Hepatitis C and interferon induced thyroiditis

https://doi.org/10.1016/j.jaut.2009.11.008Get rights and content

Abstract

Autoimmune thyroid diseases (AITDs) are complex diseases that develop as a result of interactions between genetic, epigenetic, and environmental factors. Significant progress has been made in our understanding of the genetic and environmental triggers contributing to AITD. The major environmental triggers of AITD include iodine, smoking, medications, pregnancy, and possibly stress. In this review we will focus on two well-documented environmental triggers of AITD, hepatitis C virus (HCV) infection and interferon alpha (IFNa) therapy. Chronic HCV infection has been shown to be associated with increased incidence of clinical and subclinical autoimmune thyroiditis (i.e. the presence of thyroid antibodies in euthyroid subjects). Moreover, IFNa therapy of chronic HCV infection is associated with subclinical or clinical thyroiditis in up to 40% of cases which can be autoimmune, or non-autoimmune thyroiditis. In some cases interferon induced thyroiditis (IIT) in chronic HCV patients may result in severe symptomatology necessitating discontinuation of therapy. While the epidemiology and clinical presentation of HCV and interferon induced thyroiditis have been well characterized, the mechanisms causing these conditions are still poorly understood.

Introduction

While abundant data point to a strong genetic susceptibility to the development of autoimmune thyroid disease (AITD), including Grave's disease (GD) and Hashimoto's thyroiditis (HT) (reviewed in [1]), environmental factors also play an important role. Since monozygotic twins do not show 100% concordance for AITD non-genetic factors must also play a role. Indeed, a recent twin study estimated that about 20% of the liability to the development of GD is attributable to non-genetic factors [2]. The environmental factors postulated to precipitated AITD include iodine [3], [4], medications, such as amiodarone and interferon alpha [5], infections [6], smoking, and possibly stress (reviewed in [7]). Recently, HCV infection [8] and interferon alpha (IFNa) therapy [9] emerged as the most substantiated environmental triggers of AITD.

Section snippets

Infection and AITD

One of the most intriguing environmental triggers of autoimmune thyroid diseases is infection (reviewed in [10]). Evidence supporting infectious cause of AITD include seasonality in the incidence of AITD [11], geographic variation [12], and serological evidence for a recent bacterial or viral infection [13]. Several infectious agents have been implicated in the pathogenesis of AITD including Yersinia enterocolitica [14], [15], [16], [17], Coxsackie B virus [18], retroviruses [19], [20], [21],

Interferon induced thyroiditis (IIT)

Interferon alpha (IFNa) is a type I interferon that has been widely used as a therapeutic agent mostly, for infectious and malignant diseases [52]. IFNa binds to interferon receptors, and activates various signaling pathways, including the JAK-STAT pathway, and the MAP kinase pathway leading to transcription of target proteins which mediate its immune and anti-tumor effects [53], [54], [55]. One of the most remarkable successes of IFNa as a therapeutic agent has been in the treatment of chronic

Conclusions

One of the commonest complications of IFNa therapy for chronic hepatitis C infection is interferon induced thyroiditis (IIT) [9]. Recent data supports the notion that IFNa triggers thyroiditis in genetically predisposed individuals by both direct thyroid-toxic mechanisms and immune-modulatory mechanisms [77]. It is likely that the HCV infection itself contributes to the initiation of thyroid autoimmunity [51]. Since IIT is very common in HCV patients receiving IFNa therapy all patients should

Acknowledgments

This work was supported in part by: DK61659 from NIDDK and a VA Merit Award (to YT).

References (91)

  • A. Antonelli et al.

    Thyroid disorders in chronic hepatitis C

    Am J Med

    (2004)
  • J. Boadas et al.

    Prevalence of thyroid autoantibodies is not increased in blood donors with hepatitis C virus infection

    J Hepatol

    (1995)
  • E. Roti et al.

    Multiple changes in thyroid function in patients with chronic active HCV hepatitis treated with recombinant interferon-alpha

    Am J Med

    (1996)
  • M.B.A. Oldstone

    Molecular mimicry and autoimmune diseases

    Cell

    (1987)
  • G.J. Fournie et al.

    Induction of autoimmunity through bystander effects. Lessons from immunological disorders induced by heavy metals

    J Autoimmun

    (2001)
  • N. Arata et al.

    By-stander activation in autoimmune thyroiditis: studies on experimental autoimmune thyroiditis in the GFP+ fluorescent mouse

    Clin Immunol

    (2006)
  • A. Balasubramanian et al.

    Hepatitis C virus and HIV envelope proteins collaboratively mediate interleukin-8 secretion through activation of p38 MAP kinase and SHP2 in hepatocytes

    J Biol Chem

    (2003)
  • N. Akeno et al.

