Digestive Diseases and Sciences

, Volume 41, Supplement 12, pp 63S–74S

Nonhepatic manifestations and combined diseases in HCV infection

  • Stephanos J. Hadziyannis


Infection with hepatitis C virus (HCV) may affect not only the liver but also various nonhepatic tissues and organs and may combine with many etiologically unrelated diseases and morbid conditions. Numerous nonhepatic manifestations in HCV infection have been previously reported. For some (eg, cryoglobulinemia), the association is well established. For others, such as sialadenitis and lichen planus, the association is probable (but not completely documented) and, for the remainder, the associations are weak. Extrahepatic manifestations may result from immunological mechanisms as well as virus invasion and replication in the affected extrahepatic tissues and organs. Thyroid abnormalities, primarily Hashimoto's disease, and isolated increases of anti-thyroid antibodies (ATPO) appear to be more frequent in chronic hepatitis C than B or D, with high ATPO titers clustering mainly among females. Interferon-α (IFN-α) therapy is associated with development of thyroid dysfunction in 5.5–12.9% of patients, usually exposing preexisting subclinical thyroid abnormalities. Mixed cryoglobulinemia (MC) is commonly found (36–45%) in patients with chronic HCV infection; however, only in a minority of cases does it become clinically manifested as systemic vasculitis with purpura, neuropathy, or Raynaud's phenomenon. In a number of patients, MC may terminate in non-Hodgkin's B-cell lymphoma. Treatment of these lymphoproliferative disorders with IFN-α is advocated. Idiopathic thrombocytopenia is now recognized more frequently in association with chronic HCV infection and is usually aggravated by IFN-α therapy. Patients with porphyria cutanea tarda (PCT) have demonstrated serological markers of HCV infection in 62–82% of cases. The usefulness of IFN-α in PCT remains to be demonstrated. Lichen planus has also been found in association with chronic HCV infection, particularly when severe or affecting the oral cavity. Other nonhepatic manifestations have also been reported in HCV infection such as diabetes, corneal ulceration, uveitis, and sialadenitis. These manifestations deserve further study and documentation. Finally, markers of autoimmunity occur with high frequency in chronic HCV infection; however, combination with the classical syndrome of autoimmune hepatitis is rare. In the presence of various autoantibodies, the clinical features of chronic hepatitis C do not appear to be modified and, contrary to general perception, IFN-α therapy within randomized controlled trials should not be withheld since the response rate to IFN-α does not appear to differ in the presence or absence of low titers of these markers.

Key words

hepatitis C virus thyroid diseases mixed cryoglobulinemia non-Hodgkin's lymphoma idiopathic thrombocytopenia porphyria cutanea tarda interferon 


  1. 1.
    Koff RS, Dienstag JL: Extrahepatic manifestations of hepatitis C and the association with alcoholic liver disease. Semin LIver Dis 15:101–109, 1995Google Scholar
  2. 2.
    Nowicki MJ, Balisteri WF: The hepatitis C virus: Identification, epidemiology, and clinical controversies. J Pediatr Gastroenterol Nutr 20:248–274, 1995Google Scholar
  3. 3.
    Gumber SC, Chopra S: Hepatitis C: A multifaced disease. Review of extrahepatic manifestations. Ann Intern Med 123:615–620, 1995Google Scholar
  4. 4.
    Berris B, Feinman SV: Thyroid dysfunction and liver injury following alpha-interferon treatment of chronic viral hepatitis. Dig Dis Sci 36:1657–1660, 1991Google Scholar
  5. 5.
    Lisker-Melman M, Di Bisceglie AM, Usala SJ, Weintraub B, Murray LM, Hoofnagle JH: Development of thyroid disease during therapy of chronic viral hepatitis with interferon alpha. Gastroenterology 102:2155–2160, 1992Google Scholar
  6. 6.
    Baudin E, Marcellin P, Pouteau M, Colas-Linhart N, Le Floch J-P, Lemonnier C, Benhamou J-P, Bok B: Reversibility of thyroid dysfunction induced by recombinant alpha interferon in chronic hepatitis C. Clin Endocrinol 39:657–661, 1993Google Scholar
  7. 7.
    Marcellin P, Pouteau M, Renard P, Grynblat J-M, Colas Linhart N, Bardet P, Bok B, Benhamou J-P: Sustained hypothyroidism induced by recombinantα interferon in patients with chronic hepatitis C. Gut 33:855–856, 1992Google Scholar
  8. 8.
    Tran A, Quaranta J-F, Benzaken S, Thiers V, Chau HT, Hastier P, Regnier D, Dreyfus G, Pradier C, Sadoul J-L, Hebuterne X, Rampal P: High prevalence of thyroid autoantibodies in a prospective series of patients with chronic hepatitis C before interferon therapy. Hepatology 18:253–257, 1993Google Scholar
  9. 9.
    Tran A, Quaranta JF, Beusnel C, Thiers V, De Souza M, Francois E, Hebuterne X, Rampal P: Hepatitis C virus and Hasimoto's thyroiditis. Eur J Med 1:116–118, 1992Google Scholar
  10. 10.
    Duclos-Vallee JC, Johanet C, Duron F, Pateron D, Homberg JC, Beaugrand M: High prevalence of anti-HCV antibodies in patients with Hashimoto's thyroiditis. J Hepatol 16(suppl 1):S56, 1992Google Scholar
  11. 11.
    Pateron D, Hartmann DJ, Duclos-Vallee JC, Jouanolle H, Beaugrand M: Latent autoimmune thyroid disease in patients with chronic HCV hepatitis. J Hepatol 16:244–245, 1992 (letter)Google Scholar
  12. 12.
