Hepatitis C, porphyria cutanea tarda and liver iron: An update

Liver International

Volumn 32, Issue 6, 2012, Pages 880-893

  Ryan Caballes, F ^a,b   Sendi, Hossein ^a   Bonkovsky, Herbert L ^b,c  

^a CAROLINAS MEDICAL CENTER   (United States)

^b CMC   (United States)

^c Department of Medicine   (United States)

Author keywords

Chloroquine; Chronic hepatitis C; Hepatitis C virus; Hereditary hemochromatosis; Iron; Oxidative stress; Porphyria cutanea tarda; Reactive oxygen species; Therapeutic phlebotomy; Uroporphyrinogen decarboxylase

Indexed keywords

ALPHA INTERFERON; ANTIMALARIAL AGENT; BILIVERDIN; BOCEPREVIR; CHLOROQUINE; DEFERASIROX; DEFERIPRONE; DEFEROXAMINE; GLYCINE; HEME; HEME OXYGENASE; HEPCIDIN; HFE PROTEIN; HYDROXYCHLOROQUINE; IRON; PEGINTERFERON; PORPHYRIN; PROTEINASE INHIBITOR; REACTIVE OXYGEN METABOLITE; RIBAVIRIN; SUCCINYL COENZYME A; SUNSCREEN; TELAPREVIR; UROPORPHYRIN; UROPORPHYRINOGEN; UROPORPHYRINOGEN DECARBOXYLASE;

ALCOHOL LIVER DISEASE; ALOPECIA; BLISTER; CHLORACNE; CLINICAL FEATURE; DIET THERAPY; DISEASE ASSOCIATION; DYSTROPHY; ENZYME ACTIVITY; FATTY LIVER; GENE MUTATION; HEMOCHROMATOSIS; HEMOSIDEROSIS; HEPATITIS C; HEPATITIS C VIRUS; HISTOPATHOLOGY; HUMAN; HYPERTRICHOSIS; IRON ABSORPTION; IRON CHELATION; IRON OVERLOAD; LABORATORY TEST; LIVER CELL; LIVER CELL CARCINOMA; LIVER CIRRHOSIS; LOW DRUG DOSE; NONHUMAN; ONYCHOLYSIS; OXIDATIVE STRESS; PATHOGENESIS; PHLEBOTOMY; PORPHYRIA CUTANEA TARDA; PROTECTIVE CLOTHING; REVIEW; RISK FACTOR; SIDEROSIS; SKIN MANIFESTATION; SKIN ULCER; SUN EXPOSURE; URINARY EXCRETION;

ANIMALS; ANTIMALARIALS; HEPACIVIRUS; HEPATITIS C, CHRONIC; HUMANS; IRON; IRON METABOLISM DISORDERS; LIVER; PHLEBOTOMY; PORPHYRIA CUTANEA TARDA; PROGNOSIS; RISK FACTORS;

EID: 84861983980     PISSN: 14783223     EISSN: 14783231     Source Type: Journal    
DOI: 10.1111/j.1478-3231.2012.02794.x     Document Type: Review

References (99)

