Extrahepatic Manifestations Of Chronic Hepatitis Research Articles

Extrahepatic manifestations in chronic hepatitis C infected patients

The importance of chronic hepatitis C infection is significant. 3% of the World's population is infected. There is at least one extrahepatic manifestation in 50% of HCV patients, which makes the prognosis and mortality worse. The pathomechanisms included are cryoglobulin production, immunmechanisms, and direct viral effects. The authors summarize the main extrahepatic manifestations, as well as treatment possibilities. The aim is to draw attention to this colourful infection in order to improve the recognition in the era of the new effective direct antiviral agents. Orv. Hetil., 2017, 158(16), 603-612.

Autoimmune thyroid diseases in patients with chronic hepatitis C treated by pegylated interferon-alpha and ribavirin: A prospective study

Introduction/Objective. Despite sufficiently explained pathogenesis, today autoimmune thyroid diseases (AITD) are recognized as one of extra-hepatic manifestations of systemic hepatitis C virus infection. The aim of the present study was to determine clinical characteristics and to estimate the success of pegylated interferon-?2a plus ribavirin (pegIFN-?2a + RBV) therapy in patients with AITD as an extrahepatic manifestation of chronic hepatitis C infection (CHC). Methods. This prospective study included 91 CHC patients treated with pegIFN-?2a + RBV from 2010 to 2012 (39 women and 52 men, mean age 41.6 ?} 11.9). The study group (group A) consisted of 31 patients with CHC and AITD. Control group (group B) consisted of 60 patients with CHC without AITD. We analyzed clinical, biochemical, virological, and histopathological markers of CHC, as well as response and side effects of pegIFN-?2a + RBV therapy. Results. There was a statistically significant difference in sex (p = 0.011), age (p = 0.001), AST level (p = 0.013), level of gamma globulins (p < 0.001), level of IgM (p = 0.007), IgG (p < 0.001), in the success of therapy of CHC with pegIFN-?2a + RBV between the groups. Odds ratio (OR) for unfavorable outcome in group A was 4.200 [95% confidence interval (CI): 1.545?11.417]. In final multivariate logistic regression analysis in group A, the only factor predicting sustained virological response was patients? age (OR = 0.781; 95% CI: 0.603?0.959). The main side effects in group A were interferon induced thyroiditis (IIT) (41.9% vs. 3.3%; p < 0.001) and anemia, which was the only reason for dose reduction of ribavirin (29% vs. 6.7%; p = 0.027). Conclusion. Patients with AITD as an extra-hepatic manifestation of CHC achieve poorer virological response and their antiviral therapy is inevitably followed by a manifestation of adverse effects, predominantly solvable IITs and anemia.

Insulin resistance and tumor necrosis factor-α in chronic viral hepatitis C in Makurdi, Nigeria

Background: Type 2 diabetes mellitus has been reported by studies as an extrahepatic manifestation of chronic hepatitis C (CHC). Aim: The present study aimed at determining the impact of CHC disease on insulin resistance (IR) and its correlation with tumor necrosis factor-α (TNF-α) in this infection. Materials and Methods: The present case–control study adopted purposive sampling technique in selecting 36 CHC and 36 anthropometrically matched apparently healthy individuals, who fulfilled the inclusion criteria. CHC was defined as persistent infection without remission for a period up to 1 year. Results: A statistically significant (P < 0.02) elevated TNF-α, fasting serum insulin (FSI), fasting plasma glucose, and homeostasis model of insulin resistance (HOMA-IR) were observed in CHC compared with the controls. The liver function profile of CHC group showed that plasma total protein and albumin were significantly low when compared to controls, whereas significant high aspartate and alanine aminotransferase levels were observed in the CHC group compared to controls. There was a statistically significant (P < 0.001) positive correlation between TNF-α and HOMA-IR (r = 0.751) and TNF-α and FSI (r = 0.694) in CHC patients. Conclusion: CHC disease could induce increased IR, partly mediated by TNF-α. We recommend metabolic profiling of chronic viral hepatitis C patients during disease management.

Extrahepatic Manifestations of Chronic Hepatitis C Infection: a Review and Update

Hepatitis C virus (HCV) has become an increasingly concerning global disease. While it is well known to causes a chronic hepatitis that can be largely asymptomatic until the development of cirrhosis and/or hepatocellular carcinoma (HCC), chronic HCV can also lead to extrahepatic manifestations (EHMs) which can contribute to further morbidity and mortality. This chapter will discuss the pathophysiology and data supporting the causal relationship between chronic HCV infection and its EHMs as well as address the influence of HCV treatment on these disorders, particularly in the age of direct-acting antiviral agents.

