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Porphyria Cutanea Tarda and Human Immunodeficiency Virus: Two Cases Associated With Hepatitis C

      Hepatitis C virus (HCV) was recently recognized as a probable etiologic factor for porphyria cutanea tarda (PCT). A review of the literature revealed 40 cases of PCT associated with the human immunodeficiency virus (HIV). In most of these cases, hepatitis C status was unknown. We describe two patients with PCT who were coinfected with HIV and HCV and discuss the interaction of these two viruses. A diagnosis of PCT, especially in a young patient, should prompt investigation for underlying HIV and HCV infection. Porphyrin studies should be performed in any patient with HIV and photosensitivity. Clinicians should be aware of the infectious risk associated with the vesicles and erosions in these patients.
      HCV (hepatitis C virus), HIV (human immunodeficiency virus), PCT (porphyria cutanea tarda)
      Recently, hepatitis C virus (HCV) was recognized as a possible cause of porphyria cutanea tarda (PCT). Forty cases of PCT in conjunction with human immunodeficiency virus (HIV) have been previously reported. Hepatitis C status was unknown in most of these cases. In this article, we describe two patients with PCT who had coinfection with HIV and HCV.

      REPORT OF CASES

      Case 1

      A 45-year-old man with a history of intravenous drug abuse and HIV seropositivity of 3 years' duration sought medical assessment because of a blistering eruption on the dorsal aspects of his hands. His medical history included cytomegalovirus retinitis, Candida esophagitis, herpes zoster, and pneumocystis pneumonia. He had received zidovudine monotherapy for 1 year, didanosine monotherapy for 10 months, and stavudine during the preceding 3 months. He also received clarithromycin, ganciclovir, fluconazole, and trimethoprim-sulfamethoxazole. His family history was unremarkable. He had abused alcohol until 8 years previously. He had used cocaine and intravenously administered heroin. No history of homosexual contact was noted.
      On examination, the patient had multiple bullous lesions on the backs of both hands, with evidence of postinflammatory hyperpigmentation and milia. The largest bulla, 5 cm, was on the left index finger, and a smaller lesion, 0.6 cm, was on the third left finger (Fig. 1). The patient also had facial hypertrichosis with evidence of cutaneous sclerosis.
      Figure thumbnail gr1
      Fig. 1 (case 1)Bullae on left third and fifth fingers of 45-year-old man with human immunodeficiency virus.
      Laboratory studies yielded the following results: hemoglobin, 10.4 g/dL.; platelet count, 62 × 109/L; leukocyte count, 1.4 × 109/L; CD4 count, 1 × 106/L; alkaline phosphatase, 213 U/L (normal, 98 to 251); aspartate aminotransferase, 114 U/L (normal, 12 to 31); alanine aminotransferase, 126 U/L (normal, 10 to 45); ferritin, 1,070 μg/L (normal, 200 to 600); and erythrocyte uroporphyrinogen decarboxylase, 0.42 U/L (normal, 1 to 3).
      Porphyrin findings in urine were classic for PCT: uroporphyrin, 2,113 μg/24 h (normal, 0 to 46); heptacarboxylporphyrin, 1,289 μg/24 h (normal, 0 to 13); hexacarboxylporphyrin, 259 μg/24 h (normal, 0 to 5); pentacarboxylporphyrin, 328 μg/24 h (normal, 0 to 4); and coproporphyrin, 211 μg/24 h (normal, 0 to 96). Fecal coproporphyrin was also increased at 381 μg/24 h (normal, less than 200).
      Skin biopsy showed a cell-poor subepidermal bulla with prominent “festooning” of the dermal papilla. Results of direct immunofluorescence of perilesional skin were consistent with porphyria, showing IgG, IgM, IgA, C3, and fibrinogen around many thick-walled superficial vessels and many scattered and clumped cytoids with IgM (Fig. 2). Hepatitis A IgM was negative, hepatitis B core antibody was positive and core antigen negative, and results of hepatitis C enzyme immunoassay and recombinant immunoblot assay were positive. The patient was treated with low-dose chloroquine, and response was good.
      Figure thumbnail gr2
      Fig. 2 (case 1)Direct immunofluorescence of perilesional skin, showing IgM around many thick-walled vessels and festooning of dermal papillae.