    Quaranta J-F, Tran A, Régnier D, Lestestu R, Beusnel C, Fuzibet JG, Thiers V, Rampal P: High prevalence of antibodies to hepatitis C virus (HCV) in patients with anti-thyroid autoantibodies. J Hepatol 18:136–138, 1993 (letter)Google Scholar
  13. 13.
    Pawlotsky J-M, Yahia MB, Andre C, Voisin M-C, Intrator L, Roudot-Thoraval F, Duvoux C, Zafrani E-S, Duval J, Dhumeaux D: Immunological disorders in C virus chronic active hepatitis: A prospective case-control study. Hepatology 19:841–848, 1994Google Scholar
  14. 14.
    Alison MED, Wreghitt T, Palmer CR, Alexander GJM: Evidence for a link between hepatitis C virus infection and diabetes mellitus in a cirrhotic population. J Hepatol 21:1135–1139, 1994Google Scholar
  15. 15.
    Uzunalimoglu Ö, Sipahi N, Dökmeci A, Özden A, Sümer N, Kesim E, Cetinkaya H, Dönderici O, Karayalçin S, Yurdaydin C: A link between hepatitis C infection and diabetes mellitus in a Mediterranean population. J Hepatol 23(suppl 1):179, 1995 (abstract)Google Scholar
  16. 16.
    Haddad J, Deny P, Munz-Gotheil C, Ambrosini J-C, Trinchet J-C, Pateron D, Mal F, Callard P, Beaugrand M: Lymphocytic sialadenitis of Sjögren's syndrome associated with chronic hepatitis C virus liver disease. Lancet 339:321–323, 1992Google Scholar
  17. 17.
    Pirisi M, Scott C, Fabris C, Ferraccioli G, Soardo G, Ricci R, Toniutto P, Avellini C, Vitulli D, Miotti AM, Beltrami CA, Bartoli E: Mild sialoadenitis: A common finding in patients with hepatitis C virus infection. Scand J Gastroenterol 29:940–942, 1994Google Scholar
  18. 18.
    Wilson SE, Lee WM, Murakami C, Weng J, Moninger GA: Mooren's corneal ulcers and hepatitis C virus infection. N Engl J Med 329:62, 1993 (letter)Google Scholar
  19. 19.
    Wilson SE, Lee WM, Murakami C, Weng J, Moninger GA: Mooren-type hepatitis C virus-associated corneal ulceration. Ophthalmology 101:736–745, 1994Google Scholar
  20. 20.
    Grateau G, Bachmeyer C, Malek N, Jublanc C, Caputo G, Renard G: Mooren-type hepatitis C virus-associated corneal ulceration. Eur J Intern Med 6(suppl 1):24, 1995 (abstract)Google Scholar
  21. 21.
    Disdier P, Bolla G, Veit V, Ridings B, Gambarelli-Mouillac N, Harle JR, Weiller PJ: Association of uveitis and hepatitis C: 5 cases. Presse Med 23:541, 1994 (letter) (in French)Google Scholar
  22. 22.
    Ferri C, Greco F, Longombardo G, Palla P, Moretti A, Marzo E, Mazzoni A, Pasero G, Bombardieri S, Highfield P, Corbishley T: Association between hepatitis C virus and mixed cryoglobulinemia. Clin Exp Rheumatol 9:621–624, 1991Google Scholar
  23. 23.
    Agnello V, Chung RT, Kaplan LM: A role for hepatitis C virus infection in type II cryoglobulinemia. N Engl J Med 327:1490–1495, 1992Google Scholar
  24. 24.
    Misiani R, Bellavita P, Fenili D, Borelli G, Marchesi D, Massazza M, Vendramin G, Comotti B, Tanzi E, Scudeller G, Zanetti A: Hepatitis C virus infection in patients with essential mixed cryoglobulinemia. Ann Intern Med 117:573–577, 1992Google Scholar
  25. 25.
    Dammacco F, Sansonno D: Antibodies to hepatitis C virus in essential mixed cryoglobulinemia. Clin Exp Immunol 87:352–356, 1992Google Scholar
  26. 26.
    Hibbs JR, Issaragrisil S, Young NS: High prevalence of hepatitis C viremia among aplastic anemia patients and controls from Thailand. Am J Trop Med Hyg 46:564–570, 1992Google Scholar
  27. 27.
    Gruber A, Grillner L, Norder H, Magnius L, Björkholm M: Severe aplastic anemia associated with seronegative community-acquired hepatitis C virus infection. Ann Hematol 66:157–159, 1993Google Scholar
  28. 28.
    Durand JM, Lefevre P, Telle H, Kaplanski G, Quiles N, Soubeyrand J: Thrombocytopenic purpura and hepatitis C virus infection. Hematologia 78:135, 1993 (letter)Google Scholar
  29. 29.
    Durand JM, Cretel E, Retornaz F, Lefevre P, Kaplanski G, Soubeyrand J: Alpha interferon therapy in thrombocytopenia associated with hepatitis C virus infection. J Hepatol 21:277–278, 1994 (letter)Google Scholar
  30. 30.
    Ferri C, Monti M, La Civita L, Careccia G, Mazzaro C, Longombardo G, Lombardini F, Greco F, Pasero G, Bonbardieri S, Zignego AL: Hepatitis C virus infection in non-Hodgkin's B-cell lymphoma complicating mixed cryoglobulinemia. Eur J Clin Invest 24:781–784, 1994Google Scholar
  31. 31.
    Zignego AL, Ferri C, Giannini C, Caracciolo F, Monti M, La Civita L, Careccia G, Longombardo G, Ballesi G, Innocenti F, Thiers V, Gentilini P: HCV infectin in B-cell non-Hodgkin's lymphoma. J Hepatol 23(suppl 1):77, 1995 (abstract)Google Scholar
  32. 32.