Alterations in serum levels of fetuin A and selenoprotein P in chronic hepatitis C patients with concomitant type 2 diabetes: A case-control study

Insulin resistance (IR) and type2 diabetes mellitus (T2DM) are serious extrahepatic manifestations of chronic hepatitis C virus (HCV) infection. However, the mechanism underlying the IR in chronic HCV is obscure. Hepatokines are group of liver-derived protein, which affect the glucose and lipid metabolism in several tissues. Fetuin A (also known as human α2-HS-glycoprotein) is one of the hepatokines, which was recognized as a natural inhibitor of the insulin receptor tyrosine kinase in liver and skeletal muscle. Additionally, selenoprotein P has emerged as an important hepatokine, which primarily acts as selenium transporter and has been reported to be implicated in glucose homeostasis in human. The aim of the current case-control study was to investigate the serum levels of both fetuin A and selenoprotein P in chronic hepatitis C patients with or without T2DM and to correlate their levels with other biochemical parameters of insulin resistance. Our results showed that, serum fetuin A levels increased significantly in HCV patients compared with controls (P<0.01) and surplus increase was found in HCV with concomitant T2DM (P>0.001). However, selenoprotein P levels significantly elevated only in patients with both HCV and T2DM (P<0.05) compared with the healthy subjects. Both fetuin A and selenoprotein P were positively correlated with fasting blood glucose. Yet, only fetuin A was significantly correlated to the HOMA-IR (r=0.28; P=0.03). These results indicate crucial roles played by fetuin A and selenoprotein P in the IR caused by HCV and that both hepatokines may be targets for the development of therapies to treat or inhibit insulin resistance associated to HCV. However, further studies on large scale should be conducted to confirm our findings.

Myocardial injury associated with chronic hepatitis C: Clinical types and pathogenetic components

Heart injury is one of the extrahepatic manifestations of chronic hepatitis C (CHC). The paper gives Russian and foreign authors' data on a relationship between CHC and myocardial injury. It discusses different pathogenetic components (the direct effect of the virus, immunological components), through which hepatitis C virus can induce myocarditis and cardiomyopathies in patients with CHC.

Extrahepatic manifestations of chronic hepatitis C virus infection.

During hepatitis C virus (HCV) chronic infection, extrahepatic manifestations are frequent and polymorphous. This article reports on a large cohort of patients with HCV-related autoimmune or lymphoproliferative disorders, from mixed cryoglobulinemia vasculitis to frank lymphomas. The relationship between HCV infection and such immune-related diseases has been formally demonstrated by epidemiological, clinical, immunological and pathological data, and results of therapeutic trials. More recently, other nonliver-related HCV disorders have been reported, including cardiovascular (i.e. stroke, ischemic heart disease), renal, metabolic and central nervous system diseases. For these manifestations, most evidence comes from large epidemiological studies; there is a need for mechanistic studies and therapeutic trials for confirmation. Beyond the risk of developing liver complications, that is, cirrhosis and liver cancer, patients with HCV infection have an increased risk of morbidity and mortality related to nonliver diseases. HCV chronic infection should be analyzed as a systemic disease in which extrahepatic consequences increase the weight of its pathological burden. The need for effective viral eradication measures is underlined.

Extrahepatic manifestations in chronic hepatitis C virus carriers.

Patients with chronic hepatitis C virus (HCV) infection frequently present with extrahepatic manifestations covering a large spectrum, involving different organ systems leading to the concept of systemic HCV infection. These manifestations include autoimmune phenomena and frank autoimmune and/or rheumatic diseases and may dominate the course of chronic HCV infection. Chronic HCV infection causes liver inflammation affecting the development of hepatic diseases. HCV is also a lymphotropic virus that triggers B cells and promotes favorable conditions for B lymphocyte proliferation, including mixed cryoglobulinemia (MC) and MC vasculitis, which is the most prominent extrahepatic manifestation of chronic HCV infection. HCV may also promote a low-grade chronic systemic inflammation that may affect the development of some extrahepatic manifestations, particularly cardiovascular and cerebral vascular diseases. Recognition of extrahepatic symptoms of HCV infection could facilitate early diagnosis and treatment. The development of direct-acting antiviral agents (DDAs) has revolutionized HCV treatment. DDAs, as well as new B-cell-depleting or B-cell-modulating monoclonal antibodies, will expand the panorama of treatment options for HCV-related extrahepatic manifestations including cryoglobulinemic vasculitis. In this context, a proactive, integrated approach to HCV therapy should maximize the benefits of HCV therapy, even when liver disease is mild.