1. Chan OT, Tsai N, Wong RL, Izumi AK. The additive effects of hepatitis C infection and end-stage renal disease in porphyria cutanea tarda. Cutis 2006; 78: 397-400.
2. Frank J, Poblete-Gutierrez P. Porphyria cutanea tarda-when skin meets liver. Best Pract Res Clin Gastroenterol 2010; 24: 735-45.
3. Lim HW. Role of viral infection in porphyria cutanea tarda. Photodermatol Photoimmunol Photomed 1997; 13: 75-7.
4. Sams H, Kiripolsky MG, Bhat L, Stricklin GP. Porphyria cutanea tarda, hepatitis C, alcoholism, and hemochromatosis: a case report and review of the literature. Cutis 2004; 73: 188-90.
5. Chemmanur AT, Bonkovsky HL. Hepatic porphyrias: diagnosis and management. Clin Liver Dis 2004; 8: 807-38, viii.
6. Alla V, Bonkovsky HL. Iron in nonhemochromatotic liver disorders. Semin Liver Dis 2005; 25: 461-72.
7. Badenas C, To-Figueras J, Phillips JD, et al. Identification and characterization of novel uroporphyrinogen decarboxylase gene mutations in a large series of porphyria cutanea tarda patients and relatives. Clin Genet 2009; 75: 346-53.
8. Bonkovsky HL, Lambrecht RW. Hemochromatosis, iron overload, and porphyria cutanea tarda. In: Barton JC, Edwards CQ, eds. Hemochromatosis-Genetics, Pathophysiology, Diagnosis and Treatment, 2nd edn. Cambridge, UK: Cambridge University Press, 2000; 453-67.
9. Desnick RJ, Astrin KH. The porphyrias. In: Fauci A, Braunwald E, Kasper D, eds. Harrison's: Principles of Internal Medicine, 17th edn. New York: McGraw Hill, 2008; 2434-44.
10. Foran SE, Abel G. Guide to porphyrias. A historical and clinical perspective. Am J Clin Pathol 2003; 119(Suppl): S86-93.
11. Pietrangelo A. The porphyrias: pathophysiology. Intern Emerg Med 2010; 5(Suppl. 1): S65-71.
12. Desnick RJ, Bishop DF, Sassa S, Anderson KE. Disorders of heme biosynthesis: X-linked sideroblastic anaemia and the porphyrias. In: Scriver C, ed. The Metabolic and Molecular Bases of Inherited Disease, 8th edn. New York: McGraw Hill, 2001; 2991-3062.
13. Phillips JD, Bergonia HA, Reilly CA, Franklin MR, Kushner JP. A porphomethene inhibitor of uroporphyrinogen decarboxylase causes porphyria cutanea tarda. Proc Natl Acad Sci U S A 2007; 104: 5079-84.
14. Danton M, Lim CK. Porphomethene inhibitor of uroporphyrinogen decarboxylase: analysis by high-performance liquid chromatography/electrospray ionization tandem mass spectrometry. Biomed Chromatogr 2007; 21: 661-3.
15. English JC 3rd, Peake MF, Becker LE. Hepatitis C and porphyria cutanea tarda. Cutis 1996; 57: 404-8.
16. Hussain I, Hepburn NC, Jones A, O'Rourke K, Hayes PC. The association of hepatitis C viral infection with porphyria cutanea tarda in the Lothian region of Scotland. Clin Exp Dermatol 1996; 21: 283-5.
17. Jalil S, Grady JJ, Lee C, Anderson KE. Associations among behavior-related susceptibility factors in porphyria cutanea tarda. Clin Gastroenterol Hepatol 2010; 8: 297-302.
18. Sarkany RP. Making sense of the porphyrias. Photodermatol Photoimmunol Photomed 2008; 24: 102-8.
19. Mahmoud BH, Hexsel CL, Hamzavi IH, Lim HW. Effects of visible light on the skin. Photochem Photobiol 2008; 84: 450-62.
20. Anderson KE. The porphyrias. In: Boyer T, Wright T, Manns M, eds. Zakim and Boyer's Hepatology: A Textbook of Liver Disease, 5th edn. Philadelphia: Saunders-Elsevier, 2006; 1391-420.
21. Chiaverini C, Halimi G, Ouzan D, et al. Porphyria cutanea tarda, C282Y, H63D and S65C HFE gene mutations and hepatitis C infection: a study from southern France. Dermatology 2003; 206: 212-6.
