Porphyria cutanea tarda associated with the acquired immune deficiency syndrome

American Journal of Hematology 25107-113 (1987)

Porphyria Cutanea Tarda Associated With the Acquired Immune Deficiency Syndrome Paul S. Wissel, Peter Sordillo, Karl E. Anderson, Shigeru Sassa, Robert L. Savillo, and Attallah Kappas The Rockefeller University Hospital (P.S.W , K.E.A., S.S., A. K.), Memorial Sloan-Keitering Cancer Center (P.S.), and The New York Hospital-Cornell Medical Center (R. L.S.), New York, New York Three male subjects with cutaneous symptoms and biochemical signs typical of porphyria cutanea tarda (PCT) developed acquired immune deficiency syndrome (AIDS). All three were in a classic high risk group for the latter disease and developed a typical progressive illness. Two patients succumbed to opportunistic infections; the third is alive but critically ill. The symptomatic prodrome of AIDS developed concurrently with or followed the onset of symptoms of PCT in all three individuals. PCT and AIDS are both uncommon disorders; their association in three patients is thus of inherent clinical interest. If this association is not coincidental, it raises the possibility that the occurrence of photosensitivity, skin lesions, and evidence of biochemical changes characteristic of PCT may, in certain patients at risk for AIDS, presage the subsequent full clinical expression of the latter disease.

Key words: human immunodeficiency virus, photosensitivity, hepatic porphyria

INTRODUCTION

The acquired immune deficiency syndrome (AIDS) has been recognized as a transmitted disease of potentially epidemic nature. While the incidence of this disease is yet unclear, as more groups become susceptible, patterns of accompanying disease states have been recognized [11. For example, AIDS has also been associated with a higher incidence of other disorders including opportunistic infections, primary neoplasms, hematologic disorders, and dermatologic pathology, including Kaposi sarcoma [2-4]. Kaposi sarcoma frequently may appear together with other constitutional complaints during the early phase of AIDS. The initial presentation of a pigmented plaque or nodule on the leg or foot may develop into a multicentric, ulcerative, exophytic “florid” transformation as the primary immunologic deficiency progresses

[51. Porphyria cutanea tarda (PCT) is a relatively rare disorder although it is the most common of the porphyric diseases of man [ 6 ] .It is characterized clinically by cutaneous photosensitivity, liver abnormalities, and the excessive excretion of 8through 5-carboxylate porphyrins as well as isocoproporphyrin in urine and feces. The enzymological defect in this disorder is a decreased activity of hepatic uroporphyrinogen decarboxylase [7]. Cutaneous photosensitivity is the major symptom,

Received for publication September 9, 1986; accepted November 11, 1986. Address reprint requests to Dr. Paul S. Wissel, The Rockefeller University Hospital, 1230 York Avenue, New York, NY 10021.

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typically affecting sun-exposed areas. Skin lesions vary from small white plaques to fluid-filled vesicles and bullae that may crust over and heal slowly. Facial hypertrichosis and a facial violaceous or erythematous hue are common. PCT is not associated with opportunistic infections or hematologic disorders; however, the disease is associated with hepatocellular damage and a modest increase in the occurrence of hepatocellular carcinoma. We report in this paper three patients with PCT who were in a classic high risk population for AIDS, and who, concurrent with or subsequent to, the recognition of PCT in them developed the typical progressive AIDS syndrome. The occurrence of these two relatively uncommon diseases in the three patients described here may be coincidental. However, the association is of inherent clinical interest and raises the possibility that there may be some shared biological link(s) between these two disorders in certain patients. MATERIALS AND METHODS

Analyses of urines for content of 6-aminolevulinic acid (ALA), porphobilinogen (PBG), and total porphyrins were made by standard methods [8,9]. Stool analyses for total porphyrins and quantitation of each specific porphyrin including isocoproporphyrin were performed by thin layer chromatography as described elsewhere [6]. Plasma PBG and total porphyrins were assayed by standard methods as was erythrocyte uroporphyrinogen decarboxylase (URO-D) activity [ 101. Case 1