A Case of Hepatitis B Virus Related Membranous Glomerulonephritis That Well Responsed to Low Dose Corticosteroid Therapy

©Copyright 2014 by Bezmialem Vakif University Available online at www.bezmialemscience.org ©Telif Hakki 2014 Bezmialem Vakif Universitesi Makale metnine www.bezmialemscience.org web sayfasindan ulasilabilir. Glomerulonephritis (GN) is a common extrahepatic manifestation of chronic hepatitis B virus (HBV) infection, affecting approximately 20% of patients from the Middle East and Far East Asia, where HBV infection is prevalent (1) Recent data show that 30% of patients with HBV-related GN eventually progress to renal failure (2). The major pathogenetic mechanism of HBV-related GN is immune complex deposits in the kidney, leading to destruction of the epithelial side of the glomerular basement membrane and eventually resulting in protein loss into the tubules. Although treatment strategies of HBV and membranous nephropathy are well established, there is still a lack of available data in patients who not respond well to primary intervention or who have failed to sustain the response.

Extrahepatic manifestations of chronic hepatitis C virus infection: 297 cases from a tertiary medical center in Beijing, China

Background Chronic hepatitis C virus (HCV) infection can affect multiple organ systems and cause a variety of extrahepatic manifestations (EMs). We sought to assess the constituent ratio of EMs in Chinese patients with chronic HCV infection and identify the clinical and biological factors associated with EM. Methods The medical records of 297 patients with chronic HCV infection were analyzed and demographic and epidemiological information was collected. The diagnosis of chronic HCV infection was based on positive anti-HCV combined with a positive HCV-RNA or at least two times of elevated aminotransferases attributable to HCV infection. Patients with HBV and/or HIV coinfection, autoimmune hepatitis, and history of alcohol abuse were excluded. Results Sixty-two percent (184/297) of the patients had at least one EM, including fatigue (29.4%), type 2 diabetes mellitus (28.2%), renal involvement (12.5%), lymphadenopathy (9.6%), fever (9.4%), thyroid dysfunction (8.1%), and arthralgia (7.4%). Neuropathy, sicca syndrome, B-cell lymphoma, Raynaud's phenomenon, and lichen planus were rare. The mean age of patients with EM was older compared with those without EM. Conclusions EMs were common in Chinese patients with chronic HCV infection, particularly fatigue, type 2 diabetes, renal impairment, lymphadenophy, fever, and thyroid dysfunction. Older age was associated with EMs.

Atherosclerosis as a Possible Extrahepatic Manifestation of Chronic Hepatitis C Virus Infection

Chronic infection and associated inflammation may play a role in various unfavorable pathologic conditions, including atherosclerosis. Chronic hepatitis C virus (HCV) infection is thought to be associated with a higher prevalence of atherosclerotic vascular changes in the coronary artery, cerebrovascular artery, and carotid artery; however, little is known about the precise mechanisms by which HCV enhances atherogenic processes. Furthermore, some studies have found no association, or even an inverse association, between HCV infection and atherosclerotic vascular changes or cardiovascular events. Differences in data regarding the mode of association may be because of variations in sample size, target population, and study design. Nevertheless, physicians should be aware of cardiovascular disorders as a possible comorbidity – owing to their considerable consequences – among patients with chronic HCV infection.

The impact and effect of liver insufficiency of HCV infection on patients with chronic obstructive pulmonary diseases