    Franzin F, Ebremov D, Pozzato G, Pussini E, Tulissi P, Burrone O: Monoclonal B-cell expansion, non-Hodgkin's lymphomas and HCV infection. J Hepatol 23(suppl 1):89, 1995 (abstract)Google Scholar
  33. 33.
    Rollino C, Roccatello D, Giachino O, Basolo B, Piccoli G: Hepatitis C virus infection and membranous glomerulone-phritis. Nephron 59:319–320, 1991Google Scholar
  34. 34.
    Johnson RJ, Gretch DR, Yamabe H, Hart J, Bacchi CE, Hartwell P, Couser WG, Covey L, Wener MH, Alpers CE, Willson R: Membranoproliferative glomerulonephritis associated with hepatitis C virus infection. N Engl J Med 328:465–470, 1993Google Scholar
  35. 35.
    Burstein DM, Rodby RA: Membranoproliferative glomerulonephritis associated with hepatitis C virus infection. J Am Soc Nephrol 4:1288–1293, 1993Google Scholar
  36. 36.
    Arai H, Tanaka M, Ohta K, Kojo T, Niijima K, Imawari M: Symptomatic myopathy associated with interferon therapy for chronic hepatitis C. Lancet 345:582, 1995 (letter)Google Scholar
  37. 37.
    Dale JK, Di Bisceglie AM, Hoffnagle JH, Straus SE: Chronic fatigue syndrome: Lack of association with hepatitis C virus infection. J Med Virol 34:119–121, 1991Google Scholar
  38. 38.
    Horsmans Y, Geubel AP: Symptomatic myopathy in hepatitis C infection without interferon therapy. Lancet 345:1236, 1995 (letter)Google Scholar
  39. 39.
    Sawada T, Hirohata S, Inoue T, Ito K: Development of rheumatoid arthritis after hepatitis C virus infection. Arthritis Rheum 34:1620–1621, 1991Google Scholar
  40. 40.
    Borque L, Elena A, Maside C, Rus A, Del Cura J: Rheumatoid arthritis and hepatitis C virus antibodies. Clin Exp Rheumatol 9:617–619, 1991Google Scholar
  41. 41.
    Durand JM, Lefevre P, Harle JR, Boucrat J, Vitvitski L, Soubeyrand J: Cutaneous vasculitis and cryoglobulinemia type II associated with hepatitis C virus infection. Lancet 337:449–500, 1991 (letter)Google Scholar
  42. 42.
    Pakula AS, Garden JM, Roth SI: Cryoglobulinemia and cutaneous leukocytoclastic vasculitis associated with hepatitis C virus infection. J Am Acad Dermatol 28:850–853, 1993Google Scholar
  43. 43.
    Daoud MS, Gibson LE, Daoud S, el-Azhary RA: Chronic hepatitis C and skin diseases: A review. Mayo Clin Proc 70:559–564, 1995Google Scholar
  44. 44.
    Fargion S, Piperno A, Cappellini MD, Sampietro M, Fracanzani AL, Romano R, Caldarelli R, Marcelli R, Vecchi L, Fiorelli G: Hepatitis C virus and prophyria cutanea tarda: Evidence of a strong association. Hepatology 16:1322–1326, 1992Google Scholar
  45. 45.
    DeCastro M, Sánchez J, Herrera JF, Cháves A, Durán R, García-Buey L, García-Monzón C, Sequí J, Moreno-Otero R: Hepatitis C virus antibodies and liver disease in patients with porphyria cutanea tarda. Hepatology 17:551–557, 1993Google Scholar
  46. 46.
    Mokni M, Rybojad M, Puppin D Jr, Catala S, Venezia F, Djian R, Morel P: Lichen planus and hepatitis C virus. J Am Acad Dermatol 24:792, 1991Google Scholar
  47. 47.
    Agner T, Fogh H, Weismann K: The relation between lichen planus and hepatitis C: A case report. Acta Derm Venereol 72:380, 1992Google Scholar
  48. 48.
    Santander C, DeCastro M, García-Monzón C, García-Buey L, Sanchez J, Herera JF, Borque MJ, Moreno-Otero R: Prevalence of hepatitis C virus (HCV) infection and liver damage in patients with lichen planus (LP). Hepatology 20(4 Pt 2):238A, 1994 (abstract)Google Scholar
  49. 49.
    Antinori S, Esposito R, Aliprandi CA, Tadini G: Erythema multiforme and hepatitis C. Lancet 337:428, 1991 (Letter)Google Scholar
  50. 50.
    Domingo P, Ris J, Martinez E, Casas F: Erythema nodosum and hepatitis C. Lancet 336:1377, 1990 (letter)Google Scholar
  51. 51.
    Bodokh I, Lacour JP, Perrin C, Rainero C, Lebreton E, Grosshan E, Ortonne JP: Cutaneous malacoplakia associated with chronic hepatitis caused by hepatitis C virus. Ann Dermatol Venereol 120:808–810, 1993Google Scholar
  52. 52.
    Reichel M, Mauro TM: Urticaria and hepatitis C. Lancet 336:822–823, 1990 (letter)Google Scholar
  53. 53.
    Fisher DA, Wright TL: Pruritus as a symptom of hepatitis C. J Am Acad Dermatol 30:629–632, 1994Google Scholar
  54. 54.
    Quint L, Deny P, Guillevin L, Granger B, Jarrousse B, Lhote F, Scavizzi M: Hepatitis C virus in patients with polyarteritis nodosa. Prevalence in 38 patients. Clin Exp Rheumatol 9:253–257, 1991Google Scholar
  55. 55.
    Cacoub P, Lunel-Fabiani F, Du LTH: Polyarteritis nodosa and hepatitis C virus infection. Ann Intern Med 116:605–606, 1992 (letter)Google Scholar
  56. 56.