This patient was a 35-year-old white male homosexual who was referred to The Rockefeller University Hospital in 1982 with suspected PCT. He complained of blistering on sun-exposed skin but otherwise had no major complaints. There was a history of intravenous drug abuse and mild hepatitis 13 years previously, pneumonia 3 years previously, and shingles 2 years previously. He reported a minimal intake of ethanol (1-2 drinks per week). He had received no blood transfusions. Physical examination revealed blistering and crusting skin lesions on the dorsa of both hands, hepatosplenomegaly, and generalized lymphadenopathy. Skin biopsy was consistent with PCT. Liver biopsy showed patchy steatosis, small lobular aggregates of mononuclear cells, a mild increase in iron, and no fibrosis. Laboratory studies included a white blood cell (WBC) count of 2,800/mm3 (normal 4.8-1O.Q with a normal differential, and a platelet count of 55,000/mm3 (normal 160,000-300,000), alkaline phosphatase 226 U/1 (normal < 115), SGOT 46 U/1 (normal < 25), and LDH 251 U/1 (normal < 230). The diagnosis of PCT was confirmed by the results shown in Table I [6]. Frequent therapeutic phlebotomy was performed with disappearance of skin lesions and a decrease in plasma porphyrins to 1.1 pg/dl and urine porphyrins to 690 nmo1/24 h after 14 phlebotomies. However, during the autumn of 1983, the patient developed progressive neutropenia and thrombocytopenia, which was followed by weight loss, peripheral lymphadenopathy, and widespread multiple reddish-blue skin lesions over his extremities. Biopsy of the new skin lesions revealed Kaposi sarcoma. The patient was diagnosed as having AIDS, and expired August 1984 from respiratory failure secondary to Pneurnonocystis Curini pneumonia. The diagnosis of AIDS was established on clinical grounds, i. e., homosexuality, drug abuse, opportunistic infec-

0-7

Reference range

aND, not done. bDetermined at recurrence.

0.9

3.0

3

0-4

2.1

9.8

2

1.3

5.2

1

Case no.

&Aminolevulinic Porphoacid bilinogen (mg/day) (mg/day)

Urinary porphyrin precursors

TABLE I. Porphyrin Analysis

0-300

20,443

43,440

8,565

Total porphyrins (pmol/day) 8-,7-,4-,5-, 6-carboxy late porphyrins, isocoproporphyrin 8-,7-,6-,5-, 4-carboxy late porphyrins, isocoproporphyrin 8-,7-,4-,5-, 6-carboxy late porphyrins, isoproporphyrin 4-carboxylate, f trace 8-carboxylate porphyrins

Thin layer chromatography (rank order of amounts)

Urinary porphyrins

0-200

641

NDa

84

Isocoproporphyrin 7-,6-,5-,4-, 2-carboxylate porphyrins 2-carboxylate > 4-carboxylate prophyrins

Isocoproporphyrin, 4-,5-,6-,7-,8-, 2-carboxylate porphyrins NDa

Thin layer chromatography (rank order of amounts)

Fecal porphyrins Total porphyrins (nmol/g dry wt)

Undetectable

46.9

79.5

28.6

Total porphyrins (pg/dl)

-

619

619

619

Neutral spectral peak (pm)

81.9

46b

65

95

19.8 [ I l l

Erythrocyte uroporphyrinogen decarboxylase (nmol/ml RBC/hr)

Plasma porphyrins

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tions, and Kaposi sarcoma, as well as the presence of antibody to HTLV-111 (ELISA) which was performed on frozen sera. Case 2

A 35-year-old Hispanic homosexual male was evaluated elsewhere in 1984 for skin hyperpigmentation and blisters of 7 months duration. History was also significant for heavy ethanol abuse since age 17, non-intravenous drug abuse (LSD, amphetamines, and sedatives) since age 21, gonorrheal urethritis, proctitis, and homosexuality with multiple partners, malaise, anorexia, and a 20-pound weight loss over a period of 4 months, and fever, diarrhea, and dyspnea for 1 month. There was no history of blood transfusion. Physical examination revealed cachexia, hyperpigmentation, and residual scarring from previous blisters in sun-exposed areas, shotty cervical and axillary lymphadenopathy, and mild hepatosplenomegaly. Laboratory results included WBC 5 ,500/m3 with a normal differential, hemo69), and ferritin 405 ng/ globin 13.5 gm/dl, SGOT 79 U/L, y-GTP 110 (normal ml (normal 12-300). Liver-spleen Tc-sulfur colloid scan showed minimal hepatomegaly with moderate splenomegaly. Chest radiogram revealed new pulmonary infiltration. Analysis of porphyrins are listed in Table I. Within the same month that the patient was diagnosed as having PCT, he developed respiratory insufficiency and was hospitalized for evaluation. Significant findings during this admission included a bronchoscopy-obtained specimen that was positive for Pneumocystis Carini, and stools were positive for Cryptosporidium and Giardia. The patient’s hospitalization was complicated by a persistent febrile course despite multiple antibiotics and he expired 2 months after the initial diagnosis of PCT, and 9 months after the initial complaints of photosensitivity and skin lesions. AIDS was diagnosed by sexual history and exposure, clinical course, and the occurrence of typical opportunistic infections terminating fatally.