BackgroundHepatitis C virus (HCV) infection is associated with a wide series of extrahepatic manifestations. Pulmonary involvement is one of the extrahepatic manifestations of chronic hepatitis C virus (HCV) infection. The objective of this study was to determine the impact of HCV infection and the degree of liver dysfunction in patients with chronic obstructive pulmonary disease (COPD). MethodsThis study was conducted on COPD patients. They were selected from outpatient chest clinic in the Menoufia University Hospital. They were classified into 2 groups the first group COPD patients (n=40) without hepatitis C and the second group COPD patients with chronic hepatitis C. Second group (COPD with HCV) classified into 3 subgroups according Child–Pugh classification to determine the degree of liver insufficiency. Group IIA: patients Child–Pugh (A), group IIB: patients Child–Pugh (B) and group IIC: patients Child–Pugh (C). The following pulmonary function parameters were recorded: Forced Expiratory Volume in the first second (FEV1), Forced Expiratory Volume percent (FEV1/FVC%), Forced Expiratory Flow 25–75% (FEF 25–75%) and Maximal Voluntary Ventilation (MVV). ResultsThe study included 80 patients with COPD, 40 patients without chronic HCV infection (group I), and 40 patients with chronic HBV infection (group II).COPD patients with HCV infection have increased deterioration in pulmonary function (FEV1, FEV1/FVC, FEF 25–75% and MVV) than COPD patients without HCV infection. Also there were significant decreases in pulmonary function tests (FEV1, FEV1/FVC, FEF 25–75% and MVV) in group II subgroups IIA, IIB and IIC according to the degree of decompensation. ConclusionPatients with COPD with HCV infection, have increased deterioration in pulmonary function than patients with COPD without HCV infection and the deterioration increases with hepatitis decompensation.

Hepatitis C virus (HCV) infection of peripheral blood mononuclear cells in patients with type II cryoglobulinemia

ObjectivesType II cryoglobulinemia is a common extrahepatic manifestation of chronic hepatitis C virus (HCV) infection. The mechanisms behind its development are unclear, but could be related to direct infection of the immune cells. MethodsPeripheral blood mononuclear cells from 18 patients with type II cryoglobulinemia were separated into CD3+ (T cells), CD19+ (B cells) and CD14+ (monocytes) and analyzed for the presence of negative strand HCV RNA, which is a viral replicative intermediate, and for the presence of HCV non-structural protein 3 (NS3). Control group consisted of 182 consecutive chronic hepatitis C patients prior to initiation of antiviral therapy. ResultsNegative strand HCV RNA was detected in PBMC from six (33.3%), patients and in 15 (8.2%) controls (p<0.01). Negative strand was most frequently detected in B cells (3 patients), followed by T cells (2 patients), and monocytes (2 patients). One patient was positive both in CD3+ and CD14+ cells. NS3 protein was detected in six (33.3%) patients; five were positive in T cells, three in B cells, and another three were positive in monocytes. Two patients were positive in all analyzed cell subpopulation and one patient was positive in CD14+ and CD19+ cells, but not in CD3+ cells. Altogether, 11 patients (61.1%) were positive either for the negative strand HCV RNA or NS3 protein in at least one of the analyzed cell compartments. ConclusionOur findings of common presence of viral replication in cells of the immune system suggest that direct HCV infection could play a role in the etiology of cryoglobulinemia.

Extrahepatic manifestations of chronic hepatitis C and their influence on response to treatment with Pegylated interferon alfa-2a and ribavirin

Thirty to 50% of patients with chronic hepatitis C (CHC) have one or more extrahepatic manifestations (EHMs) of hepatitis C virus (HCV) infection. The aim of this study was to evaluate the frequency of EHMs and to investigate the efficacy of pegylated interferon (Peg-IFN)-alpha-2a plus ribavirin therapy in patients with HCV-related EHMs. The study included 280 patients suffering from CHC and treated with Peg-IFN-alpha-2a and ribavirin.The patients were divided in two groups according to presence or absence of EHMs. We evaluated virological response to antiviral therapy. One or more EHMs were found among 27.9% of patients. Most frequently they had rheumatoid factor in serum (12.5%), organ-nonspecific antibodies ANA and AGMA (12.4%), thyroid hormone disorders (9.3%), vasculitis (5.7%), diabetes mellitus (4.65%), glomerulonephritis (0.71%), and porphyria cutanea tarda (0.36%). Among the patients with EHMs there was 52.6% of females vs. 30.2% of females in the group of patients without EHMs (p=0.001). HCV genotypes 1 and 4 had 85.9% patients with EHMs vs. 58.4% of patients without EHMs (p=0.000). Progressive fibrosis and cirrhosis were more frequently recorded in the EHM group of patients (32% vs. 23.2%), but without statistically significant difference (p=0.532). Serious adverse events of Peg-IFN-alpha-2a and ribavirin were statistically significantly recorded among the patients with EHMs (46.1% vs. 12.9%; p=0.000). Sustained virological response among the patients with and without EHMs rated 56.9% and 70.8% respectively (p=0.125). Patients with CHC and EHMs treated with combined Peg-IFN-alpha-2a and ribavirin experience handling difficulties, more often have serious adverse events, while successful outcome is achieved in about 50% of patients.