22. Ellervik C, Birgens H, Tybjaerg-Hansen A, Nordestgaard BG. Hemochromatosis genotypes and risk of 31 disease endpoints: meta-analyses including 66, 000 cases and 226, 000 controls. Hepatology 2007; 46: 1071-80.
23. Azim J, McCurdy H, Moseley RH. Porphyria cutanea tarda as a complication of therapy for chronic hepatitis C. World J Gastroenterol 2008; 14: 5913-5.
24. Cribier B, Chiaverini C, Dali-Youcef N, et al. Porphyria cutanea tarda, hepatitis C, uroporphyrinogen decarboxylase and mutations of HFE gene. A case-control study. Dermatology 2009; 218: 15-21.
25. Dienhart P, Sterling R. Management of hepatitis C virus in patients with porphyria cutanea tarda. Curr Hepat Rep 2005; 4: 104-11.
26. Bonkovsky HL, Poh-Fitzpatrick M, Pimstone N, et al. Porphyria cutanea tarda, hepatitis C, and HFE gene mutations in North America. Hepatology 1998; 27: 1661-9.
27. Wickliffe JK, Abdel-Rahman SZ, Lee C, et al. CYP1A2*1F and GSTM1 alleles are associated with susceptibility to porphyria cutanea tarda. Mol Med 2011; 4: 241-7.
28. Scribner A, Houck D, Huang Z, et al. Synthesis and biological evaluation of [D-lysine]8cyclosporin A analogs as potential anti-HCV agents. Bioorg Med Chem Lett 2010; 20: 6542-6.
29. Wright TL, Manns M. Hepatitis C. In: Boyer T, Wright TL, Manns M, eds. Zakim and Boyer's Hepatology: A Textbook of Liver Disease, 5th edn. Philadelphia: Saunders-Elsevier, 2006; 665-86.
30. Bostan N, Mahmood T. An overview about hepatitis C: a devastating virus. Crit Rev Microbiol 2010; 36: 91-133.
31. Ashfaq UA, Javed T, Rehman S, Nawaz Z, Riazuddin S. An overview of HCV molecular biology, replication and immune responses. Virol J 2011; 8: 161.
32. Berenguer M, Lopez-Labrador FX, Wright TL. Hepatitis C and liver transplantation. J Hepatol 2001; 35: 666-78.
33. Chuang TY, Brashear R, Lewis C. Porphyria cutanea tarda and hepatitis C virus: a case-control study and meta-analysis of the literature. J Am Acad Dermatol 1999; 41: 31-6.
34. Dabrowska E, Jablonska-Kaszewska I, Bielawski KP, Falkiewicz B. Influence of hepatitis C virus (HCV) infection on porphyrin and iron metabolism in porphyria cutanea tarda (PCT) patients. Med Sci Monit 2001; 7(Suppl. 1): 190-6.
35. 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: 620-7.
36. O'Reilly FM, Darby C, Fogarty J, et al. Porphyrin metabolism in hepatitis C infection. Photodermatol Photoimmunol Photomed 1996; 12: 31-3.
37. Kawamura Y, Akuta N, Sezaki H, et al. Determinants of serum ALT normalization after phlebotomy in patients with chronic hepatitis C infection. J Gastroenterol 2005; 40: 901-6.
38. Narang T, Sendi H, Scobey M, Bonkovsky H. Iron and Hepatitis C. Curr Hepat Rep 2010; 9: 169-77.
39. Lambrecht RW, Thapar M, Bonkovsky HL. Genetic aspects of porphyria cutanea tarda. Semin Liver Dis 2007; 27: 99-108.
40. Roberts AG, Whatley SD, Morgan RR, Worwood M, Elder GH. Increased frequency of the haemochromatosis Cys282Tyr mutation in sporadic porphyria cutanea tarda. Lancet 1997; 349: 321-3.
41. Santos M, Clevers HC, Marx JJ. Mutations of the hereditary hemochromatosis candidate gene HLA-H in porphyria cutanea tarda. N Engl J Med 1997; 336: 1327-8.
42. Price L, Kowdley KV. The role of iron in the pathophysiology and treatment of chronic hepatitis C. Can J Gastroenterol 2009; 23: 822-8.
43. Furutani T, Hino K, Okuda M, et al. Hepatic iron overload induces hepatocellular carcinoma in transgenic mice expressing the hepatitis C virus polyprotein. Gastroenterology 2006; 130: 2087-98.
