Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Endocrine manifestations of hepatitis C virus infection

Nature Clinical Practice Endocrinology & Metabolism volume 5, pages 26–34 (2009)Cite this article

Abstract

Chronic infection with hepatitis C virus (HCV) can result in both hepatic and extrahepatic disease and endocrine dysfunction represents an important class of HCV-related extrahepatic disease. The most frequently occurring—and clinically important—of these endocrine disorders are thyroid disease and type 2 diabetes mellitus. In this Review, we evaluate the evidence in support of a link between HCV infection and endocrine-system dysfunction, and discuss potential pathophysiological mechanisms. A meta-analysis of the literature has revealed significant associations between chronic HCV infection, thyroid autoimmunity and hypothyroidism. Furthermore, a high prevalence of thyroid cancer has been reported in HCV-positive patients. Several clinicoepidemiological studies have demonstrated that chronic HCV infection could lead to the development of type 2 diabetes mellitus, possibly as a result of HCV-induced metabolic disturbances. Some researchers have postulated that a type 1 T-helper -cell mediated immune response underpins the association of chronic HCV infection with endocrine disease. Indeed, the available data suggest that a common immunological, type 1 T-helper cell pattern of cytokine expression and activation (via interferon-γ) could provide the pathophysiological basis for this association. Nonetheless, additional studies will be necessary to elucidate fully all the mechanisms involved in HCV-related endocrine dysfunction.

Key Points

  • A high prevalence of autoimmune thyroid disorders and hypothyroidism has been reported in patients with chronic hepatitis C virus (HCV) infection

  • Female sex is a risk factor for autoimmune thyroid disorders; female sex and thyroid peroxidase antibody positivity are major risk factors for hypothyroidism

  • An increased prevalence of papillary thyroid cancer has been reported in HCV-positive patients with thyroid autoimmunity

  • HCV-related type 2 diabetes mellitus occurs in association with hepatic steatosis, insulin resistance and high levels of both tumor-necrosis factor and CXCL10

  • HCV-related gonadal alterations, such as erectile dysfunction and low levels of adrenal–gonadal androgens, have been reported in some preliminary studies

  • A common T-helper 1 immune pattern could provide the pathophysiological basis of the association between HCV and endocrine disease

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Potential regulation of the endocrine manifestations of hepatitis C virus infection.
Figure 2: Association of serum CXCL10 level and autoimmune thyroiditis.
Figure 3: Association of serum CXCL10 level and type 2 diabetes mellitus.

Similar content being viewed by others

References

  1. Ferri C et al. (2007) B-cells and mixed cryoglobulinemia. Autoimmun Rev 7: 114–120

    Article  CAS  Google Scholar 

  2. Sansonno D et al. (2007) Hepatitis C virus infection, cryoglobulinaemia, and beyond. Rheumatology (Oxford) 46: 572–578

    Article  CAS  Google Scholar 

  3. Antonelli A et al. (2008) HCV infection: pathogenesis, clinical manifestations and therapy. Clin Exp Rheumatol 26 (Suppl 48): S39–S47

    CAS  PubMed  Google Scholar 

  4. Antonelli A et al. (2008) Immunopathogenesis of HCV-related endocrine manifestations in chronic hepatitis and mixed cryoglobulinemia. Autoimmun Rev [10.1016/j.autrev.2008.07.017]

  5. Pateron D et al. (1992) Latent autoimmune thyroid disease in patients with chronic HCV hepatitis. J Hepatol 16: 244–245

    Article  CAS  Google Scholar 

  6. Antonelli A et al. (2006) Thyroid disorders in chronic hepatitis C virus infection. Thyroid 16: 563–572

    Article  Google Scholar 

  7. Antonelli A et al. (2004) Thyroid disorders in chronic hepatitis C. Am J Med 117: 10–13

    Article  CAS  Google Scholar 

  8. Antonelli A et al. (2004) Thyroid involvement in patients with overt HCV-related mixed cryoglobulinaemia. QJM 97: 499–506

    Article  CAS  Google Scholar 

  9. Pazienza V et al. (2007) The hepatitis C virus core protein of genotypes 3a and 1b downregulates insulin receptor substrate 1 through genotype-specific mechanisms. Hepatology 45: 1164–1171