    Carson CW, Conn DL, Czaja AJ, Wright TL, Brecher ME: Frequency and significance of antibodies to hepatitis C virus in polyarteritis nodosa. J Rheumatol 20:304–309, 1992Google Scholar
  57. 57.
    Ueda T, Ohta K, Suzuki N, Yamaguchi M, Hirai K, Horiuchi T, Wantanbe J, Miyamoto T, Ito KF: Idiopathic pulmonary fibrosis and high prevalence of serum antibodies to hepatitis C virus. Am Rev Respir Dis 146:266–268, 1992Google Scholar
  58. 58.
    Bianchi FB: Autoimmune hepatitis: The lesson of the discovery of hepatitis C virus. J Hepatol 18:273–275, 1993Google Scholar
  59. 59.
    Maddrey WC: How many types of autoimmune hepatitis are there? Gastroenterology 105:1571–1575, 1993Google Scholar
  60. 60.
    Vergani D, Mieli-Vergani G: Type II autoimmune hepatitis. What is the role of the hepatitis C virus? Gastroenterology 104:1870–1873, 1993Google Scholar
  61. 61.
    Czaja AJ: Autoimmune hepatitis and viral infection. Gastroenterol Clin North Am 23:547–566, 1994Google Scholar
  62. 62.
    Clifford BD, Donahue D, Smith L, Cable E, Luttig B, Manns M, Bronkovsky HL: High prevalence of serological markers of autoimmunity in patients with chronic hepatitis C. Hepatology 21:613–619, 1995Google Scholar
  63. 63.
    Pontisso P, Ruvoletto MG, Fattovich G, Chemello L, Gallorini A, Ruol A, Alberti A: Clinical and virological profiles in patients with multiple hepatitis virus infections. Gastroenterology 105:1529–1533, 1993Google Scholar
  64. 64.
    Feray C, Gigou M, Samuel D, Reyes G, Bernuau J, Reynes M, Bismuth H, Brechot C: Hepatitis C virus RNA and hepatitis B virus DNA in serum and liver of patients with fulminant hepatitis. Gastroenterology 104:549–555, 1993Google Scholar
  65. 65.
    Kaklamani E, Trichopoulos D, Tzonou A, Zavitsanos X, Karmantaki Y, Hatzakis A, Hsieh CC, Hadziyannis S: Hepatitis B and C viruses and their interaction in the origin of hepatocellular carcinoma. JAMA 265:1974–1976, 1991Google Scholar
  66. 66.
    Hadziyannis SJ, Giannoulis G, Hadziyannis E, Kaklamani E, Alexopoulou A, Dourakis S, Trichopoulos D: Hepatitis C virus infection in Greece and its role in chronic liver disease and hepatocellular carcinoma. J Hepatol 17(suppl 3):S72-S77, 1993Google Scholar
  67. 67.
    Hadziyannis S, Wages J, Kim JP, Karayiannis P, Hess G, Piatak M, Lifson J, Vrettou H, Horsch A, Foung S, Thomas HC: Frequency of viremia with a new hepatitis virus (HGV) in patients with liver disease and in groups at high risk of exposure to blood and blood products. J Hepatol 23(suppl 1):78, 1995 (abstract)Google Scholar
  68. 68.
    Hadziyannis SJ, Dawson GJ, Vrettou E, Gioustozi A, Schlauder G, Desai S: Infection with the novel GB-C virus in multiply transfused patients and in various forms of chronic liver disease. Hepatology 22(4 Pt 2):218A, 1995 (abstract)Google Scholar
  69. 69.
    Hayashi PH, Flynn N, McCurdy SA, Kuramoto IK, Holland PV, Zeldis JB: Prevalence of hepatitis C virus antibodies among patients infected with human immunodeficiency virus. J Med Virol 33:177–180, 1991Google Scholar
  70. 70.
    McNair ANB, Main J, Thomas HC: interactions of the human immunodeficiency virus and the hepatotropic viruses. Semin Liver Dis 12:188–196, 1992Google Scholar
  71. 71.
    Wright TL, Hollander H, Pu X, Held MJ, Lipson P, Quan S, Polito A, Thaler MM, Bacchetti P, Scharschmidt BF: Hepatitis C in HIV-infected patients with and without AIDS: Prevalence and relationship to patient survival. Hepatology 20:1152–1155, 1994Google Scholar
  72. 72.
    Guido M, Rugge M, Fattovich G, Rocchetto P, Cassaro M, Chemello L, Noventa F, Giustina G, Alberti A: Human immunodeficiency virus infection and hepatitis C pathology. Liver 14:314–319, 1994Google Scholar
  73. 73.
    Abeck D, Brandt O, Weichenthal M, Kowalzick L, Mensing H: Chronic mucocutaneous herpes simplex infection. Occurrence within the scope of liver-induced immunodeficiency. Hautarzt 44:670–673, 1993 (in German)Google Scholar
  74. 74.
    Kamel MA, Miller FD, el Masry AG, Zakaria S, Kahattab M, Essmat G, Ghaffar YA: The epidemiology of schistosoma mansoni, hepatitis B and hepatitis C infection in Egypt. Ann Trop Med Parasitol 88:501–509, 1994Google Scholar
  75. 75.
    Koshy A, al-Nakib B, al-Mufti S, Madda JP, Hira PR: Anti-HCV-positive cirrhosis associated with schistosomiasis. Am J Gastroenterol 88:1428–1431, 1993Google Scholar
  76. 76.
