Letter to the Editor Porphyria cutanea tarda and HIV Infection: Effect of Zidovudine Treatment on a Patient Introduction
Porphyria cutanea tarda (PCT) is a relatively rare disorder characterized by decreased activity of uroporphyrinogen decarboxylase and excessive excretion of porphyrins in urine and faeces. Clinical signs include skin lesions distributed over face, trunk and extremities, with itchy, ery~hematous vesicles, or bullae, photosensitivity, generalized hyperpigmentation and facial hypertrichosis. PCT can be inherited but is usually seen as a sporadic disease of the adult, often associated with alcohol abuse, hepatotoxic drugs or estrogen exposure. We describe an asymptomatically HIV-infected patient who developed PCT with no known exposure to porphyrin inducing toxic chemicals. Here we have documented the safety and, possibly, the beneficial effects of zidovudine. Case Report
A 35-year-old heterosexual man, a heroin addict until January 1983, and since then not exposed to any risk behaviour, was diagnosed as HIV-1 infected in March 1988 by enzyme linked immunoassay, confirmed by Western blot. He had no history of alcohol abuse, blood transfusion, sexually transmitted disease or diabetes. He had had acute hepatitis B in 1978 and subsequently transaminases were reported as normal: the only hepatitis B virus serological marker still present was anti-HBc. After giving up the use of drugs he began to work as a carpenter in the building trade and was therefore constantly exposed to UV rays. He enjoyed excellent health until October 1989 when he began to complain of skin lesions, bullae, scabs, and itching of sun-exposed areas. Examination revealed cutaneous hyperpigmentation, but no temporal hypertrichosis was observed. The liver was slightly enlarged, the spleen was normal in size; there was no lymphoadenopathy and neurological examination was negative. The patient's white blood cell count was 6,240/mm 3, platelets 203,000 mm 3, hemoglobin 17.1 g/dl, ASAT 64 mU/ml (normal range 7--40), ALAT 119 mU/ml (7-40), alkaline phosphatase 220 mU/mi (90-279), total bilirubin 0.7 mg/dl, GGT 88 mU/ml (6--28), iron 118 p.g/dl, TIBC 215 Ixg/dl (250-350). HIV p24 antigen and hepatitis C virus antibodies anti-HCV were present in serum, CD4 + cell count was 382/mm 3, CD4 +/CD8 + ratio 0.84, beta2 microglobulin level 2 ~g/ml. No opportunistic infection was present and the patient was classified as belonging to CDC group II. A 24-h urine sample revealed a uroporphyrin excretion of 5,795 txg/ 24 h (normal < 120). A percutaneous liver biopsy showed a mild steatosis and small groups of mononuclear cells in portal spaces, with few areas of piecemeal necrosis. No Pearls positive iron overload or fibrosis was observed. In November 1989, the patient was started on zidovudine at a daily dose of 1,200 mg with mild, transitory digestive problems as the sole adverse effect. After 30 days, his skin lesions began to heal and after four months healing was complete despite his working without gloves or any other protective clothing. The drug dosage was reduced to 750 mg/d in August 1990. The urinary porphyrin level remained elevated but the patient was still asymptomatic in April 1991, without skin lesions, despite a porphyrin excretion of 10,600 rtg/24 h. At that time, results of
laboratory studies showed CD4 + cells 294/mm 3, CD4 +/CD8 + ratio 0.38, beta2 microglobulin 2.73 Ixg/ml, white blood cells 4,760/mm 3, hemoglobin 13.8 g/dl, platelets 146;000/ram 3, A L A T 144 mU/ml, ASAT 128 mU/ml, alkaline phosphatase 184 mU/ml, total bilirubin 0.8 mg/dl, GGT 70 mU/ml, iron 180 ixg/dl, and anti-HCV still present. Discussion