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Case 3

A 22-year-old Hispanic homosexual male was evaluated in 1979 for recurrent blisters and ulcerations on sun-exposed areas and facial hypertrichosis of 5 months duration. Examination revealed skin blisters and ulcerations on the hands and face, facial hypertrichosis, and hepatosplenomegaly. The patient admitted active, multipartner homosexual activity since the age of 12 and denied the use of intravenous drugs; he had never received a blood transfusion. He worked as a cosmetologist and was said to have been exposed to hair sprays and setting lotions. Habits included minimal ethanol use (1-2 drinkdweek) and frequent cannabis use. In the past he had been treated with antibiotics for urethritis, gonorrhea, and syphilis. Laboratory evaluation revealed no hematological abnormalities, alkaline phosphatase 114, SGOT 38, LDH 135, and ferritin 260. Analysis of porphyrins are listed in Table I. After multiple therapeutic phlebotomies in 1979 and 1980 (total 12 units), the skin lesions resolved, plasma porphyrins became undetectable, and urine porphyrins fell within normal limits. He remained in remission until 1982 and was then lost for followup until September, 1985, when the patient presented with recurrent photosensitive skin lesions on sun exposed areas. He also complained of lethargy and a 5kg weight loss. Examination revealed a 2 X -cm right posterior cervical lymph node. It was learned that three of his known homosexual partners preceeding his 1979 diagnosis of PCT were subsequently diagnosed elsewhere as having AIDS. Two of

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the three had died from opportunistic infections, and the third was symptomatic for the disease. Laboratory evaluation of the patient at this time revealed antibody to HTLV-I11 (Western blot) positive. Urinary output of total porphyrins was 12,325 nrno1/24 h. Plasma porphyrins were 38.4 pgldl. Erythrocyte URO-D activity was 50% of normal (45.8 nmol C’genlml RBC/h). Alkaline phosphatase decreased to was 237 U/1, SGOT 112 U/1, LDH 240 U/1, y-GTP 240 U/1, and ferritin 299 ng/ml. W C was 4,500/mm3, hemoglobin 16.9 g/dl, MCV 86 fl, and platelets 232,000/ mm3. He was VDRL positive and FTA-ABS, 4+ reactive. The patient is presently undergoing therapeutic phlebotomy for PCT and penicillin therapy for the persistently reactive FTA-ABS. He is currently hospitalized with fever of unknown origin, weight loss, malaise, and dyspnea with a new intersitial infiltration pattern on chest X-ray, stuporous mental states, and evidence of mycoplasma meningitis.

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DISCUSSION

We report here three patients with PCT who also developed AIDS. The latter diagnosis was evident from the presence of known risk factors, progressive immunodeficiency, serological studies, and life-threatening opportunistic infections. PCT was diagnosed prior to the development of symptomatic AIDS by characteristic cutaneous manifestations and porphyrin excretory patterns. Two patients underwent therapeutic phlebotomy with resulting clinical improvement in PCT skin lesions and normalization of porphyrin excretion. The origin of the PCT in two of the three patients is presumed to be acquired rather than genetic, as their erythrocyte URO-D activities were normal at the time of intial presentation of their porphyric symptoms. In the third patient the URO-D level 50% of the normal mean; this subject probably had a familial form of the was disease [ 111. It is well known that ethanol, estrogens, polychlorinated biphenyls (TCDD), hexachlorobenzene, and other (PCB), 2,3,7,8-tetrachloro-dibenzo-p-dioxin chemicals can induce alterations in porphyrin metabolism that lead to symptomatic PCT-like porphyria in experimental animals and possibly in man [ 12,131. While none of the three patients admitted to recent hepatotoxin exposure known to produce a PCT-like syndrome, this association is based on history alone. The basis for the association between PCT and AIDS in the three patients reported here is not known; the possibility that this association is coincidental despite the relative rarity of each disorder cannot be excluded. However, in view of the protean clinical manifestations of AIDS, it may be of interest to speculate that the infectious agent of this disease can lead in some fashion to an impairment of porphyrin metabolism of sufficient degree to produce the signs and symptoms of PCT. This impairment might extend to the cytochrome P-450 dependent mixed-function oxidase system (MFOS) as well, since a wide range of interferon-inducing agents, eg, endotoxins, are known to depress both the MFOS and ALA-synthetase activity and to induce heme oxygenase [14-161. If infection with HTLV-I11 or the opportunistic infections associated with AIDS produce similar suppression of the MFOS [17- 181 during its prodromal stage, it may be possible that the altered ability to detoxify chemicals in such subjects brings about an aberration of porphyrin metabolism similar to those observed in PCT patients. Since one of the PCT patients had the familial form of the disease, the possibility that the decreased URO-D activity in this subject

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enhanced his susceptibility to infection with AIDS cannot be excluded, although this possibility appears quite speculative. If the association between PCT and AIDS in the three patients described here is not coincidental, our findings raise the possibility that PCT may be a presenting illness in the prodromal phase of what proves to be fully developed AIDS, in selective HTLV-I11 virus-infected individuals. The possibility that other AIDS patients with less overt symptoms and signs of this disease may also display disturbances of porphyrin metabolism that are more subtle than those identified in the three PCT patients described here merits further investigation.