44. Fillebeen C, Muckenthaler M, Andriopoulos B, et al. Expression of the subgenomic hepatitis C virus replicon alters iron homeostasis in Huh7 cells. J Hepatol 2007; 47: 12-22.
45. Nishina S, Hino K, Korenaga M, et al. Hepatitis C virus-induced reactive oxygen species raise hepatic iron level in mice by reducing hepcidin transcription. Gastroenterology 2008; 134: 226-38.
46. Miura K, Taura K, Kodama Y, Schnabl B, Brenner DA. Hepatitis C virus-induced oxidative stress suppresses hepcidin expression through increased histone deacetylase activity. Hepatology 2008; 48: 1420-9.
47. Fujita N, Sugimoto R, Takeo M, et al. Hepcidin expression in the liver: relatively low level in patients with chronic hepatitis C. Mol Med 2007; 13: 97-104.
48. Girelli D, Pasino M, Goodnough JB, et al. Reduced serum hepcidin levels in patients with chronic hepatitis C. J Hepatol 2009; 51: 845-52.
49. Ajioka RS, Phillips JD, Weiss RB, et al. Down-regulation of hepcidin in porphyria cutanea tarda. Blood 2008; 112: 4723-8.
50. Weber T, Theurich S, Christopeit M, Klapperstueck T, Behre G. Human herpesvirus-6 as an inducer of porphyria cutanea tarda: implications from a case. Transpl Infect Dis 2010; 12: 432-6.
51. Sinclair PR, Gorman N, Walton HS, et al. CYP1A2 is essential in murine uroporphyria caused by hexachlorobenzene and iron. Toxicol Appl Pharmacol 2000; 162: 60-7.
52. Dereure O, Jumez N, Bessis D, Gallix B, Guillot B. Measurement of liver iron content by magnetic resonance imaging in 20 patients with overt porphyria cutanea tarda before phlebotomy therapy: a prospective study. Acta Derm Venereol 2008; 88: 341-5.
53. Linde Y, Harper P, Floderus Y, Ros AM. The prevalence of hepatitis C in patients with porphyria cutanea tarda in Stockholm, Sweden. Acta Derm Venereol 2005; 85: 164-6.
54. Gil-Mosquera M, Vano-Galvan S, Gomez-Guerra R, Jaen P. Lesions on the hands, high aminotransferase levels. Cleve Clin J Med 2010; 77: 34-6.
55. Di Padova C, Marchesi L, Cainelli T, et al. Effects of phlebotomy on urinary porphyrin pattern and liver histology in patients with porphyria cutanea tarda. Am J Med Sci 1983; 285: 2-12.
56. Moran MJ, Fontanellas A, Brudieux E, et al. Hepatic uroporphyrinogen decarboxylase activity in porphyria cutanea tarda patients: the influence of virus C infection. Hepatology 1998; 27: 584-9.
57. Ratnaike S, Blake D, Campbell D, Cowen P, Varigos G. Plasma ferritin levels as a guide to the treatment of porphyria cutanea tarda by venesection. Australas J Dermatol 1988; 29: 3-8.
58. Rocchi E, Gibertini P, Cassanelli M, et al. Serum ferritin in the assessment of liver iron overload and iron removal therapy in porphyria cutanea tarda. J Lab Clin Med 1986; 107: 36-42.
59. Kostler E, Wollina U. Therapy of porphyria cutanea tarda. Expert Opin Pharmacother 2005; 6: 377-83.
60. Sarkany RP. The management of porphyria cutanea tarda. Clin Exp Dermatol 2001; 26: 225-32.
61. Bonkovsky HL, Naishadham D, Lambrecht RW, et al. Roles of iron and HFE mutations on severity and response to therapy during retreatment of advanced chronic hepatitis C. Gastroenterology 2006; 131: 1440-51.
62. Harper P, Wahlin S. Treatment options in acute porphyria, porphyria cutanea tarda, and erythropoietic protoporphyria. Curr Treat Options Gastroenterol 2007; 10: 444-55.
63. Stolzel U, Kostler E, Koszka C, et al. Low prevalence of hepatitis C virus infection in porphyria cutanea tarda in Germany. Hepatology 1995; 21: 1500-3.