    Mendenhall CL, Seeff L, Dichl AM, Ghosn SJ, French SW, Gartside PS, Rouster SD, Buskell-Bales Z, Grossman CJ, Roselle GA, Weesner RE, Garcia-Pont P, Goldberg SJ, Kiernan TW, Tamburro CH, Zetterman R, Chedid A, Chen T, Rabin L, and the VA cooperative study group (no. 119): Antibodies to hepatitis B virus and hepatitis C virus in alcoholic hepatitis and cirrhosis: Their prevalence and clinical relevance. Hepatology 14:581–589, 1991Google Scholar
  77. 77.
    Fong T-L, Kanel GC, Conrad A, Valinluck B, Charboneau F, Adkins RH: Clinical significance of concomitant hepatitis C infection in patients with alcoholic liver disease. Hepatology 19:554–557, 1994Google Scholar
  78. 78.
    Zignego AL, Foschi M, Laffi G, Monti M, Careccia G, Romanelli RG, De Majo E, Mazzanti R, Buzzelli G, La Villa G, Gentilini P: “Inapparent” hepatitis B virus infection and hepatitis C virus replication in alcoholic subjects with and without liver disease. Hepatology 19:577–582, 1994Google Scholar
  79. 79.
    Yokoyama H, Ishii H, Moriya S, Nagata S, Watanabe T, Kamegaya K, Takahashi H, Maruyama K, Haber P, Tsuchiya M: Relationship between hepatitis C virus subtypes and clinical features of liver disease seen in alcoholics. J Hepatol 22:130–134, 1995Google Scholar
  80. 80.
    von Weizsacker F, Maeda E, Brown N, Poynard T, Galun E, Labeit S, Caput J-C, Arima T, Blum H, Wands JR: Hepatitis B and C virus infection in HBsAg-negative alcoholics without i.v. drug abuse or previous blood transfusions. Int Hepatol Commun 4/2:80–87, 1995Google Scholar
  81. 81.
    van den Hock JAR, van Haastrecht HJA, Goudsmit J, de Wolf F, Coutinho RA: Prevalence, incidence, and risk factors of hepatitis C virus infection among drug users in Amsterdam. J Infect Dis 162:823–826, 1990Google Scholar
  82. 82.
    Tibbs CJ: Methods of transmission of hepatitis C. J Viral Hepatitis 2:113–119, 1995Google Scholar
  83. 83.
    Rodriguez M, Riestra S, San Roman F, Navascues CA, Suarez A, Perez R, Lombrana JL, Rodrigo L: Prevalence of antibody to hepatitis C virus in acute non-A, non-B hepatitis in patients from different epidemiological categories. Arch Virol 4(suppl):319–320, 1992Google Scholar
  84. 84.
    Olynyk JK, Rajender Reddy K, Di Bisceglie AM, Jeffers LJ, Parker TI, Radick JL, Schiff ER, Bacon BR: Hepatic iron concentration as a predictor of response to interferon alfa therapy in chronic hepatitis C. Gastroenterology 108:1104–1109, 1995Google Scholar
  85. 85.
    Barton AL, Banner BF, Cable EE, Bonkovsky HL: Distribution of iron in the liver predicts the response of chronic hepatitis C infection to interferon therapy. Am J Clin Pathol 103:419–424, 1995Google Scholar
  86. 86.
    Farinati F, Cardin R, De Maria N, Della Libera G, Marafin C, Lecis E, Burra P, Floreani A, Cecchetto A, Naccarato R: Iron storage, lipid peroxidation and glutathione turnover in chronic anti-HCV positive hepatitis. J Hepatol 22:449–456, 1995Google Scholar
  87. 87.
    Zeldis JB, Depner TA, Kuramoto IK, Gish RG, Holland PV: The prevalence of hepatitis C virus antibodies among hemodialysis patients. Ann Intern Med 112:958–960, 1990Google Scholar
  88. 88.
    Sakamoto N, Enomoto N, Marumo F, Sato C: Prevalence of hepatitis C virus infection among long-term hemodialysis patients: Detection of hepatitis C virus RNA in plasma. J Med Virol 39:11–15, 1993Google Scholar
  89. 89.
    Okuda K, Hayashi H, Kobayashi S, Irie Y: Mode of hepatitis C infection not associated with blood transfusion among chronic hemodialysis patients. J Hepatol 23:28–31, 1995Google Scholar
  90. 90.
    Hou C-H, Chen W-Y, Kao J-H, Chen D-S, Yang Y, Chen J-J, Lee S-H, Wu D-J, Yang S-C: Intrafamilial transmission of hepatitis C virus in hemodialysis patients. J Med Virol 45:381–385, 1995Google Scholar
  91. 91.
    Mangia A, Cascavilla L, Musto P, Clemente R, Carotenuto M, Rizzetto M, Andriulli A: Hepatitis C virus infection in patients with monoclonal gammopathy. J Hepatol 23(suppl 1):188, 1995 (abstract)Google Scholar
  92. 92.
    Rodriquez-Rosado R, Belogui O, Fernandez J, Inoges S, Prieto J: Detection of anticardiolipin antibodies andβ-2-GPI in cryoprecipitate of patients with chronic hepatitis C and cryoglobulinemia. J Hepatol 23(suppl 1):95, 1995 (abstract)Google Scholar
  93. 93.
    Holló G, Szalay F, Nemesánszky E: Dry eye syndrome in chronic hepatic diseases. J Hepatol 23(suppl 1):250, 1995 (abstract)Google Scholar
  94. 94.
    Perez-Calvo, Torralba MA, Cebollada J, Morandeira MJ, Otal I, Barrao F: Chronic C hepatitis and coincidental liver granulomatosis. Eur J Intern Med 6(suppl 1):13, 1995 (abstract)Google Scholar
  95. 95.
    Huang M-J, Liaw Y-F: Clinical associations between thyroid and liver diseases. J Gastroenterol Hepatol 10:344–350, 1995Google Scholar
  96. 96.