    HCV E2 protein binds directly to thyroid cells and induces IL-8 production: a new mechanism for HCV induced thyroid autoimmunity

    J Autoimmun

    (2008)
  • M.W. Russo et al.

    Side effects of therapy for chronic hepatitis C

    Gastroenterology

    (2003)
  • I.S. Fentiman et al.

    Primary hypothyroidism associated with interferon therapy of breast cancer

    Lancet

    (1985)
  • M. Lisker-Melman et al.

    Development of thyroid disease during therapy of chronic viral hepatitis with interferon alfa

    Gastroenterology

    (1992)
  • J.D. Farrar et al.

    Type I interferons and T helper development

    Immunol Today

    (2000)
  • H. Tilg

    New insights into the mechanisms of interferon alfa: an immunoregulatory and anti-inflammatory cytokine

    Gastroenterology

    (1997)
  • I. Krause et al.

    Autoimmune aspects of cytokine and anticytokine therapies

    Am J Med

    (2003)
  • E.M. Jacobson et al.

    The HLA gene complex in thyroid autoimmunity: from epidemiology to etiology

    J Autoimmun

    (2008)
  • E.M. Jacobson et al.

    The CD40, CTLA-4, thyroglobulin, TSH receptor, and PTPN22 gene quintet and its contribution to thyroid autoimmunity: back to the future

    J Autoimmun

    (2007)
  • Y. Ban et al.

    The regulatory T cell gene FOXP3 and genetic susceptibility to thyroid autoimmunity: an association analysis in Caucasian and Japanese cohorts

    J Autoimmun

    (2007)
  • S. Kakizaki et al.

    HLA antigens in patients with interferon-alpha-induced autoimmune thyroid disorders in chronic hepatitis C

    J Hepatol

    (1999)
  • C.J. Ross et al.

    Pharmacogenomics and its implications for autoimmune disease

    J Autoimmun

    (2007)
  • A. Huber et al.

    Joint genetic susceptibility to type 1 diabetes and autoimmune thyroiditis: from epidemiology to mechanisms

    Endocr Rev

    (2008)
  • T.H. Brix et al.

    Evidence for a major role of heredity in Grave's disease: a population-based study of two Danish twin cohorts

    J Clin Endocrinol Metab

    (2001)
  • Y. Tomer et al.

    Infection, thyroid disease and autoimmunity

    Endocr Rev

    (1993)
  • S.P. Cox et al.

    Does infection initiate Grave's disease? A population based 10 year study

    Autoimmunity

    (1989)
  • D.I. Phillips et al.

    The geographical distribution of thyrotoxicosis in England according to the presence or absence of TSH-receptor antibodies

    Clin Endocrinol (Oxf)

    (1985)
  • V.V. Valtonen et al.

    Serological evidence for the role of bacterial infections in the pathogenesis of thyroid diseases

    Acta Med Scand

    (1986)
  • D. Corapcioglu et al.

    Relationship between thyroid autoimmunity and Yersinia enterocolitica antibodies

    Thyroid

    (2002)
  • T.H. Brix et al.

    Too early to dismiss Yersinia enterocolitica infection in the aetiology of Grave's disease: evidence from a twin case-control study

    Clin Endocrinol (Oxf)

    (2008)
  • M.H. Kraemer et al.

    Relationship between HLA antigens and infectious agents in contributing towards the development of Grave's disease

    Immunol Invest

    (1998)
  • A. Nagasaka et al.

    Reverse transcriptase is elevated in the thyroid tissue from Grave's disease patients

    Clin Endocrinol (Oxf)

    (2000)
  • J.B. Jaspan et al.

    Evidence for a retroviral trigger in Grave's disease

    Autoimmunity

    (1995)
  • J.B. Jaspan et al.

    The interaction of a type A retroviral particle and class II human leukocyte antigen susceptibility genes in the pathogenesis of Grave's disease

    J Clin Endocrinol Metab

    (1996)
  • K. Yokoi et al.

    Presence of human T-lymphotropic virus type II-related genes in DNA of peripheral leukocytes from patients with autoimmune thyroid diseases

    J Med Virol

    (1995)
  • T. Tomoyose et al.

    Cytotoxic T-lymphocyte antigen-4 gene polymorphisms and human T-cell lymphotrophic virus-1 infection: their associations with Hashimoto's thyroiditis in Japanese patients

    Thyroid

    (2002)
  • D.A. de Luis et al.

    Helicobacter pylori infection is markedly increased in patients with autoimmune atrophic thyroiditis

    J Clin Gastroenterol

    (1998)
  • N. Figura et al.

    The infection by Helicobacter pylori strains expressing CagA is highly prevalent in women with autoimmune thyroid disorders

    J Physiol Pharmacol

    (1999)
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