B cell homeostasis in chronic hepatitis C virus–related mixed cryoglobulinemia is maintained through naïve B cell apoptosis

Mixed cryoglobulinemia (MC) is the most common extrahepatic manifestation of chronic hepatitis C virus (HCV) infection. Although the formation of inflammation-triggering immune complexes is driven by clonal expansions of autoreactive B cells, we found total B cell numbers paradoxically reduced in HCV-infected patients with MC. HCV patients with MC (n = 17) also displayed a reduced number and a reduced frequency of naïve B cells compared with HCV-infected patients without MC (n = 19), hepatitis B virus-infected patients (n = 10), and uninfected controls (n = 50). This was due to an increased sensitivity of naïve B cells to apoptosis resulting in a reduction in the size of the naïve B cell subset. In addition, 4-fold expansion and skewing (lower T1/T2-ratio) of the immature B cell subset was noted in MC patients, suggesting that apoptosis of naïve B cells triggered the release of B cell precursors from bone marrow in an attempt to maintain normal B cell numbers. Following treatment of MC with the B cell-depleting antibody rituximab, the size of all B cell subsets, the T1/T2-ratio, and the cyroglobulin levels all normalized. Cryoglobulin levels correlated with in vivo proliferation of T2 B cells, suggesting a link between the skewing of the T1/T2 ratio and the formation of immune complexes. This study provides insight into the mechanisms maintaining B cell homeostasis in HCV-induced MC and the ability of rituximab therapy to restore normal B cell compartments. (HEPATOLOGY 2012;56:1602-1610).

Thyroid Dysfunction in Chinese Patients with Chronic Hepatitis C Treated with Interferon Alpha: Incidence, Long-Term Outcome and Predictive Factors

BackgroundThyroid dysfunction (TD) represents an extra-hepatic manifestation of chronic hepatitis C (CHC) and it may also be a side effect of interferon-alpha (IFN-α) based treatment. However, previous studies have shown a wide variation in the incidence of TD in patients with CHC. Furthermore, the long-term outcomes and the predictive factors of TD in patients who receive IFN-α based treatment have still not been fully studied.ObjectivesThe purpose of this study was to describe the incidence and long-term outcomes of TD in Chinese patients with CHC receiving IFN-αbased treatment. We also aimed to identify the predictive factors of TD associated with this type of therapy.Patients and MethodsA retrospective case-series study of 592 consecutive CHC patients with normal baseline thyroid functions, who received IFN-αbased therapy, was performed. Thyroid function was assessed at baseline and every three months during treatment, as well as in the follow-up after cessation of therapy. The incidence and long-term outcomes of TD were observed. The prevalence of pretreatment thyroid peroxidase antibodies (TPOAb) were assayed in a sex- and age-matched nested case-control study. Multivariable stepwise regression analysis was used to explore the independent effects of the baseline factors, on the incidence of TD.ResultsAt the end of the IFN-αbased therapy, 68 patients (11.5%) in the study had developed TD, 58 patients (85.3%) presented with subclinical TD, and only 10 patients (14.7%) developed overt thyroiditis. The thyroid function of 46 patients (67.8%) spontaneously returned to normal in the six months of follow-up and only three patients (4.4%) had persistent overt TD symptoms after the 24 month follow-up period. Multivariate stepwise analysis suggested that gender and pretreatment TPOAb were the independent factors related to the incidence of TD. Both female patients (OR, 4.31; 95%CI, 2.06–7.31; P = 1.26×10-4) and participants with a positive pretreatment TPOAb (OR = 3.9, 95%CI, 1.72–8.54, P = 0.008) had an increased risk for the development of TD.ConclusionsThe incidence of TD in Chinese patients with CHC during IFN-αbased therapy was 11.5%, the majority of which was subclinical, while only a very small group had long-term overt TD requiring ongoing medical therapy. Female gender and pretreatment TPOAb positivity are risk factors for the development of TD during IFN-αbased therapy.