    Golding PL, Smith M, Williams R: Multisystem involvement in chronic liver disease. Studies on the incidence and pathogenesis. Am J Med 55:772–782, 1973Google Scholar
  97. 97.
    Crowe JP, Christensen E, Buttler J, Wheeler P, Doniach D, Keenan J, Williams R: Primary biliary cirrhosis: The prevalence of hypothyroidism and its relationship to thyroid auto-antibodies and sicca syndrome. Gastroenterology 78:1437–1441, 1980Google Scholar
  98. 98.
    Huang MJ, Chien RN, Tsai SL, Liaw YF: High prevalence thyroid autoantibodies in patients with chronic hepatitis C. Int Hepatol Commun 3(suppl):S50, 1995Google Scholar
  99. 99.
    Marcellin P, Pouteau M, Benhamou J-P: Hepatitis C virus infection, alpha interferon therapy and thyroid dysfunction. J Hepatol 22:364–369, 1995Google Scholar
  100. 100.
    Di Bisceglie AM, Martin P, Kassianides C, Lisker-Melman M, Murray L, Waggoner J, Goodman Z, Banks SM, Hoofnagle JH: Recombinant interferon alfa therapy for chronic hepatitis C. A randomized, double-blind, placebo-controlled trial. N Engl J Med 321:1506–1510, 1989Google Scholar
  101. 101.
    Kodama T, Katabami S, Kamijo K, Katanuma A, Yamashita K, Azuma N, Tamaki T, Yachi A: Development of transient thyroid disease and reaction during treatment of chronic hepatitis C with interferon. J Gastroenterol 29:289–292, 1994Google Scholar
  102. 102.
    Boadas J, Rodríguez-Espinosa J, Enríquez J, Miralles F, Martínez-Cerezo FJ, González P, Madoz P, Vilardell F: Prevalence of thyroid autoantibodies is not increased in blood donors with hepatitis C virus infection. J Hepatol 22:611–615, 1995Google Scholar
  103. 103.
    Watanabe U, Hashimoto E, Hisamitsu T, Obata H, Hayashi N: The risk factor for development of thyroid disease during interferon-α therapy for chronic hepatitis C. Am J Gastroenterol 89:399–403, 1994Google Scholar
  104. 104.
    Wang J-T, Want T-H, Sheu J-C, Lin J-T, Chen D-S: Hepatitis C virus RNA in saliva of patients with posttransfusion hepatitis and low efficiency of transmission among spouses. J Med Virol 36:28–31, 1992Google Scholar
  105. 105.
    Mariette X, Loiseau P, Morinet F: Hepatitis C virus in saliva. Ann Intern Med 122:556, 1995 (letter)Google Scholar
  106. 106.
    King PD, McMurray RW, Becherer PR: Sjögren's syndrome without mixed cryoglobulinemia is not associated with hepatitis C virus infection. Am J Gastroenterol 89:1047–1050, 1994Google Scholar
  107. 107.
    Bouffard P, Hayashi PH, Acevedo R, Levy N, Zeldis JB: Hepatitis C virus is detected in a monocyte/macrophage subpopulation of peripheral blood mononuclear cells of infected patients. J Infect Dis 166:1276–1280, 1992Google Scholar
  108. 108.
    Ferri C, Monti M, La Civita L, Longombardo G, Greco F, Pasero G, Gentilini P, Bombardieri S, Zignego AL: Infection of peripheral blood mononuclear cells by hepatitis C virus in mixed cryoglobulinemia. Blood 82:3701–3704, 1993Google Scholar
  109. 109.
    Agnello V, Abel G, Knight GB, Monteverde A, Ballare M, Bertoncelli MC, Pileri SA, Hitchcock L: Detection of hepatitis C virus (HCV) in liver, bone marrow, and lymph nodes in type II mixed cryoglobulinemia (MC) usingin situ hybridization. Fifth International Symposium on Hepatitis C Virus and Related Viruses. Gold Coast, Australia, 1995, C163 (abstract)Google Scholar
  110. 110.
    Abel G, Knight GB, Agnello V: Hepatitis C virus (HCV) infection of keratinocytes of vasculitis lesions in type II cryoglobulinemia (MC). Fifth International Symposium on Hepatitis C Virus and Related Viruses. Gold Coast, Australia, 1995, C152 (abstract)Google Scholar
  111. 111.
    Freni MA, Artuso D, Gerken G, Spanti C, Marafioti T, Alessi N, Spadaro A, Ajello A, Ferrau O: Focal lymphocytic aggregates in chronic hepatitis C: occurrence, immunohistochemical characterization, and relation to markers of autoimmunity. Hepatology 22:389–394, 1995Google Scholar
  112. 112.
    Meltzer M, Franklin EC: Cryoglobulinemia—a study of twenty-nine patients. I. IgG and IgM cryoglobulins and factors affecting cryoprecipitability. Am J Med 40:828–836, 1966Google Scholar
  113. 113.
    Ferri C, Monti M, Lo Jacono F, Caracciolo F, La Civita L, Careccia G, Longombardo G, Giannini C, Greco F, Mazzoni A, Ceccherini-Nelli L, Zignego AL: Infection by HCV and other lymphotropic viruses in B-cell non-Hodgkin's lymphoma. J Hepatol 23(suppl 1):98, 1995 (abstract)Google Scholar
  114. 114.
    Hartmann H, Schott P, Polzien F, Mihm S, Ramadori G: Cryoglobulinemia in chronic hepatitis C virus infection: Is cross-reactivity of anti-HCV IgM to IgG a pathogenetic mechanism? J Hepatol 23(suppl 1):80, 1995 (abstract)Google Scholar
  115. 115.
