappeared. She experienced hyperpigmentation, crusts and scars in areas of the face, hands and arms exposed to light, so a dermatological examination was performed. The microscopic findings of skin biopsy revealed subepidermal bulla with festooning of the base and PAS-positive hyaline deposition around the papillary capillaries. Figure1. The long and short axis views of echocardiographic findings, indicating a highly dense pericardium which suggests constrictive pericarditis. A: patient 1, B: patient 2.
Vol38 No5 PORPHYRIA WITH CONSTRICTIVE PERICARDITIS 751 Figure2. Pathological findings of the pericardium of the sister (Patient 1). A: macroscopic examination (upper side: serose side), B: microscopic examination (original magnification: ~100). The levels of urinary uroporphyrin and coproporphyrin were 1500ƒÊg/day (normal value under 20ƒÊ/day) and 2670ƒÊg/day (normal value under 110ƒÊg/day), respectively (Table). The patient was diagnosed as PCT based on the clinical signs, histologic findings of skin biopsy and elevated urinary excretion levels of uroporphyrin and coproporphyrin.2) Patient 2: The 48 year-old, younger brother of patient 1, came to our hospital because of mild dyspnea and pretibial edema. Chest roentgenogram revealed cardiomegaly and pleural effusion. Cardiac catheterization was performed on the second hospital day. Right ventricular pressure showed an early diastolic dip followed by a plateau. His echocardiograms showed abnormal thickening of the pericardium (Figure1B). We diagnosed the patient as constrictive pericarditis based on pressure waveform and echocardiogram data. The level of urinary uroporphyrin and coproporphyrin increased (801ƒÊg/day and 2560ƒÊg/day, re-
752 ADACHI ET AL Jpn Heart J September 1997 Table. Laboratory Data of Porphyrin Products spectively) (Table), and we made a diagnosis of PCT based on the criteria.2) His symptoms improved after taking diuretics and vasodilator. DISCUSSION UROD is a cytosolic enzyme which catalyzes the sequential removal of the carboxyl groups of the carboxymethyl side chains in uroporphyrinogen to yield coproporphyrinogen. Recently, a complete human UROD cdna has been cloned and sequenced. Garey et al. reported that a point mutation of UROD gene was detected,3) and, in 1990, the splice site mutation was found at the UROD locus in a pedigree with familial PCT.4) The familial form of PCT is characterized by an inherited deficiency of its enzyme activity. Clinically, the common condition of familial PCT is characterized by mechanical fragility and blistering formation of light-exposed skin. Most PCT patients exhibit symptoms after forties, and associations of this disease with systemic lupus erythematosus, diabetes mellitus, and hemochromatosis have been reported.2,5) However, cardiac complications of the porphyria have not been reported before. Only one report describing pericarditis in a patient with acute porphyria can be found.6) Constrictive pericarditis is present when a fibrotic, thickened, and adherent pericardium restricts diastolic filling of the heart. Most cases of constrictive pericarditis are of unknown etiology.7) In our cases, as these diseases were observed in siblings, the existence of constrictive pericarditis may be related to PCT, that is, other manifestations of PCT. Unfortunately, we could not examine the parents because they were already dead (unknown causes). The siblings may be homozygous for the same gene defect and the genetic disorder may be responsible for the cardiac involvement. However, the possibility that the mutation in
Vol38 PORPHYRIA WITH CONSTRICTIVE PERICARDITIS 753 No5 UROD affects another molecular lesion caused by constrictive pericarditis cannot be excluded. We have described the first documented case of familial PCT with constrictive pericarditis. Clinicians should be aware of the possibility of overlooking PCT in constrictive pericarditis patients and that PCT may be an etiology of constrictive pericarditis. REFERENCES 1. Jackson AH, Sancovich HA, Ferramola AM, et al. Macrocyclic intermediates in the biosynthesis of porphyrins. Phil Trans R Soc Lond Ser B 1976; 273: 191-206. 2. Clemmensen O, Thomsen K. Porphyria cutanea tarda and systemic lupus erythematosus. Arch Dermatol 1982; 118: 160-2. 3. Garey JR, Hansen JL, Harrison LM, Kennedy JB, Kushner, JP. A point mutation in the coding region of uroporphyrinogen decarboxylase associated with familial porphyria cutanea tarda. Blood 1989; 73: 892-5. 4. Garey JR, Harrison LM, Franklin KF, Metcalf KM, Radisky ES, Kushner JP. Uroporphyrinogen decarboxylase: a splice site mutation causes the deletion of exon 6 in multiple families with porphyria cutanea tarda. J Clin Invest 1990; 86: 1416-22. 5. Kushner JP, Edwards CQ Dadone MM, Skolnick MH. Heterozygosity for HLA-linked hemochromatosis as a likely cause of the hepatic siderosis associated with sporadic porphyria cutanea tarda. Gastroenterology 1985; 88: 1232-8. 6. Chaudhry MR. Meningism, pericarditis/myocarditis-unrecognized manifestations of acute porphyria. JPMA 1986; 36: 239-43. 7. Cameron J, Oesterle SN, Baldwin JC, Hancock EW. The etiologic spectrum of constrictive pericarditis. Am Heart J 1987; 113: 354.