64. Okano J, Horie Y, Kawasaki H, Kondo M. Interferon treatment of porphyria cutanea tarda associated with chronic hepatitis type C. Hepatogastroenterology 1997; 44: 525-8.
65. 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: 249-50.
66. Rossini A, Contessi G, Bozzetti F. Efficacy of iron depletion and antiviral therapy in patients with porphyria cutanea tarda (PCT) and hepatitis C virus (HCV) chronic infection. Hepatology 2004; 40: 320A.
67. Bonkovsky HL, Banner BF, Rothman AL. Iron and chronic viral hepatitis. Hepatology 1997; 25: 759-68.
68. Di Bisceglie AM, Bonkovsky HL, Chopra S, et al. Iron reduction as an adjuvant to interferon therapy in patients with chronic hepatitis C who have previously not responded to interferon: a multicenter, prospective, randomized, controlled trial. Hepatology 2000; 32: 135-8.
69. Fernandez I, Castellano G, De Salamanca RE, et al. Porphyria cutanea tarda as a predictor of poor response to interferon alfa therapy in chronic hepatitis C. Scand J Gastroenterol 2003; 38: 314-9.
70. Desai TK, Jamil LH, Balasubramaniam M, Koff R, Bonkovsky HL. Phlebotomy improves therapeutic response to interferon in patients with chronic hepatitis C: a meta-analysis of six prospective randomized controlled trials. Dig Dis Sci 2008; 53: 815-22.
71. Scobey M, Bonkovsky HL. Iron: a putative reason for gender-based differences in chronic liver disease. In: Simizu I, ed. Female Hepatology: Impact of Female Sex Against Progression of Liver Disease. Kerala, India: Research Signpost Publishing, 2009: 97-128.
72. Pianko S, McHutchison JG, Gordon SC, et al. Hepatic iron concentration does not influence response to therapy with interferon plus ribavirin in chronic HCV infection. J Interferon Cytokine Res 2002; 22: 483-9.
73. Rulyak SJ, Eng SC, Patel K, et al. Relationships between hepatic iron content and virologic response in chronic hepatitis C patients treated with interferon and ribavirin. Am J Gastroenterol 2005; 100: 332-7.
74. Gentile I, Viola C, Paesano L, et al. Iron depletion before HCV antiviral therapy: a pilot, randomized, controlled trial. J Clin Apher 2009; 24: 190-6.
75. Distante S, Bjoro K, Hellum KB, et al. Raised serum ferritin predicts non-response to interferon and ribavirin treatment in patients with chronic hepatitis C infection. Liver 2002; 22: 269-75.
76. Ferrara F, Ventura P, Vegetti A, et al. Serum ferritin as a predictor of treatment outcome in patients with chronic hepatitis C. Am J Gastroenterol 2009; 104: 605-16.
77. Lindsay KL, Morishima C, Wright EC, et al. Blunted cytopenias and weight loss: new correlates of virologic null response to re-treatment of chronic hepatitis C. Clin Gastroenterol Hepatol 2008; 6: 234-41.
78. Lambrecht RW, Sterling RK, Naishadham D, et al. Iron levels in hepatocytes and portal tract cells predict progression and outcomes of patients with advanced chronic hepatitis C. Gastroenterology 2011; 140: 1490-500.
79. Hayashi H, Takikawa T, Nishimura N, et al. Improvement of serum aminotransferase levels after phlebotomy in patients with chronic active hepatitis C and excess hepatic iron. Am J Gastroenterol 1994; 89: 986-8.
80. Kato J, Miyanishi K, Kobune M, et al. Long-term phlebotomy with low-iron diet therapy lowers risk of development of hepatocellular carcinoma from chronic hepatitis C. J Gastroenterol 2007; 42: 830-6.