    Levo Y, Gorevic PD, Kassab HJ, Tobias H, Franklin EC: Liver involvement in the syndrome of mixed cryoglobulinemia. Ann Intern Med 87:287–292, 1977Google Scholar
  116. 116.
    Hijikata M, Shimizu YK, Kato H, Iwamoto A, Shih JW, Alter HJ, Purcell RH, Yoshikura H: Equilibrium centrifugation studies of hepatitis C virus: Evidence for circulating immune complexes. J Virol 67:1953–1958, 1993Google Scholar
  117. 117.
    Casato M, Taliani G, Pucillo LP, Goffredo F, Lagana B, Bononio L: Cryoglobulinemia and hepatitis C virus. Lancet 337:1047–1048, 1991Google Scholar
  118. 118.
    Pascual M, Perrin L, Giostra E, Schifferli JA: Hepatitis C virus in patients with cryoglobulinemia type II. J Infect Dis 162:569–570, 1990 (letter)Google Scholar
  119. 119.
    Marcellin P, Descamps V, Martinot-Peignoux M, Larque D, Xu L, Boyer N, Pharm B-N, Crickx B, Guillevin L, Belaich S, Erlinger S, Benhamou J-P: Cryoglobulinemia with vasculitis associated with hepatitis C virus infection. Gastroenterology 104:272–277, 1993Google Scholar
  120. 120.
    Lunel F, Musset L, Cacoub P, Frangeul L, Cresta P, Perrin M, Grippon P, Hoang C, Piette JC, Huraux J-M, Opolon P: Cryoglobulinemia in chronic liver diseases: Role of hepatitis C virus and liver damage. Gastroenterology 106:1291–1300, 1994Google Scholar
  121. 121.
    Kakumu S, Alyama T, Yoshioka K, Okumura A, Takayanagi M, Iwata K, Yamada M: Cryoglobulinemia and chronic hepatitis C virus disease among Japanese patients. Int Hepatol Commun 3(suppl):S49, 1995Google Scholar
  122. 122.
    Cacoub P, Frangeul L, Lunel F, Musset L, Piette J-C, Opolon P, Huraux J-M, Godeau P, Poynard T: Mixed cryoglobulinemia and hepatitis C virus infection: A multivariate analysis. Arth Rheum 38(suppl 9):S199, 1995Google Scholar
  123. 123.
    Schirren CA, Zachoval R, Schirren CG, Gerbes AL, Pape GR: A role for chronic hepatitis C virus infection in a patient with cutaneous vasculitis, cryoglobulinemia, and chronic liver disease. Dig Dis Sci 40:1221–1225, 1995Google Scholar
  124. 124.
    Zenda T, Okamoto R, Sanada H, Okada T, Masunaga T, Takeda Y, Takeda R, Nonomura A, Funaki N: A possible pathogenic relation between hepatitis C virus and essential cryoglobulinemia, rheumatoid factor and consumption of complement following interferon-beta therapy for chronic active hepatitis C. Acta Hepatol Japon 36:381–385, 1995Google Scholar
  125. 125.
    Martins A, Goncalves G, Costa A, Ribeiro S, Reis A: Mixed cryoglobulinemia type III associated to chronic hepatitis C virus infection. Eur J Intern Med 6(suppl 1):71, 1995 (abstract)Google Scholar
  126. 126.
    Misiani R, Bellavita P, Fenili D, Vicari O, Marchesi D, Suroni PL, Zilio P, Vernocchi A, Massazza M, Vendramin G, Tanzi E, Zanetti A: Interferon alfa-2a therapy in cryoglobulinemia associated with hepatitis C virus. N Engl J Med 330:751–756, 1994Google Scholar
  127. 127.
    Bordin G, Ballare M, Bertoncelli MC, Paccagnino L, Zigrossi P, Monteverde A: HCV-associated thrombocytopenia, thrombokinetic study. Fifth International Symposium on Hepatitis C Virus and Related Viruses. Gold Coast, Australia, 1995, C151 (abstract)Google Scholar
  128. 128.
    Theilmann L, Gmelin K, Kallinowski B, Kommerell B, Koderisch J, Andrassy K: Prevalence of antibodies to hepatitis C virus in sera from patients with systemic necrotizing vasculitis. Nephron 57:482, 1991 (letter)Google Scholar
  129. 129.
    Hearth-Holmes M, Zahradka S, Baethge BA, Wolf RE: Leukocytoclastic vasculitis associated with hepatitis C. Am J Med 90:765–766, 1991 (letter)Google Scholar
  130. 130.
    Rémond B, Reygagne P, Aractingi S, Dubertrer L: Vascularite cutanée avec cryoglobulinémie mixte au cours d'une hépatite chronique C. Ann Dermatol Venereol 119:827–829, 1992Google Scholar
  131. 131.
    Durand JM, Kaplanski G, Richard MA, Lefevre P, Quiles N, Trepo C, Soubeyrand J: Cutaneous vasculitis in a patient infected with hepatitis C virus. Detection of hepatitis C virus RNA in the skin by polymerase chain reaction. Br J Dermatol 128:359–360, 1993 (letter)Google Scholar
  132. 132.
    Zimmermann R, König V, Bauditz J, Hopf U: Interferon alfa in leukocytoclastic vasculitis, mixed cryoglobulinemia, and chronic hepatitis C. Lancet 341:561–562 (letter)Google Scholar
  133. 133.
    Levey JM, Bjornsson B, Banner B, Kuhns M, Malhotra R, Whitman N, Romain PL, Cropley TG, Bonkovsky HL: Mixed cryoglobulinemia in chronic hepatitis C infection. A clinicopathologic analysis of 10 cases and review of recent literature. Medicine 73:53–67, 1994Google Scholar
  134. 134.