There are 16 previously described cases of association between PCT and HIV infection [ 1-10]. The hypothesis that this association is not coincidental cannot be excluded; indeed, PCT has never been documented in association with immunodeficiencies other than HIV infection, but the biological basis for the association with PCT is not known. It has been suggested that HIV infection, directly or through the alteration of cytochrome P450 dependent mixed function oxidase system, affects the hepatic porphyrin metabolism [1] or, as hypothesized by others, that PCT becomes clinically relevant as a consequence of coexistent infections or toxic agents [2, 6, 8]. Other authors have speculated that AIDS-related impairment of endogenous estrogen metabolism, in individuals with genetically enhanced susceptibility, may induce a defective synthesis of heme proteins [4]. We have reported this case because the patient had no heavy hepatic damage, nor exposure to toxic agents. Anti-HCV is detectable in the serum of most HIV + and H I V drug users of the same area [11]. Whether HCV has a pathogenetic role in our case remains mere speculation. Furthermore, the treatment with zidovudine coincided with the healing of the skin lesions and the patient was asymptomatic for as long as 12 months, without receiving any of the usual treatment for PCT, such as antimalarials or phlebotomies. This clinical improvement persisted despite the steadily elevated porphyrin level in urine and the daily exposure to UV light. A confirmation of some beneficial effect in such cases might help to explain the mechanism of this association. S. Gaffl, A. Zannini, C. Gabrielli Received: 8 May 1992/Revision accepted: 25 August 1992 S. Gaff, M. D., C. Gabrielli, M. D., Divisione di Malattie Infettive, A. Zannini, M. D., Serv~io Tossico-dipendenza, USL 9, I- 42100 Reggio Emilia, Italy. Correspondence and reprint requests to: S. Gaff, Divisione Malattie Infettive, Arcispedale S. Maria Nuova, Viale Risorgimento 80, I- 42100 Reggio Emilia, Italy. References 1. Wissel, P. S., Sordillo, P., Anderson, K. E., Sassa, S., Savlllo, It. L., Kappas, A.: Porphyria cutanea tarda association with the acquired immuno-deficiency syndrome. Am. J. Hematol. 25 (1987) 107-113. 2. Hogan, D, Card, R. T., Gadially, R., McShaffrey, J. B, Lane, P.: Human immunodeficiency virus infection and porphyria cutanea tarda. J. Am. Acad. Dermatol. 20 (1989) 17-20. 3. Conrad, M. E.: Aids and porphyria cutanea tarda. Am. J. Derrnatol. 28 (1988) 207. 4. Reynaud, P., Goodfellow, K., Sve¢, F.: Porphyria cutanea tarda as initial presentation of the acquired immunodeficiency syndrome in two patients. J. Infect. Dis. 161 (1990) 1032-1033.
Infection 20 (1992) No. 6 © MMV Medizin Verlag GmbH M~inchen, Miinchen 1992
373 / 71
S. Gaf~ et al.: Porphyria cutanea tarda and H I V
5. Cohen, P. R., Suarez, S. M., De Leo, V. A.: Porphyria cutanea tarda in human immunodeficiency infected patients. JAMA 264 (1990) 13151316.
6. Larnier, C., Avene, M, Rousselet, M. C., Touehais, E., Verret, J. L, Boyer, J.: H~patite granulomateuse ~ mycobact&ie aviaire au cours d'un S1DA r6vel6 par une porphyrie cutan6e tardive. Gastroenterot. Clin. BioL. 11 (1987) 264-265. 7. Nip-Sakamoto, C. J , Wong, IL H. W, Izumi, A. K.: Porphyria cutanea tarda and AIDS. Cutis 44 (1989) 470-471. 8. Lobato, M. N., Berger, T. G.: Porphyria cutanea tarda associated with the acquired immunodeficiency syndrome. Arch. Dermatol. 124 (1988) 1009-1010.
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9. Lafeuillade, A., Gamby, T., Dhiver, C., Poizot-Martin, I., Quiliehini, R., Gastant, J. A.: Porphyrie cutan6e tardive .associ6e h l'infection par le virus de l'immunod6ficience humaine. Presse M6d. 19 (1990) 1995-1996. 10. Massone, L., Priano, L., Pestarino, A., Isola, V., Solari, G.: Porphyria cutanea tarda and HIV infection. AIDS 4 (1990) 925. 1L Zannini, A., Giudiei, M. G., Barchi, E., Ursitti, A., Gabrielli, C., Gaff, S.: Hepatitis C virus infection in a cohort of HIV + and H I V drug abusers of the Reggio Emilia area. VII International Conference on AIDS: Abstract M.C.3085.
Infection 20 (1992) No. 6 © MMV Medizin Verlag GmbH Miinchen, Mtinchen 1992
Porphyria cutanea tarda (PCT) is a relatively rare disorder characterized by decreased activity of uroporphyrinogen decarboxylase and excessive excretion of porphyrins in urine and faeces. Clinical signs include skin lesions distributed over face, trunk and extremities, with itchy, ery~hematous vesicles, or bullae, photosensitivity, generalized hyperpigmentation and facial hypertrichosis. PCT can be inherited but is usually seen as a sporadic disease of the adult, often associated with alcohol abuse, hepatotoxic drugs or estrogen exposure. We describe an asymptomatically HIV-infected patient who developed PCT with no known exposure to porphyrin inducing toxic chemicals. Here we have documented the safety and, possibly, the beneficial effects of zidovudine. Case Report
A 35-year-old heterosexual man, a heroin addict until January 1983, and since then not exposed to any risk behaviour, was diagnosed as HIV-1 infected in March 1988 by enzyme linked immunoassay, confirmed by Western blot. He had no history of alcohol abuse, blood transfusion, sexually transmitted disease or diabetes. He had had acute hepatitis B in 1978 and subsequently transaminases were reported as normal: the only hepatitis B virus serological marker still present was anti-HBc. After giving up the use of drugs he began to work as a carpenter in the building trade and was therefore constantly exposed to UV rays. He enjoyed excellent health until October 1989 when he began to complain of skin lesions, bullae, scabs, and itching of sun-exposed areas. Examination revealed cutaneous hyperpigmentation, but no temporal hypertrichosis was observed. The liver was slightly enlarged, the spleen was normal in size; there was no lymphoadenopathy and neurological examination was negative. The patient's white blood cell count was 6,240/mm 3, platelets 203,000 mm 3, hemoglobin 17.1 g/dl, ASAT 64 mU/ml (normal range 7--40), ALAT 119 mU/ml (7-40), alkaline phosphatase 220 mU/mi (90-279), total bilirubin 0.7 mg/dl, GGT 88 mU/ml (6--28), iron 118 p.g/dl, TIBC 215 Ixg/dl (250-350). HIV p24 antigen and hepatitis C virus antibodies anti-HCV were present in serum, CD4 + cell count was 382/mm 3, CD4 +/CD8 + ratio 0.84, beta2 microglobulin level 2 ~g/ml. No opportunistic infection was present and the patient was classified as belonging to CDC group II. A 24-h urine sample revealed a uroporphyrin excretion of 5,795 txg/ 24 h (normal < 120). A percutaneous liver biopsy showed a mild steatosis and small groups of mononuclear cells in portal spaces, with few areas of piecemeal necrosis. No Pearls positive iron overload or fibrosis was observed. In November 1989, the patient was started on zidovudine at a daily dose of 1,200 mg with mild, transitory digestive problems as the sole adverse effect. After 30 days, his skin lesions began to heal and after four months healing was complete despite his working without gloves or any other protective clothing. The drug dosage was reduced to 750 mg/d in August 1990. The urinary porphyrin level remained elevated but the patient was still asymptomatic in April 1991, without skin lesions, despite a porphyrin excretion of 10,600 rtg/24 h. At that time, results of
laboratory studies showed CD4 + cells 294/mm 3, CD4 +/CD8 + ratio 0.38, beta2 microglobulin 2.73 Ixg/ml, white blood cells 4,760/mm 3, hemoglobin 13.8 g/dl, platelets 146;000/ram 3, A L A T 144 mU/ml, ASAT 128 mU/ml, alkaline phosphatase 184 mU/ml, total bilirubin 0.8 mg/dl, GGT 70 mU/ml, iron 180 ixg/dl, and anti-HCV still present. Discussion