81. Sumida Y, Kanemasa K, Fukumoto K, Yoshida N, Sakai K. Effects of dietary iron reduction versus phlebotomy in patients with chronic hepatitis C: results from a randomized, controlled trial on 40 Japanese patients. Intern Med 2007; 46: 637-42.
82. Sartori M, Andorno S, Rossini A, et al. A case-control histological study on the effects of phlebotomy in patients with chronic hepatitis C. Eur J Gastroenterol Hepatol 2011; 23: 1178.
83. Hayashi H, Piperno A, Tomosugi N, et al. Patients with chronic hepatitis C may be more sensitive to iron hepatotoxicity than patients with HFE-hemochromatosis. Intern Med 2010; 49: 2371-7.
84. Alsatie M, Kwo P. Treatment of chronic hepatitis C in patients who have failed to respond to IFN or IFN and ribavirin combination therapy. Curr Hepatitis Rep 2003; 2: 32-9.
85. Scheuer P, Lefkowitch J. Liver Biopsy Interpretation. Philadelphia: Saunders Co, 2000.
86. Egger NG, Goeger DE, Payne DA, et al. Porphyria cutanea tarda: multiplicity of risk factors including HFE mutations, hepatitis C, and inherited uroporphyrinogen decarboxylase deficiency. Dig Dis Sci 2002; 47: 419-26.
87. Bulaj ZJ, Phillips JD, Ajioka RS, et al. Hemochromatosis genes and other factors contributing to the pathogenesis of porphyria cutanea tarda. Blood 2000; 95: 1565-71.
88. Rossmann-Ringdahl I, Olsson R. Porphyria cutanea tarda in a Swedish population: risk factors and complications. Acta Derm Venereol 2005; 85: 337-41.
89. Nagy Z, Koszo F, Par A, et al. Hemochromatosis (HFE) gene mutations and hepatitis C virus infection as risk factors for porphyria cutanea tarda in Hungarian patients. Liver Int 2004; 24: 16-20.
90. Tannapfel A, Stolzel U, Kostler E, et al. C282Y and H63D mutation of the hemochromatosis gene in German porphyria cutanea tarda patients. Virchows Arch 2001; 439: 1-5.
91. Ivanova A, von Ahsen N, Adjarov D, et al. C282Y and H63D mutations in the HFE gene are not associated with porphyria cutanea tarda in Bulgaria. Hepatology 1999; 30: 1531-2.
92. Lamoril J, Andant C, Bogard C, et al. Epidemiology of hepatitis C and G in sporadic and familial porphyria cutanea tarda. Hepatology 1998; 27: 848-52.
93. Roberts AG, Whatley SD, Nicklin S, et al. The frequency of hemochromatosis-associated alleles is increased in British patients with sporadic porphyria cutanea tarda. Hepatology 1997; 25: 159-61.
94. Herrero C, Vicente A, Bruguera M, et al. Is hepatitis C virus infection a trigger of porphyria cutanea tarda? Lancet 1993; 341: 788-9.
95. Fargion S, Piperno A, Cappellini MD, et al. Hepatitis C virus and porphyria cutanea tarda: evidence of a strong association. Hepatology 1992; 16: 1322-6.
96. Stuart KA, Busfield F, Jazwinska EC, et al. The C282Y mutation in the haemochromatosis gene (HFE) and hepatitis C virus infection are independent cofactors for porphyria cutanea tarda in Australian patients. J Hepatol 1998; 28: 404-9.
97. Mendez M, Rossetti MV, Del CBAM, Parera VE. The role of inherited and acquired factors in the development of porphyria cutanea tarda in the Argentinean population. J Am Acad Dermatol 2005(3 Pt. 1); 52: 417-24.
98. Martinelli AL, Zago MA, Roselino AM, et al. Porphyria cutanea tarda in Brazilian patients: association with hemochromatosis C282Y mutation and hepatitis C virus infection. Am J Gastroenterol 2000; 95: 3516-21.
99. Caballes FR, Bonkovsky HL. Cutaneous porphyrias. In: Bacon BR, Spechler S, Forsmark C, eds. Gastroenterology and Hepatology. Wilmington, DE: Decision Support in Medicine, LLC, 2012, in press.