Low 25-hydroxyvitamin D serum levels correlate with the presence of extra-hepatic manifestations in chronic hepatitis C virus infection

Chronic HCV infection is associated with extra-hepatic manifestations. Recent studies have suggested an immunomodulatory role for vitamin D during HCV infection. We investigated the association between serum vitamin D status and the presence of HCV extra-hepatic manifestations. 25(OH)D serum levels were assessed in 94 HCV(+)RNA(+) patients [including 48 patients with mixed cryoglobulinaemia (MC) vasculitis]. Correlations between serum 25(OH)D levels and the presence of extra-hepatic manifestations of HCV infection were analysed. Overall, 84 of 94 patients (89%) had hypovitaminosis D (≤30 ng/ml). Patients with vitamin D deficiency vs insufficiency vs sufficiency more frequently had systemic vasculitis (P = 0.02), in particular purpura (P = 0.006), detectable MC (P = 0.008) and low C4 serum levels (P = 0.006). Serum levels of 25(OH)D were also correlated with cryoglobulin and C4 levels and with marginal zone B cells and regulatory T cells. In multivariate analysis, the presence of MC and systemic vasculitis remained independently associated with low 25(OH)D levels. In chronic HCV infection, low 25(OH)D levels correlate with the presence of mixed cryoglobulinaemia and systemic vasculitis in chronic HCV infection. These findings suggest the potential multifaceted benefits of vitamin D supplementation in HCV-infected patients with extra-hepatic manifestations, but interventional studies are needed to confirm these data.

Autoimmunity and Extrahepatic Manifestations in Treatment-Naïve Children with Chronic Hepatitis C Virus Infection

Hepatitis C virus (HCV) infection has been associated with autoimmunity and extrahepatic manifestations in adults. Few data are available on these topics in children. Nonorgan specific auto-antibodies development is part of the natural course of chronic hepatitis C in children. Smooth muscle autoantibody is the most common autoantibody found, while liver-kidney microsomal type-1 antibody positivity is the most peculiar autoimmune feature of children with HCV infection. The clinical significance of non-organ specific autoantibodies in the course of paediatric chronic hepatitis C is still debated. Autoantibody positivity can be considered neutral for most patients, while it can be associated with negative connotations for others, especially those positive for liver-kidney microsomal type-1 autoantibody. Subclinical hypothyroidism but not autoimmune thyroiditis has been demonstrated in HCV infection in children, while only few cases of HCV-associated membranoproliferative glomerulonephritis have been described. Single reports are available in the literature reporting the anecdotal association between chronic hepatitis C and other extrahepatic manifestations such as myopathy and opsoclonus-myoclonus syndrome. Despite the low incidence of extrahepatic manifestations of chronic hepatitis C in children, overall, available data suggest a careful monitoring.

Hepatitis B and Renal Disease

Glomerulonephritis is an important extrahepatic manifestation of chronic hepatitis B virus (HBV) infection. The uncommon occurrence, variability in renal histopathology, and heterogeneity in clinical course present challenges in clinical studies and have resulted in a relative paucity of data and uncertainty with regard to the optimal management of HBV-related glomerular diseases. The advent of nucleos(t)ide analogue medications that effectively suppress HBV replication has markedly altered the clinical outcomes of kidney transplant recipients with HBV infection, but the emergence of drug resistance is an escalating problem. This article reviews the recent knowledge of the pathogenesis and treatment of HBV-related membranous nephropathy, and discusses the management of hepatitis B in kidney transplant recipients, which is continuously evolving.

Thyroid dysfunction in patients with chronic hepatitis C: Virus‐ or therapy‐related?

Thyroid dysfunction (TD) represents an extrahepatic manifestation of chronic hepatitis C (CHC). Moreover, the currently approved treatment of CHC is often associated with TD. However, it remains debatable if TD is mainly virus- or treatment-related. The aim of this study was to assess the incidence and features of TD, and to identify its predictors in treated and untreated CHC patients. Ninety-four patients with CHC and normal thyroid function were evaluated long-term for TD: 33 were untreated (control group) and 61 were treated with pegylated interferon alpha (PEG-IFN-alpha) plus ribavirin (treatment group). Mean follow up was 80.1 and 39.4 months, respectively. All patients in the control group remained euthyroid, while 13 treated patients (21.3%) developed TD (P < 0.001). Eleven of these were diagnosed with hypothyroidism and two with hyperthyroidism, which then converted to hypothyroidism. In the majority of cases (9/13, 69.2%) TD did not reverse after treatment discontinuation and required hormone replacement therapy. Pretreatment virological parameters did not predict TD, according to multiple logistic regression analysis. TD was not associated with total dose of PEG-IFN-alpha or ribavirin, viral kinetics or with virological outcome, but it was linked to development of other therapy-related autoimmune disorders (odds ratio, 8.29). Antiviral therapy of CHC possibly induces de novo or exacerbates pre-existing silent TD. TD does not seem to correlate with any pretreatment virological parameter; it is probably not related to dose or treatment duration, nor linked to viral kinetics or virological outcome. The role of chronic hepatitis C per se in TD remains to be determined.