      Case 2

      A 36-year-old man with a history of intravenous drug abuse had blisters, erosions, and scarring of 12 months' duration on the dorsal aspects of his hands and on his face. The outbreak was more pronounced during the summer months. He had noticed increased growth of facial hair. No family history of PCT was noted. He had been HIV-positive for 7 years, and his wife and daughter were also positive. He had stopped abusing intravenous drugs 7 years previously and was receiving methadone as maintenance therapy. He drank five beers daily. His medications were zidovudine, 250 mg twice a day, and trimethoprimsulfamethoxazole as prophylaxis against pneumocystis pneumonia.
      On examination, the dorsal aspects of the patient's hands contained erosions and scattered hyperpigmented and hypopigmented scars in a photosensitive distribution. Postinflammatory milia were also evident (Fig. 3). His face had similar erosions, postinflammatory milia, and hypertrichosis without evidence of sclerodermoid features.
      Figure thumbnail gr3
      Fig. 3 (case 2)Postinflammatory milia on hands of 36-year-old man with human immunodeficiency virus.
      A complete blood cell count was normal, and the hemoglobin level was 13 g/dL. Liver function was abnormal, with an increased aspartate aminotransferase value, 90 IU/L (normal, 12 to 31), and an increased alanine aminotransferase level, 73 IU/L (normal, 10 to 45). The patient was immunosuppressed, with a T-cell CD4+ count of 210 × 10−6L. Porphyrin profiles were diagnostic of PCT. Plasma porphyrins were increased to 208 nmol/L. Fecal porphyrin screening results were positive, with high-performance liquid chromatography showing both isocoproporphyrin and heptacarboxylporphyrin in the stool. Urine total porphyrin screen findings were positive, with a substantially increased porphyrin level of 2,570 μg/24 h. Quantitative urine estimation showed increased uroporphyrin at 1,250 nmol/24 h (normal, less than 36), coproporphyrin at 168 nmol/24 h (normal, less than 246), and hepta 3 subunit at 1,140 nmol/24 h (normal, less than 4). Hepatitis C antibody status was positive by third-generation enzyme immunoassay and confirmed by third-generation recombinant immunoblot assay. Screens for hepatitis A and B were negative. The patient is currently receiving low-dose chloroquine and has no clinical evidence of porphyria.

      DISCUSSION

      Our two patients with PCT associated with HIV were both seropositive for hepatitis C. In many of the 40 cases reported to date,
      • Conlan MG
      • Hoots WK
      Porphyria cutanea tarda in association with human immunodeficiency virus infection in a hemophiliac.
      • Castanet J
      • Lacour JP
      • Bodokh J
      • Bekri S
      • Ortonne JP
      Porphyria cutanea tarda in association with human immunodeficiency virus infection: is it related to hepatitic C virus infection? [letter].
      • Ong EL
      • Ellis ME
      • McDowell D
      • Gebril M
      • Welnkove C
      • Ead R
      Porphyria cutanea tarda in association with the human immunodeficiency virus infection.
      • Lobato MN
      • Berger TG
      Porphyria cutanea tarda associated with the acquired immunodeficiency syndrome [letter].
      • Cohen PR
      Porphyria cutanea tarda in human immunodeficiency virus-seropositive men: case report and literature review.
      • Scannell KA
      Porphyria cutanea tarda and acquired immunodeficiency syndrome: case reports and literature review (letter).
      • Nip-Sakamoto CJ
      • Wong RH
      • Liumi AK
      Porphyria cutanea tarda and AIDS.
      • Gafa S
      • Zanninl A
      • Gabrielli C
      Porphyria cutanea tarda and HIV infection: effect of zidovudine treatment on a patient [letter].
      • Conrad ME
      AIDS and porphyria cutanea tarda [letter].
      • Lacoma F
      • Yebra M
      • Albarran F
      • Moya M
      Porphyria cutanea tarda and human immunodeficiency virus: two new cases [letter].
      • Wissel PS
      • Sordllto P
      • Anderson KE
      • Saasa S
      • Savllit RL
      • Kappas A
      Porphyria cutanea tarda associated with the acquired immune deficiency syndrome.
      • Hogan D
      • Card RT
      • Ghadially R
      • McSheffrey JB
      • Lane P
      Human immunodeficiency virus infection and porphyria cutanea tarda.
      • Russel MG
      • Lustermans FA
      • White J
      • van Pelt J
      Porphyria cutanea tarda in a patient with AIDS.
      hepatitis C status was unknown.
      • Blauvert A
      • Harris HR
      • Hogan DJ
      • Jimenez-Acosta F
      • Ponce I
      • Pardo RJ
      Porphyria cutanea tarda and human immunodeficiency virus infection.
      The association between HCV and PCT is now well recognized.
      • Murphy A
      • Dooley S
      • Hillary IB
      • Murphy GM
      HCV infection in porphyria cutanea tarda [letter].
      • Coburn PR
      • Coleman JC
      • Cream JJ
      • Hawk JL
      • Lamb SGS
      • Murray-Lyon IM
      Porphyria cutanea tarda and porphyria variegata unmasked by viral hepatitis.
      • Lacour JP
      • Bodokh I
      • Castanet J
      • Bekil S
      • Ortonne JP
      Porphyria cutanea tarda and antibodies to hepatitis C virus.
      • McAllster F
      • McClean K
      • Hamilton PG
      • Houston S
      Human immunodeficiency virus infection and porphyria cutanea tarda: coexistence of risk factors or causative association?.
      In both our patients, PCT was diagnosed after the diagnosis of HIV. In many of the cases reported to date, PCT was the initial manifestation.
      • Reynaud P
      • Goodfellow K
      • Svec F
      Porphyria cutanea tarda as initial presentation of the acquired immunodeficiency syndrome in two patients [letter].
      Of interest, one of our patients (case 1) received stavudine 3 months before assessment. Zidovudine has previously been reported to precipitate PCT,
      • Blauvert A
      • Harris HR
      • Hogan DJ
      • Jimenez-Acosta F
      • Ponce I
      • Pardo RJ
      Porphyria cutanea tarda and human immunodeficiency virus infection.
      but this effect has not been described with other antiretroviral agents. Other risk factors for that patient were hepatitis B, excess use of alcohol in the remote past, and several potentially hepatotoxic drugs. This patient's porphyria would be classified as type 2 (familial) because his erythrocyte uroporphyrinogen decarboxylase levels were depressed. Risk factors for our other patient (case 2) were excess intake of alcohol and zidovudine therapy.
      Studies of 33 HIV-positive patients revealed abnormal porphyrin excretion profiles in 40%. Most of these patients were hepatitis C-positive and had greater immunosuppression, with lower CD4 counts. Twelve percent had biochemical excretion profiles of PCT without clinical features.
      • O'Connor WJ
      • Murphy GM
      • Darby C
      • Fogarty J
      • Mulcahy F
      • O'Moore R
      • et al.
      Porphyrin abnormalities in acquired immunodeficiency syndrome.
      Studies of HIV-negative, hepatitis C-positive patients, however, have not shown similar abnormalities. Only 1 of 34 women who had acquired HCV from immunization with anti-D immunoglobulin had mildly abnormal porphyrin profiles about 20 years after infection.
      • O'Reilly FJ
      • Darby C
      • O'Moore R
      • Courtney MG
      • O'Connor J
      • Fielding JF
      • et al.
      Porphyrin metabolism in hepatitis C infection secondary to anti-D immunoglobulin and intravenous drug abuse [abstract].
      Higher HCV viremia and more rapid progression to cirrhosis have been reported in patients coinfected with HCV and HIV.
      • Cribier B
      • Rey D
      • Schmitt C
      • Lang JM
      • Kirn A
      • Stoll Keller F
      High hepatitis C viraemia and impaired antibody response in patients coinfected with HIV.
      Among coinfected patients with hemophilia, HCV RNA levels increased 53-fold in comparison with a 3-fold increase in HIV-negative patients during a 5-year study period.
      • Eyster ME
      • Fried MW
      • Dl Bisceglie AM
      • Goedert JJ
      Increasing hepatitis C virus RNA levels in hemophiliacs: relationship to human immunodeficiency virus infection and liver disease.
      Liver failure occurs more frequently in coinfected patients than in those infected with HCV alone.
      • Eyster ME
      • Diamondstone LS
      • Lien JM
      • Ehmann WC
      • Quan S
      • Goedert JJ
      Natural history of hepatitis C virus infection in multitransfused hemophiliacs: effect of coinfection with human immunodeficiency virus.
      Maximally abnormal urinary coproporphyrin levels were found in coinfected patients. But not in patients infected with either virus alone.
      • Crlbier B
      • Rey D
      • Uhl G
      • Le Croz C
      • Hirth C
      • Libbrecht E
      • et al.
      Abnormal urinary coproporphyrin levels in patients infected by hepatitis C virus with or without human immunodeficiency virus.
      Thus, although HCV seems to be important in inducing porphyrin abnormalities in susceptible persons, the combination of HCV and HIV seems to be more potent.
      • Blauvelt A
      Hepatitis C virus and human immunodeficiency virus infection can alter porphyrin metabolism and lead to porphyria cutanea tarda [editorial].
      Patients coinfected with HIV have higher hepatitis C viremia and more rapid progression to cirrhosis. Additional factors related to HIV, such as immunosuppression, zidovudine therapy, iron overload, and hepatotoxins (including alcohol), may also precipitate PCT in predisposed persons.
      A diagnosis of PCT, especially in a young patient, should prompt investigation for underlying HIV and hepatitis C infection. Porphyrin studies should be performed in any patient with HIV and photosensitivity. HIV has been isolated from cutaneous blister fluid in patients with PCT and HIV.
      • Supapannachart N
      • Breneman DL
      • Llnnemann Jr, CC
      Isolation of human immunodeficiency virus type 1 in cutaneous blister fluid.
      HCV transmission is also a potential risk. Low-dose chloroquine two times per week is preferable therapeutically because of the risk of infection to the phlebotomist with weekly venesection. If the patient has anemia, remission may be achieved also with erythropoietin without venesection. Clinicians should be aware of the infectious risk associated with the vesicles and erosions in these patients.

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