ACKNOWLEDGMENTS

The authors thank the nursing staff of The Rockefeller University Hospital for their support and care of patients 1 and 3. We are indebted to Ms. Jill Brighton for excellent editorial assistance and manuscript preparation. This work was supported by General Clinical Research Center grant RR00102 and grant ES-01055 from the National Institutes of Health.

REFERENCES 1. Fauci AS: The acquired immunodeficiency syndrome: An update (NIH Conference). Ann Intern Med 102:800, 1985. 2. Wormser GP: Multiple opportunistic infections and neoplasms in the acquired immunodeficiency syndrome. JAMA U253:3441, 1985. 3. Gottlieb MS: Non neoplastic AIDS syndrome. Semin Oncol VII:40, 1984. 4. Safai B, Johnson KG, Myskowski PL et al: The natural history of Kaposi’s sarcoma in the acquired immunodeficiency syndrome. Ann Intern Med 103:744, 1985. 5 . Ziegler JL, Templeton AC, Vogen CL: Kaposi’s sarcoma: A comparison of classical, endemic and epidemic forms. Semin Oncol VII:47, 1984. 6. Kappas A, Sassa S, Anderson KE: The porphyrias. In Standbury JB, Wyngaarden JB, Frederickson DS, Goldstein JL, Brown MS (eds): “The Metabolic Basis of Inherited Disease,” fifth edition. New York: McGraw-Hill, 1982, p 1301. 7. Elder GH: Porphyrin metabolism in porphyria cutanea tarda. Semin Hematol 14:227, 1977. 8. Mauzerall D, Granick S: The occurrence and determination of 6-aminolevulinic acid and porphobilinogen in urine. J Biol Chem 219:435, 1956. 9. Poh-Fitzpatrick M: A plasma porphyrin fluorescence marker for variegate porphyria. Arch Dermato1 116543, 1980. 10. Elder GH, Tovey JA: Uroporphyrinogen decarboxylase activity of human tissues. Biochem SOC Trans 5: 1470, 1977. 1 1 . Sassa S, de Verneuil H, Anderson KE, Kappas A: Purification and properties of human erythrocyte uroporphyrinogen decarboxylase: Immunological demonstration of the enzyme defect in porphyria cutanea tarda. Trans Assoc Am Physicians 96:65, 1985. 12. Elder GH: Porphyria caused by hexocholorobenzene and other polyhalogenated aromatic hydrocarbons. In DeMatteis F, Aldridge WN (eds): “Heme and Hemoproteins. ” Berlin: Springer-Verlag, 1978, p 157. 13. De Verneuil H, Sassa S , Kappas A: Effects of polychlorinated biphenyl compounds, 2,3,7,8tetrachlorodibenzo-p-dioxin,phenobarbital and iron on hepatic uroporphyrinogen decarboxylase: Implications for the pathogenesis of porphyria. Biochem J 214: 145, 1983. 14. El Azhary R, Mannering GJ: Effects of interferon inducing agents (polyriboitiosinic acid . polyribocytidylic acid, Tilorone) on hepatic hemoproteins (cytochrome P-450, catalase, tryptophan 2,3-dioxygenase, mitochondria1 cytochromes), heme metabolism and cytochrome P-450linked monooxygenase systems. Mol Pharmacol 15:698, 1979.

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16. Bissell DM, Hammaker, LE: Cytochrome P-450 heme and the regulation of hepatic heme oxygenase activity. Arch Biochem Biophys 176:91, 1976. 17. Gordin FM, Simon GL, Wofsky CB, Mills J: Adverse reactions to trimethoprine-sulfamethoxazole in patients with the acquired immunodeficiency syndrome. Ann Intern Med 100:495, 1984. 18. Volderding PA, Conant MA, Stricker RB, Lewis BJ: Chemotherapy in advanced Kaposi’s sarcoma: Implications for current cases in homosexual men. Am J Med 74:652, 1983.

Note added in proof

Case #3 expired in January 1986 secondary to overwhelming opportunistic infections.