    Ferri C, Baicchi U, La Civita L, Greco F, Longombardo G, Mazzoni A, Careccia G, Bombardieri S, Pasero G, Zignego AL, Manns MP: Hepatitis C virus-related autoimmunity in patients with porphyria cutanea tarda. Eur J Clin Invest 23:851–855, 1993Google Scholar
  135. 135.
    Herrero C, Vicente A, Bruguera M, Ercilla MG, Barrera JM, Vidal J, Terés J, Mascaró JM, Rodés J: Is hepatitis C virus infection a trigger of porphyria cutanea tarda? Lancet 341:788–789, 1993Google Scholar
  136. 136.
    Lacour JPL, Bodokh I, Castanet J, Beckri S, Ortonne JP: Porphyria cutanea tarda and antibodies to hepatitis C virus. Br J Dermatol 128:121–123, 1993Google Scholar
  137. 137.
    Koester G, Feldman J, Bigler C: Hepatitis C in patients with porphyria cutanea tarda. J Am Acad Dermatol 31:1054, 1994Google Scholar
  138. 138.
    Stölzel U, Köstler E, Stöffler-Meilicke M, Somasundaram R, Frohburg U, Doss MO, Riecken EO: Hepatitis C virus infection in porphyria cutanea tarda in Germany. Gastroenterology 106:A990, 1994Google Scholar
  139. 139.
    Navas S, Bosch O, Castillo I, Marriott E, Carreño V: Porphyria cutanea tarda and hepatitis C and B viruses infection: A retrospective study. Hepatology 21:279–284, 1995Google Scholar
  140. 140.
    Kondo M, Horie V, Okano J, Kawasaki U, Mishiro S, Yamamoto S, Okamoto H: Porphyria cutanea tarda and HCV infection. Int Hepatol Commun 3(suppl):S45, 1995Google Scholar
  141. 141.
    Rebora A, Rongioletti F: Lichen planus and chronic active hepatitis. A retrospective survey. Acta Derm Venereol 64:52–56, 1984Google Scholar
  142. 142.
    Doutre MS, Beylot C, Couzigou P, Long P, Royer P, Beylot J: Lichen planus and virus C hepatitis: Disappearance of the lichen under interferon alfa therapy. Dermatology 184:229, 1992 (letter)Google Scholar
  143. 143.
    Strumia R, Venturini D, Boccia S, Gamberini S, Gullini S: UVA and interferon-alfa therapy in a patient with lichen planus and chronic hepatitis C. Int J Dermatol 32:386, 1993 (letter)Google Scholar
  144. 144.
    Boccia S, Gamberini S, Dalla Libera M, Strumia R, Venturini D: Lichen planus and interferon therapy for hepatitis C. Gastroenterology 105:1921–1922, 1993 (letter)Google Scholar
  145. 145.
    Cecchi R, Giomi A, Tuci F, Bartoli L, Seghieri G: Pityriasis rubra pilaris, lichen planus, alopecia universalis and vitiligo in a patient with chronic viral hepatitis C. Dermatology 188:239–240, 1994Google Scholar
  146. 146.
    Papini M, Bruni PL, Bettacchi A, Liberati F: Sudden onset of oral ulcerative lichen in a patient with chronic hepatitis C on treatment with alfa-interferon. Int J Dermatol 33:221–222, 1994 (letter)Google Scholar
  147. 147.
    Protzer U, Ochsendorf FR, Leopolder-Ochsendorf A, Holtermüller K-H: Exacerbation of lichen planus during interferon alfa-2a therapy for chronic active hepatitis C. Gastroenterology 104:903–905, 1993Google Scholar
  148. 148.
    Barreca T, Corsini G, Franceschini R, Gambini C, Garibaldi A, Rolandi E: Lichen planus induced by interferon-alpha-2a therapy for chronic active hepatitis C. Eur J Gastroenterol Hepatol 7:367–368, 1995Google Scholar
  149. 149.
    Rebora A, Robert E, Rongioletti F: Clinical and laboratory presentation of lichen planus patients with chronic liver disease. J Dermatol Sci 4:38–41, 1992Google Scholar
  150. 150.
    Divano MC, Parodi A, Rebora A: Lichen planus, liver kidney microsomal (LKM1) antibodies and hepatitis C virus antibodies. Dermatology 185:132–133, 1992Google Scholar
  151. 151.
    Gandolfo S, Carbone M, Carozzo M, Gallo V: Oral lichen planus and hepatitis C virus (HCV) infection: Is there a relationship? A report of 10 cases. J Oral Pathol Med 23:119–122, 1994Google Scholar
  152. 152.
    Jubert C, Pawlotsky J-M, Pouget F, Andre C, DeForges L, Bretagne S, Mavier J-P, Duval J, Revuz J, Dhumeaux D, Bagot M: Lichen planus and hepatitis C virus-related chronic active hepatitis. Arch Dermatol 130:73–76, 1994Google Scholar
  153. 153.
    Manns MP, Griffin KJ, Sullivan KF, Johnson EF: LKM-1 autoantibodies recognize a short linear seuqence in p450IID6, a cytochrome P-450 monoxygenase. J Clin Invest 88:1370–1378, 1991Google Scholar
  154. 154.
    Abuaf N, Lunel F, Giral P, Borotto E, Laperche S, Poupon R, Opolon P, Huraux J-M, Homberg JC: Non-organ specific autoantibodies associated with chronic C virus hepatitis. J Hepatol 18:359–364, 1993Google Scholar

Copyright information

© Plenum Publishing Corporation 1996

Authors and Affiliations

  • Stephanos J. Hadziyannis
    • 1
  1. 1.Medical School, Academic Department of MedicineHippokration General HospitalAthensGreece

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