    Article  CAS  Google Scholar 

  10. Rodríguez-Torres M et al. (2008) Thyroid dysfunction (TD) among chronic hepatitis C patients with mild and severe hepatic fibrosis. Ann Hepatol 7: 72–77

    PubMed  Google Scholar 

  11. Giordano TP et al. (2007) Risk of non-Hodgkin lymphoma and lymphoproliferative precursor diseases in US veterans with hepatitis C virus. JAMA 297: 2010–2017

    Article  CAS  Google Scholar 

  12. Prummel MF and Laurberg P (2003) Interferon-α and autoimmune thyroid disease. Thyroid 13: 547–551

    Article  CAS  Google Scholar 

  13. Patzwahl R et al. (2001) Enhanced expression of interferon-regulated genes in the liver of patients with chronic hepatitis C virus infection: detection by suppression-subtractive hybridization. J Virol 75: 1332–1338

    Article  CAS  Google Scholar 

  14. Mihm S et al. (2003) Expression of the chemokine IP-10 correlates with the accumulation of hepatic IFN-γ and IL-18 mRNA in chronic hepatitis C but not in hepatitis B. J Med Virol 70: 562–570

    Article  CAS  Google Scholar 

  15. Matskevich AA and Strayer DS (2003) Exploiting hepatitis C virus activation of NFκB to deliver HCV-responsive expression of interferons α and γ. Gene Ther 10: 1861–1873

    Article  CAS  Google Scholar 

  16. Murata M et al. (2002) Increased frequency of IFN-γ-producing peripheral CD8+ T cells with memory-phenotype in patients with chronic hepatitis C. J Med Virol 67: 162–170

    Article  Google Scholar 

  17. Itoh Y et al. (2001) Clinical significance of elevated serum interferon-inducible protein-10 levels in hepatitis C virus carriers with persistently normal serum transaminase levels. J Viral Hepat 8: 341–348

    Article  CAS  Google Scholar 

  18. Shields PL et al. (1999) Chemokine and chemokine receptor interactions provide a mechanism for selective T cell recruitment to specific liver compartments within hepatitis C-infected liver. J Immunol 163: 6236–6243

    CAS  PubMed  Google Scholar 

  19. Butera D et al. (2005) Plasma chemokine levels correlate with the outcome of antiviral therapy in patients with hepatitis C. Blood 106: 1175–1182

    Article  CAS  Google Scholar 

  20. Diago M et al. (2006) Association of pretreatment serum interferon gamma inducible protein 10 levels with sustained virological response to peginterferon plus ribavirin therapy in genotype 1 infected patients with chronic hepatitis C. Gut 55: 374–379

    Article  CAS  Google Scholar 

  21. Apolinario A et al. (2005) Gene expression profile of T-cell-specific chemokines in human hepatocyte-derived cells: evidence for a synergistic inducer effect of cytokines and hepatitis C virus proteins. J Viral Hepat 12: 27–37

    Article  CAS  Google Scholar 

  22. Caturegli P et al. (2000) Hypothyroidism in transgenic mice expressing IFN-γ in the thyroid. Proc Natl Acad Sci USA 97: 1719–1724

    Article  CAS  Google Scholar 

  23. García-López MA et al. (2001) Thyrocytes from autoimmune thyroid disorders produce the chemokines IP-10 and Mig and attract CXCR3+ lymphocytes. J Clin Endocrinol Metab 86: 5008–5016

    Article  Google Scholar 

  24. Antonelli A et al. (2004) High levels of circulating CX chemokine ligand 10 are associated with chronic autoimmune thyroiditis and hypothyroidism. J Clin Endocrinol Metab 89: 5496–5499

    Article  CAS  Google Scholar 

  25. Antonelli A et al. (2005) Increase of interferon-γ inducible α chemokine CXCL10 but not beta chemokine CCL2 serum levels in chronic autoimmune thyroiditis. Eur J Endocrinol 152: 171–177

    Article  CAS  Google Scholar 

  26. Antonelli A et al. (2006) Interferon-gamma-inducible alpha-chemokine CXCL10 involvement in Graves ophthalmopathy: modulation by peroxisome proliferator-activated receptor-gamma agonists. J Clin Endocrinol Metab 91: 614–620