There are 16 previously described cases of association between PCT and HIV infection [ 1-10]. The hypothesis that this association is not coincidental cannot be excluded; indeed, PCT has never been documented in association with immunodeficiencies other than HIV infection, but the biological basis for the association with PCT is not known. It has been suggested that HIV infection, directly or through the alteration of cytochrome P450 dependent mixed function oxidase system, affects the hepatic porphyrin metabolism [1] or, as hypothesized by others, that PCT becomes clinically relevant as a consequence of coexistent infections or toxic agents [2, 6, 8]. Other authors have speculated that AIDS-related impairment of endogenous estrogen metabolism, in individuals with genetically enhanced susceptibility, may induce a defective synthesis of heme proteins [4]. We have reported this case because the patient had no heavy hepatic damage, nor exposure to toxic agents. Anti-HCV is detectable in the serum of most HIV + and H I V drug users of the same area [11]. Whether HCV has a pathogenetic role in our case remains mere speculation. Furthermore, the treatment with zidovudine coincided with the healing of the skin lesions and the patient was asymptomatic for as long as 12 months, without receiving any of the usual treatment for PCT, such as antimalarials or phlebotomies. This clinical improvement persisted despite the steadily elevated porphyrin level in urine and the daily exposure to UV light. A confirmation of some beneficial effect in such cases might help to explain the mechanism of this association. S. Gaffl, A. Zannini, C. Gabrielli Received: 8 May 1992/Revision accepted: 25 August 1992 S. Gaff, M. D., C. Gabrielli, M. D., Divisione di Malattie Infettive, A. Zannini, M. D., Serv~io Tossico-dipendenza, USL 9, I- 42100 Reggio Emilia, Italy. Correspondence and reprint requests to: S. Gaff, Divisione Malattie Infettive, Arcispedale S. Maria Nuova, Viale Risorgimento 80, I- 42100 Reggio Emilia, Italy. References 1. Wissel, P. S., Sordillo, P., Anderson, K. E., Sassa, S., Savlllo, It. L., Kappas, A.: Porphyria cutanea tarda association with the acquired immuno-deficiency syndrome. Am. J. Hematol. 25 (1987) 107-113. 2. Hogan, D, Card, R. T., Gadially, R., McShaffrey, J. B, Lane, P.: Human immunodeficiency virus infection and porphyria cutanea tarda. J. Am. Acad. Dermatol. 20 (1989) 17-20. 3. Conrad, M. E.: Aids and porphyria cutanea tarda. Am. J. Derrnatol. 28 (1988) 207. 4. Reynaud, P., Goodfellow, K., Sve¢, F.: Porphyria cutanea tarda as initial presentation of the acquired immunodeficiency syndrome in two patients. J. Infect. Dis. 161 (1990) 1032-1033.
Infection 20 (1992) No. 6 © MMV Medizin Verlag GmbH M~inchen, Miinchen 1992
373 / 71
S. Gaf~ et al.: Porphyria cutanea tarda and H I V
5. Cohen, P. R., Suarez, S. M., De Leo, V. A.: Porphyria cutanea tarda in human immunodeficiency infected patients. JAMA 264 (1990) 13151316.
6. Larnier, C., Avene, M, Rousselet, M. C., Touehais, E., Verret, J. L, Boyer, J.: H~patite granulomateuse ~ mycobact&ie aviaire au cours d'un S1DA r6vel6 par une porphyrie cutan6e tardive. Gastroenterot. Clin. BioL. 11 (1987) 264-265. 7. Nip-Sakamoto, C. J , Wong, IL H. W, Izumi, A. K.: Porphyria cutanea tarda and AIDS. Cutis 44 (1989) 470-471. 8. Lobato, M. N., Berger, T. G.: Porphyria cutanea tarda associated with the acquired immunodeficiency syndrome. Arch. Dermatol. 124 (1988) 1009-1010.
72 / 374
9. Lafeuillade, A., Gamby, T., Dhiver, C., Poizot-Martin, I., Quiliehini, R., Gastant, J. A.: Porphyrie cutan6e tardive .associ6e h l'infection par le virus de l'immunod6ficience humaine. Presse M6d. 19 (1990) 1995-1996. 10. Massone, L., Priano, L., Pestarino, A., Isola, V., Solari, G.: Porphyria cutanea tarda and HIV infection. AIDS 4 (1990) 925. 1L Zannini, A., Giudiei, M. G., Barchi, E., Ursitti, A., Gabrielli, C., Gaff, S.: Hepatitis C virus infection in a cohort of HIV + and H I V drug abusers of the Reggio Emilia area. VII International Conference on AIDS: Abstract M.C.3085.
Infection 20 (1992) No. 6 © MMV Medizin Verlag GmbH Miinchen, Mtinchen 1992
