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ISSN 1007-9327 CN 14-1219/R  World J Gastroenterol  2008 October 14; 14(38): 5913-5915

    CASE REPORT

Porphyria cutanea tarda as a complication of therapy for chronic hepatitis C

James Azim, Heather McCurdy, Richard H Moseley


James Azim, Heather McCurdy, Richard H Moseley, Division of Gastroenterology, Department of Internal Medicine, Department of Veterans Affairs Medical Center and University of Michigan School of Medicine, Ann Arbor, Michigan,

United States

Author contributions: All authors contributed equally to this work.

Correspondence to: Richard H Moseley, MD, Chief, Medical Service (111), Ann Arbor VA Healthcare System, 2215 Fuller Road, Ann Arbor, Michigan 48105, United States. rmoseley@med.umich.edu

Telephone: +1-734-8455849  Fax: +1-734-9130883

Received: July 15, 2008         Revised: September 16, 2008

Accepted: September 23, 2008

Published online: October 14, 2008

 

Abstract

There is a strong association between porphyria cutanea tarda (PCT) and chronic viral hepatitis C. Therapy for chronic viral hepatitis C may improve PCT. However, there are only a few reports of the de novo development of PCT during therapy for chronic viral hepatitis C. We describe the development of PCT in a 56-year-old patient with chronic viral hepatitis C after 12 wk of peginterferon/ribavirin therapy. In addition, the patient was homozygous for the H63D hereditary hemochromatosis gene (HFE) mutation. The association of PCT with chronic viral hepatitis C and the possible role of hepatic iron overload and ribavirin-induced hemolytic anemia in the development of PCT during therapy for chronic viral hepatitis C are discussed.

 

© 2008 The WJG Press. All rights reserved.

 

Key words: Porphyria; Hepatitis C virus; Ribavirin; Pegylated interferon; Hemochromatosis

 

Peer reviewers: Stephan Menne, Assistant Professor of Virology, Department of Clinical Sciences/GI Unit, College of Veterinary Medicine, Cornell University, C2-005 Veterinary Medical Center, Ithaca, NY 14853, United States; Eva Herrmann, Professor, Saarland University, Kirrberger Street, Homburg/Saar 66421, Germany

 

Azim J, McCurdy H, Moseley RH. Porphyria cutanea tarda as a complication of therapy for chronic hepatitis C. World J Gastroenterol 2008; 14(38): 5913-5915  Available from: URL: http://www.wjgnet.com/1007-9327/14/5913.asp  DOI: http://dx.doi.org/10.3748/wjg.14.5913

 

INTRODUCTION

Porphyria cutanea tarda (PCT), the most common of the porphyrias, results from reduced activity of uroporphyrinogen decarboxylase (UROD), an enzyme in the heme biosynthetic pathway[1]. Clinical signs of PCT include photodistributed erythema, skin fragility, bullae, erosions and hypertrichosis. A strong association between PCT and hepatitis C virus (HCV) infection is well established[2]. Improvement of PCT during HCV treatment with interferon has been frequently described[3-6]. On the other hand, de novo occurrence of PCT during interferon plus ribavirin therapy for chronic viral hepatitis C has previously been described in only four patients[7-9]. Herein we describe the de novo development of PCT in a patient with chronic HCV infection undergoing combined peginterferon/ribavirin therapy, who was also found to be homozygous for the H63D mutation of the HFE gene.

 

CASE REPORT

Chronic hepatitis C (genotype 1a) was diagnosed in a 56-year-old man with a history of blood transfusions while serving in Vietnam. Past medical history included alcohol and cocaine dependency, as well as a history of treatment for rheumatoid arthritis, which was later characterized as osteoarthritis. He denied alcohol use for more than four years prior to initiation of ribavirin/interferon therapy. Prior tests for hepatitis B and HIV were negative. He did not smoke. Family history was noncontributory. At presentation, liver biopsy showed mildly active chronic hepatitis C with portal fibrosis (Batts and Ludwig grade 2 inflammation and stage 1 fibrosis). Hepatic iron deposition was not commented on. HCV-RNA PCR showed 102500 copies and serum transaminases were mildly elevated (AST 53 IU/L and ALT 100 IU/L). The patient was treated with peginterferon-a2b (150 mg/wk) and ribavirin (1200 mg/day) for 44 weeks of a planned 48-week course. Treatment ceased early secondary to anemia and neutropenia. Viral clearance was achieved after 16 wk of treatment and HCV-RNA PCR remained negative at the end of and 6 mo following treatment.

    After 12 wk of therapy, the patient presented with multiple hand blisters and erosions in various stages of healing, consistent with PCT. Diagnosis of PCT was confirmed by detection of elevated urinary uroporphyrin (599 mg/24 h, N < 44) and heptacarboxyl-porphyrin (799 mg/24 h, N < 12) levels. Because of the patient’s anemia (hemoglobin dropped from
15.7 g/dL pretreatment to 10.4 g/dL at onset of PCT), treatment of PCT with phlebotomy was deferred until completion of his peginterferon/ribavirin treatment. Clinical resolution of PCT occurred thereafter with repeated phlebotomy. Prior to initiation of phlebotomy, ferritin was markedly elevated (2920 ng/mL, N < 464) and the transferrin saturation was 81%. The patient was found to be homozygous for the H63D HFE gene mutation.

 

DISCUSSION

PCT arises from decreased activity of hepatic uroporphyrinogen decarboxylase (UROD), an enzyme in the heme synthetic pathway[1,10]. Although about 20% of cases involve mutations in the UROD gene (type II PCT), nearly all other occurrences (approximately 80%) are considered to arise sporadically (type I PCT)[1]. The genetic defects in type II PCT alone are not sufficient to cause phenotypic PCT, for they reduce UROD activity by no more than 50%[10]. Other contributing factors, including those that may be associated with type I PCT, must be present for phenotypic expression. Whether sporadic or familial, the clinical manifestations of PCT are the same, including skin fragility, erythema, bullae, erosions, hypertrichosis and milia in sun-exposed areas of the skin[11]. These lesions result from the photosensitizing effects of porphyrins that accumulate in the skin or dermal blood vessels[12]. The pathogenesis of the enzymatic defect in sporadic PCT is unclear, but is postulated to involve increased oxidative stress in the liver, modulated by multiple exogenous and endogenous factors[12,13].

    Well-recognized risk factors for PCT include HCV infection, hereditary hemochromatosis and other iron overload syndromes, as determined by mutations in the HFE gene, excessive alcohol use, HIV infection, and exposure to estrogen (including pregnancy) and polyhalogenated aromatic compounds[10]. The association of PCT with chronic HCV infection is particularly strong. The prevalence of HCV infection in patients with PCT was found to be about 50% in a recent systematic review and meta-analysis, though there was marked regional variation[2]. The underlying mechanism is unclear, despite this strong association of PCT with chronic HCV infection[11].

    Mainstays of PCT management include phlebotomy, chloroquine and avoidance of sun exposure[12]. HCV-associated PCT has, similarly, been reported to improve following initiation of interferon monotherapy[3-6], though improvement with interferon administration is not universally described[14]. Likewise, we found a single report describing the onset of HCV-associated PCT 2 years following initiation of interferon monotherapy in a patient who also had non-Hodgkins lymphoma and dermatomyositis[15]. The skin lesions resolved with chemotherapy and the authors hypothesized that the lymphoma had triggered PCT.

    In addition to the case we report here, de novo occurrence of PCT during interferon and ribavirin therapy for chronic HCV infection has been described in only 4 other cases[7-9]. Jessner et al[7] reported what they considered to be de novo occurrence of PCT after 4 months of therapy in a woman who had noticed occasional self-resolving small blisters prior to HCV therapy. A liver biopsy showed moderate iron deposition. She was found to have both type I (“familial”) PCT and heterozygosity for the C282Y HFE gene defect. Thevenot et al[8] described two patients without HFE gene defects who had onset of PCT one and two months, respectively, after initiating ribavirin and interferon therapy. One patient was noted to have a ferritin of 2408 ng/mL and the other patients’ liver biopsy showed mild iron deposition in Kupffer cells. Mutation analysis of the UROD gene was not reported in either case. Finally, Frider et al[9] reported a 47-year-old patient who developed PCT after 44 weeks of ribavirin and interferon therapy. HFE genotyping revealed C282Y/H63D compound heterozygosity.

    In all 5 reported cases of de novo PCT during ribavirin/interferon therapy, including that we describe here, the patients had clinical evidence of systemic or hepatic iron overload. Although the mechanism is unclear, iron overload is believed to play a significant role in the pathogenesis of PCT[16,17], possibly modulated by an iron-dependent reversible inactivation of hepatic UROD[16]. Supporting this are the oft-noted observations that the majority of patients with PCT exhibit some iron overload, iron depletion improves PCT, and iron administration produces relapse[13,16,17].

    Possibly contributing to hepatic iron loading in the reported de novo occurrences of PCT was the administration of ribavirin. A well-recognized major side effect of ribavirin is dose-dependent reversible hemolytic anemia[18]. Although Thevenot et al[8] did not comment on anemia, Jessner et al[7] noted onset of anemia concomitant with diagnosis of PCT. In addition to anemia, hepatic iron stores have been found to increase following prolonged ribavirin administration[19,20], with a relatively greater concentration of iron demonstrated in hepatocytes versus Kupffer cells[20]. The additional hepatic iron loading attributable to ribavirin administration may reduce the level of UROD activity sufficiently for PCT to become manifest in otherwise susceptible individuals. Consequently, screening for treatable PCT-associated conditions, such as hemochromatosis, should be considered prior to initiation of peginterferon/ribavirin therapy for chronic HCV.

 

REFERENCES

1      Elder GH. Porphyria cutanea tarda. Semin Liver Dis 1998; 18: 67-75   PubMed   

2      Gisbert JP, Garcia-Buey L, Pajares JM, Moreno-Otero R. Prevalence of hepatitis C virus infection in porphyria cutanea

        tarda: systematic review and meta-analysis. J Hepatol 2003; 39: 620-627   PubMed    DOI

3      Okano J, Horie Y, Kawasaki H, Kondo M. Interferon treatment of porphyria cutanea tarda associated with chronic

        hepatitis type C. Hepatogastroenterology 1997; 44: 525-528   PubMed   

4      Sheikh MY, Wright RA, Burruss JB. Dramatic resolution of skin lesions associated with porphyria cutanea tarda after

        interferon-alpha therapy in a case of chronic hepatitis C. Dig Dis Sci 1998; 43: 529-533   PubMed    DOI

5      Siegel LB, Eber BB. Porphyria cutanea tarda remission. Ann Intern Med 1994; 121: 308-309   PubMed   

6      Takikawa H, Yamazaki R, Shoji S, Miyake K, Yamanaka M. Normalization of urinary porphyrin level and disappearance

        of skin lesions after successful interferon therapy in a case of chronic hepatitis C complicated with porphyria cutanea

        tarda. J Hepatol 1995; 22: 249-250   PubMed    DOI

7      Jessner W, Der-Petrossian M, Christiansen L, Maier H, Steindl-Munda P, Gangl A, Ferenci P. Porphyria cutanea tarda

        during interferon/ribavirin therapy for chronic hepatitis C. Hepatology 2002; 36: 1301-1302   PubMed    DOI

8      Thevenot T, Bachmeyer C, Hammi R, Dumouchel P, Ducamp-Posak I, Cadranel JF. Occurrence of porphyria cutanea

        tarda during peginterferon/ribavirin therapy for chronic viral hepatitis C. J Hepatol 2005; 42: 607-608   PubMed    DOI

9      Frider B, Buonsante ME, Tiscornia J, Alessio A, Pellerano G. [Development of porphyria cutanea tarda in a chronic

        hepatitis C patient with indetectable viremia under treatment with peg-interferon plus ribavirin] Acta Gastroenterol

        Latinoam 2006; 36: 38-41   PubMed   

10    Lambrecht RW, Thapar M, Bonkovsky HL. Genetic aspects of porphyria cutanea tarda. Semin Liver Dis 2007; 27: 99-

        108   PubMed    DOI

11    Berk DR, Mallory SB, Keeffe EB, Ahmed A. Dermatologic disorders associated with chronic hepatitis C: effect of

        interferon therapy. Clin Gastroenterol Hepatol 2007; 5: 142-151   PubMed    DOI

12    Chemmanur AT, Bonkovsky HL. Hepatic porphyrias: diagnosis and management. Clin Liver Dis 2004; 8: 807-838, viii   

        PubMed    DOI

13    Bonkovsky HL, Poh-Fitzpatrick M, Pimstone N, Obando J, Di Bisceglie A, Tattrie C, Tortorelli K, LeClair P, Mercurio MG,

        Lambrecht RW. Porphyria cutanea tarda, hepatitis C, and HFE gene mutations in North America. Hepatology 1998; 27:

        1661-1669   PubMed    DOI

14    Furuta M, Kaito M, Gabazza E, Fujita N, Ishida S, Tamaki S, Ikeda R, Wakisawa S, Hayashi H, Watanabe S, Adachi Y.

        Ineffective interferon treatment of chronic hepatitis C-associated porphyria cutanea tarda, but with a transient decrease

        in HCV RNA levels. J Gastroenterol 2000; 35: 60-62   PubMed    DOI

15    Bauza A, Espana A, Lloret P. Porphyria cutanea tarda, dermatomyositis and non-Hodgkin lymphoma in virus C infection.

        Eur J Dermatol 2003; 13: 302-304   PubMed   

16    Alla V, Bonkovsky HL. Iron in nonhemochromatotic liver disorders. Semin Liver Dis 2005; 25: 461-472   PubMed    DOI

17    Fargion S, Fracanzani AL. Prevalence of hepatitis C virus infection in porphyria cutanea tarda. J Hepatol 2003; 39: 635-

        638   PubMed    DOI

18    De Franceschi L, Fattovich G, Turrini F, Ayi K, Brugnara C, Manzato F, Noventa F, Stanzial AM, Solero P, Corrocher R.

        Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: role of membrane

        oxidative damage. Hepatology 2000; 31: 997-1004   PubMed    DOI

19    Di Bisceglie AM, Bacon BR, Kleiner DE, Hoofnagle JH. Increase in hepatic iron stores following prolonged therapy with

        ribavirin in patients with chronic hepatitis C. J Hepatol 1994; 21: 1109-1112   PubMed    DOI

20    Fiel MI, Schiano TD, Guido M, Thung SN, Lindsay KL, Davis GL, Lewis JH, Seeff LB, Bodenheimer HC Jr.

        Increased hepatic iron deposition resulting from treatment of chronic hepatitis C with ribavirin. Am J

        Clin Pathol 2000; 113: 35-39   PubMed    DOI

 

                                                                                    S- Editor  Zhong XY    L- Editor  Wang XL    E- Editor  Zhang WB

 

 

                                                                                     

 

 


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