    Article  CAS  Google Scholar 

  27. Gowans EJ (2000) Distribution of markers of hepatitis C virus infection throughout the body. Semin Liver Dis 20: 85–102

    Article  CAS  Google Scholar 

  28. Bartolomé J (2008) Detection of hepatitis C virus in thyroid tissue from patients with chronic HCV infection. J Med Virol 80: 1588–1594

    Article  Google Scholar 

  29. Antonelli A et al. (2008) High values of CXCL10 serum levels in patients with hepatitis C associated mixed cryoglobulinemia in presence or absence of autoimmune thyroiditis. Cytokine 42: 137–143

    Article  CAS  Google Scholar 

  30. Antonelli A et al. (2008) Alpha-chemokine CXCL10 and beta-chemokine CCL2 serum levels in patients with hepatitis C-associated cryoglobulinemia in the presence or absence of autoimmune thyroiditis. Metabolism 57: 1270–1277

    Article  CAS  Google Scholar 

  31. Antonelli A et al. (1999) Thyroid cancer in patients with hepatitis C infection. JAMA 281: 1588

    Article  CAS  Google Scholar 

  32. Antonelli A et al. (2002) Thyroid cancer in HCV-related mixed cryoglobulinemia patients. Clin Exp Rheumatol 20: 693–696

    CAS  PubMed  Google Scholar 

  33. Montella M et al. (2001) HCV and cancer: a case–control study in a high-endemic area. Liver 21: 335–341

    Article  CAS  Google Scholar 

  34. Montella M et al. (2003) Risk of thyroid cancer and high prevalence of hepatitis C virus. Oncol Rep 10: 133–136

    PubMed  Google Scholar 

  35. Antonelli A et al. (2005) Hepatitis C virus infection: evidence for an association with type 2 diabetes. Diabetes Care 28: 2548–2550

    Article  Google Scholar 

  36. Duberg AS et al. (2005) Non-Hodgkin's lymphoma and other nonhepatic malignancies in Swedish patients with hepatitis C virus infection. Hepatology 41: 652–659

    Article  Google Scholar 

  37. Antonelli A et al. (2007) Thyroid cancer in HCV-related chronic hepatitis patients: a case-control study. Thyroid 17: 447–451

    Article  CAS  Google Scholar 

  38. Ferri C et al. (1997) Hepatitis-C-virus infection and cancer. Int J Cancer 71: 1113–1115

    Article  CAS  Google Scholar 

  39. Ferri C et al. (2000) Hepatitis C virus, B-cell disorders, and non-Hodgkin's Lymphoma. In Infectious Causes of Cancer: Targets for Intervention 349–368 (Ed Goedert JJ) Totowa: Humana Press

    Chapter  Google Scholar 

  40. Mori Y et al. (2008) Hepatitis C virus core protein: its coordinate roles with PA28γ in metabolic abnormality and carcinogenicity in the liver. Int J Biochem Cell Biol 40: 1437–1442

    Article  CAS  Google Scholar 

  41. Okayasu I et al. (1995) Association of chronic lymphocytic thyroiditis and thyroid papillary carcinoma: a study of surgical cases among Japanese, and white and African Americans. Cancer 76: 2312–2318

    Article  CAS  Google Scholar 

  42. Noto H and Raskin P (2006) Hepatitis C infection and diabetes. J Diabetes Complications 20: 113–120

    Article  Google Scholar 

  43. Antonelli A et al. (2004) Type 2 diabetes in hepatitis C-related mixed cryoglobulinaemia patients. Rheumatology (Oxford) 43: 238–240

    Article  CAS  Google Scholar 

  44. Mehta SH et al. (2000) Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Ann Intern Med 133: 592–599

    Article  CAS  Google Scholar 

  45. Mehta SH et al. (2003) Hepatitis C virus infection and incident type 2 diabetes. Hepatology 38: 50–56

    Article  Google Scholar 

  46. Tanaka H et al. (1997) Changes in glucose tolerance after interferon-α therapy in patients with chronic hepatitis C. J Med 28: 335–346

    CAS  PubMed  Google Scholar 

  47. Giordanino C et al. (2008) Incidence of type 2 diabetes mellitus and glucose abnormalities in patients with chronic hepatitis C infection by response to treatment: results of a cohort study. Am J Gastroenterol [10.1111/j.1572-0241.2008.02002.x]

  48. Aytaman A and McFarlane SI (2008) Uncovering glucose abnormalities in people with hepatitis C infection: should oral glucose tolerance test become a standard of care? Am J Gastroenterol 103: 1941–1943

    Article  CAS  Google Scholar 

  49. El-Zayadi AR (2008) Hepatic steatosis: a benign disease or a silent killer. World J Gastroenterol 14: 4120–4126

    Article  Google Scholar 

  50. Cammà C et al. (2006) Insulin resistance is associated with steatosis in nondiabetic patients with genotype 1 chronic hepatitis C. Hepatology 43: 64–71

    Article  Google Scholar 

  51. Adinolfi LE et al. (2001) Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology 33: 1358–1364

    Article  CAS  Google Scholar 

  52. Rubbia-Brandt L et al. (2000) Hepatocyte steatosis is a cytopathic effect of hepatitis C virus genotype 3. J Hepatol 33: 106–115

    Article  CAS  Google Scholar 

  53. Moriya K et al. (1997) Hepatitis C virus core protein induces hepatic steatosis in transgenic mice. J Gen Virol 78: 1527–1531

    Article  CAS  Google Scholar 

  54. Knobler H and Schattner A (2005) TNF-α, chronic hepatitis C and diabetes: a novel triad. QJM 98: 1–6

    Article  CAS  Google Scholar 

  55. Shintani Y et al. (2004) Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance. Gastroenterology 126: 840–848

    Article  CAS  Google Scholar 

  56. Hussain MJ et al. (1994) Hepatic expression of tumor necrosis factor-α in chronic hepatitis B virus infection. J Clin Pathol 47: 1112–1115

    Article  CAS  Google Scholar 

  57. Masini M et al. (2005) Hepatitis C virus infection and human pancreatic β-cell dysfunction. Diabetes Care 28: 940–941

    Article  Google Scholar 

  58. Gale EA (2005) Latent autoimmune diabetes in adults: a guide for the perplexed. Diabetologia 48: 2195–2199

    Article  CAS  Google Scholar 

  59. Skowronski M et al. (2006) Hepatitis C virus infection: evidence for an association with type 2 diabetes. Diabetes Care 29: 750

    Article  Google Scholar 

  60. Antonelli A et al. (2002) Autoimmunity to CD38 and GAD in type I and type II diabetes: CD38 and HLA genotypes and clinical phenotypes. Diabetologia 45: 1298–1306

    Article  CAS  Google Scholar 

  61. Antonelli A et al. (2006) Hepatitis C virus infection: evidence for an association with type 2 diabetes. Diabetes Care 29: 751

    Article  Google Scholar 

  62. Christen U and Von Herrath MG (2004) IP-10 and type 1 diabetes: a question of time and location. Autoimmunity 37: 273–282

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. SM Ferrari is a Research Fellow and P Fallahi is a Postdoctoral Researcher in the Department of Internal Medicine, University of Pisa; C Ferri is Full Professor of Rheumatology and M Colaci is a Researcher in the Department of Internal Medicine, University of Modena; D Sansonno is an Associate Professor of Internal Medicine in the Department of Internal Medicine and Clinical Oncology, A Antonelli is an Assistant Professor of Internal Medicine, University of Bari, Italy.,

    Alessandro Antonelli, Clodoveo Ferri, Silvia Martina Ferrari, Michele Colaci, Domenico Sansonno & Poupak Fallahi

  2. C Ferri is Full Professor of Rheumatology and M Colaci is a Researcher in the Department of Internal Medicine, University of Modena,

    Alessandro Antonelli, Clodoveo Ferri, Silvia Martina Ferrari, Michele Colaci, Domenico Sansonno & Poupak Fallahi

Authors
  1. Alessandro Antonelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Clodoveo Ferri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Silvia Martina Ferrari
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michele Colaci
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Domenico Sansonno
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Poupak Fallahi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alessandro Antonelli.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Antonelli, A., Ferri, C., Ferrari, S. et al. Endocrine manifestations of hepatitis C virus infection. Nat Rev Endocrinol 5, 26–34 (2009). https://doi.org/10.1038/ncpendmet1027

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpendmet1027

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing