This is an author version of the contribution published on:
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[Minerva Endocrinol, 40(4), 2015]
ovvero [Caviglia GP, Rosso C, Fagoonee S, Cisarò F, Andrealli A, Smedile A, Pellicano
R., 40, Minerva Medica, 2014, pagg.321-329]
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Endocrine Manifestations of Chronic HCV Infection
G. P. CAVIGLIA1, C. ROSSO1, F. CISARO’2, A. SMEDILE1,2, R. PELLICANO2
1Department of Medical Sciences, University of Turin, Turin, Italy
2Department of Gastroenterology and Hepatology, Città della Salute e della Scienza - Molinette Hospital, Turin, Italy
Corresponding author: Gian Paolo Caviglia, Department of Medical Sciences, University of Turin, Via Cavour 31, Turin 10100, Italy. Tel: +39 (0)11 6333922; Fax: +39 (0)11 6333976; e-mail:
Conflict of interest statement: The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.
This work was not supported by grants.
Abstract
Chronic hepatitis C virus (HCV) infection has been associated with a great number of extra-hepatic manifestations (EHMs), including several endocrine disorders. Based on current available epidemiological, clinical and experimental data, the link between HCV and some EHMs is almost clear, whereas for others still needs further confirmation. Thyroid disorders (TDs) and type 2 diabetes are the most frequent endocrine alteration in patients with chronic HCV infection, whereas there are several evidences that HCV is involved in hypothalamic-pituitary axis perturbation, bone metabolism alteration and sexual dysfunctions induction. However, these observations need further investigation.
In addition, prospective studies have shown that interferon (IFN)-based therapy for chronic HCV infection can induce or worsen EHMs. In particular, IFN has been associated with
development of autoimmunity and/or TDs in up to 40% of chronic HCV infected patients. Therefore, a careful monitoring of thyroid should be suggested in such patients.
Finally, the approval of direct-acting antiviral agents in IFN-free regimen for chronic
hepatitis C treatment will dramatically reduce not only liver-related mortality but also mortality and morbidity from extra-hepatic diseases.
Hepatitis C virus (HCV) is an hepatotrophic virus with more than 180 million people infected worldwide.1 HCV infection becomes chronic in most of cases and, overtime, people are at
increased risk of developing cirrhosis and its complications, such as hepatocellular carcinoma (HCC).2,3 However, chronic HCV infection has been associated with several extra-hepatic
manifestations (EHMs) including a wide spectrum of organ-specific and systemic diseases such as hematologic, rheumatic, dermatologic and endocrine disorders.4-6 Based on epidemiological and
pathogenetic evidences, some EHMs are strongly associated with chronic HCV infection, whereas for others the association is only suspected or indicated by anecdotal data (TABLE I).7
In this review, we summarize and discuss the current evidence of association between chronic HCV infection and thyroid disorders (TDs), insulin resistance (IR)/type 2 diabetes (T2D), and other endocrine system dysfunctions still requiring confirmation of association.
Chronic HCV infection and thyroid
TDs are common in patients with chronic HCV infection, particularly in women and elderly. Several forms of TD such as hypo- or hyperthyroidism, Hashimoto’s thyroiditis or the presence of anti-thyroid antibodies without clinical manifestations have been observed in chronic hepatitis C.8-12
Anti-thyroid antibodies (anti-thyroid peroxidase antibody [AbTPO] and/or anti-thyroglobulin antibody [AbTG]) are present from 2% to 48% of patients with HCV infection according to several cohort studies.13,14 This heterogeneity could be explained by the variable contribution of several risk
factors including host genetic predisposition, iodine intake, selenium deficit, exposure to low dose of radiations and other viral infections.15
The largest study that explored the association of HCV infection and TD was performed on 630 consecutive chronic HCV infected patients naïve for antiviral treatment compared to a control group of 743 subjects (389 individuals from a iodine-deficient area, 286 persons living in a iodine sufficiency area and 86 patients with chronic hepatitis B virus infection).16 Thyroid hormones levels
(thyroid-stimulating hormone levels greater than 4µIU/mL) and thyroid autoimmunity (AbTPO and/or AbTG positivity) among patients with chronic HCV infection compared to control group was found.16
Specific mechanisms involved in the pathogenesis of autoimmune TD include high levels of endogenous interferon (IFN)-α, IFN-γ-inducible chemokines and a number of cytokines regulated by HCV.17-20 The virus may indirectly act by up-regulating thyrocytes chemokine CXC ligand 10
(CXCL10) secretion by an amplified feedback loop: this chemokine activates the chomotaxis of T-helper 1 lymphocytes that in turns enhance IFN-γ and tumor necrosis factor (TNF)-α production and consequently induce CXCL10 secretion stimulation, thus perpetuating the immune cascade (FIGURE I).21 Several reports, showed that increased expression of CXCL10 is associated with
autoimmune thyroiditis and, moreover, chemokine levels are correlated with serum alanine aminotransferase (ALT) and histological necroinflammatory activity in chronic hepatitis C.22-24 In
addition, the identification of HCV RNA negative strands (replicative intermediates) in thyroid cells suggest that not only the virus can infect thyrocytes but also that is able to replicate within. The direct viral infection of thyroid cells may trigger autoimmune thyroiditis by different mechanism including induction of local inflammation, cytokine release and molecular mimicry between HCV and thyroid antigens.25
Several studies have shown that up to 40% of patients with chronic HCV infection develop thyroid antibodies during IFN-α therapy and approximately 15% develop TD.26-28 The most
common form of thyroid autoimmunity is the presence of AbTPO and/or AbTG without clinical manifestations.29 Hashimoto’s thyroiditis is the commonest clinical manifestation of autoimmune
IFN-induced thyroiditis.30,31 The presence of thyroid antibodies prior to IFN-α treatment is a risk
factor for autoimmune thyroiditis development.32-34 Roti and colleagues calculated that elevated
AbTPO before IFN-α therapy had a positive predictive value of 67% for autoimmune thyroiditis development.27 In a recent study that aimed to identify TD predictors in treated and untreated
parameters were associated with TD induction.35 Regarding demographic features, women have
4.4-fold increased risk of developing IFN-α induced thyroiditis,36 whereas older patients are more likely
to develop TD (56.5 vs. 45.2 years for chronic HCV infected patients with and without TD, respectively; p=0.001).37
Another interesting aspect of chronic hepatitis C and thyroid is the high prevalence of papillary thyroid cancer (2.2%) in HCV patients.38 These data were confirmed in a case-control
study that reported an association between HCV infection and thyroid cancer (OR=2.8, 95%CI 1.2-6.3; p=0.01).39 Moreover, evidences suggest that HCV could be involved in thyroid cancer
development considering that chronic autoimmune thyroiditis has been regarded as a pre-neoplastic condition.40,41
Chronic HCV infection and Insulin resistance/type 2 diabetes
The pathogenetic mechanisms linking IR and T2D with HCV infection are complex and not yet completely clear. Several epidemiological studies demonstrate that changes in insulin secretion and action are present before the development of T2D suggesting that IR may be one of the
pathogenetic mechanism involved in glucose homeostasis perturbation already at early stages of liver disease.42 Interestingly, the use of euglycemic hyperinsulinemic clamp technique together with
the infusion of labeled tracers shows that chronic HCV infection is mainly associated with
peripheral rather than hepatic IR suggesting a crosstalk between the liver and other tissues (namely the muscle) involved in glucose homeostasis.43,44
Recently, Eslam and colleagues described a link between single nucleotide polymorphisms in the interferon lambda 3 gene and IR in HCV patients.45 Additionally, Petta and colleagues show
that the carriage of the rs12979860 CC genotype is associated with a favorable metabolic profile including a lower IR in a cohort of 434 HCV genotype 1 infected patients.46 Authors hypothesized
IFN-stimulated genes (as previously described),47 condition that prevents insulin signaling perturbation
and consequently IR development.
Several cross-sectional and longitudinal studies showed that in HCV chronic infected patients, T2D prevalence was higher compared to other chronic liver diseases suggesting a potential diabetogenic effect of the virus.48,49 Mehta and colleagues, conducted a cross-sectional survey on
9841 persons for whom data on HCV infection and diabetes were complete.50 Authors reported that
T2D occurred more frequently in older, non-white, with higher body mass index and low
socioeconomic status persons.50 Interestingly, after adjustment for these factors, subjects older than
40 years and with HCV infection showed a significantly higher risk of T2D than those without HCV infection (adjusted odds ratio=3.77, 95% CI 1.80-7.87]).50 Subsequently, Zein and colleagues
reported a significant high percentage (14.5%) of T2D in a cohort of chronic HCV infected patients compared to a 7.8% rate for the general population (p=0.0008) and to a rate of 7.3% observed in a matched group of patient with non-HCV liver disease.51 More recently, Simò and colleagues in
order to investigate the hypothesis of a causal relationship between HCV infection and T2D, compared the incidence of glucose abnormalities (diabetes and impaired fasting glucose) between HCV-infected patients with or without sustained virological response (SVR) to IFN-based
therapy.52 During follow-up, 14.6% of patients with SVR and 34.1% non-SVR developed glucose
abnormalities (p=0.001).52 Patients with SVR did not develop diabetes during follow-up, whereas 9
cases of diabetes were detected in non-SVRs (p=0.007).52 After adjustment for the recognized
predictors of both T2D and SVR, the hazard ratio for glucose abnormalities in patients with SVR was 0.48, 95% CI 0.24–0.98 (p=0.04) compared to patients without SVR.52 However, a subsequent
study of our group pointed out that more than HCV infection, genetic predisposition plays a crucial role in determine which HCV patients are at risk of developing T2D and impaired fasting glucose.53
From a metabolic point of view, HCV infection resembles non-alcoholic steatohepatitis (NASH) for the presence of IR. Conversely, the intracellular signal pathways are different according to the etiology. Particularly, HCV core protein is able to increasephosphorylation of
insulin receptor substrate-1 (IRS-1) in a direct manner interfering with insulin pathway through the inhibition of IRS and the up-regulation of the suppressor of cytokine signaling (SOCS) family, independently of viral genotype.54 Other papers suggested that SOCS members may be under
control of peroxisome proliferator activated receptor-γ (PPARγ) in HCV genotype 3 infection while in experimental models, the expression of the core protein of HCV genotype 1 is able to activate the mammalian target of rapamycin (mTOR).55,56 Another direct mechanism through which the virus
may induce IR is the increased endoplasmic reticulum stress and the resulting overexpression of the protein phosphatase 2A (PP2A) which inhibits the protein kinase Akt signaling leading to decreased glucose uptake and glycogen synthesis.43 In addition, HCV may also indirectly induce IR enhancing
pro-inflammatory cytokines production such as interleukin-18 (IL-18) and TNF-α (FIGURE II).44
Chronic HCV infection and Growth Hormone insufficiency
A link between chronic HCV infection and growth hormone (GH) insufficiency has been pointed out.57 The pituitary GH is involved in the control of several complex physiologic processes
but the major role is to stimulate the liver and other tissues to secrete insulin-like growth factor-1 (IGF-1). Plockinger and colleagues investigated basal and stimulated pituitary hormones secretion in a cohort of patients with chronic HCV infection before and during antiviral therapy and found that GH insufficiency was common in such patients. Moreover, GH secretion improved during therapy with IFN-α (from 0.5 [0.4-8.6] to 1.9 [0.5-16.0] µg/L; p<0.006), while no differences were found in IGF-1 serum levels, probably indicating a persistence of liver cell GH resistance.57 Similar
data were subsequently reported studying a cohort of 80 Egyptian HCV infected patients.58
Interestingly, authors found that patients responders to antiviral treatment had a significant higher increase of GH compared to non-responders (GH before therapy: 0.79±0.28 vs. 0.55 ± 0.32 ng/mL; p>0.05 and GH after therapy: 2.63 ± 0.62 vs. 0.86 ± 0.52 ng/mL; p<0.0001, in responders and non-responders to peg-IFN-α + ribavirin, respectively).58 Conversely, Marek and colleagues
levels were higher in patients with viral hepatitis compared to healthy individuals (4.37 ± 0.21 vs. 1.32 ± 0.14 ng/mL; p<0.001), whereas IGF-1 levels were lower.59 Despite the presence of
contradictory data, GH insufficiency seems associated with chronic HCV infection, but it still remains unclear whether GH secretion reduction could be due to a direct inhibitory effect of HCV infection at the level of pituitary gland or hypothalamus.
Chronic HCV infection and vitamin D deficiency
The interest in the role of vitamin D in chronic hepatitis has been growing in recent years. Several authors reported lower vitamin D levels in patients with chronic HCV infection compared to both healthy subjects and patients with liver diseases of other etiologies.60 Moreover, these levels
are even lower in patients with more advanced liver disease and were associated to responsiveness to IFN-α therapy.61-63 The causes of vitamin D deficiency in patients with chronic HCV infection are
not fully clear, but are likely to be multifactorial, including decreased endogenous production, reduced absorption and accelerated turnover.60 In addition, vitamin D is involved in calcium
intestinal absorption and consequently in bone metabolism. In fact, an high prevalence of
osteoporosis (from 14% to 55%) and osteopenia (form 26% to 53%) have been reported in chronic HCV infected patients.64-66 Moreover, a recent prospective study showed that bone mass is improved
and bone turnover normalized in chronic HCV patients responder to antiviral therapy with IFN-α + ribavirin.67 Although genetic factors, nutrition, hormones alterations and medications could be
involved in bone metabolism, the mechanism leading to osteoporosis and osteopenia in chronic HCV infection is still unknown.
Chronic HCV infection and sexual dysfunctions
Besides several endocrine disorders, chronic HCV infection has been associated with sexual dysfunction (SD) both in men and in women. In 2002, Ferri and colleagues reported a rate of 39% of erectile dysfunction in HCV-positive males compared to a rate of 14% of healthy controls.68
Similarly, Soykan and colleagues reported a 35% (50% in female and 21% in males) of SD prevalence in a cohort of Turkish HCV-patients.69 Considering that both HCV and SD have been
associated to depression, subsequently it has been showed that HCV infection was associated with SD even after excluding individuals with underlying depression.70 Interestingly, patients with
chronic HCV infection showed altered levels of sex hormones in comparison to healthy controls, including of androstenedione, testosterone, dehydroepiandrosterone sulphate (DHEA-S) and prolactin.71,72
Further, a 2-fold increase in sex hormone binding globulin (SHGB) was found in HCV-infected patients and it was associated with total testosterone levels, whereas free testosterone levels were low-normal.73 The possible modulation of androgen status by SHGB together with a
significantly lower follicular-stimulating hormone levels, could explain the increased SD
prevalence among male subjects with chronic HCV infection.73 However, how the virus is involved
in hypothalamic-pituitary axis impairment is still to be elucidated.
Conclusions
The evidences of association between chronic HCV infection and abovementioned
endocrine manifestations vary widely according to different studies, but a strong association with chronic HCV infection and either TD and T2D is currently recognized. Contrarily, a link between HCV andhypothalamic-pituitary axis perturbation, bone metabolism alteration and SDs needs to be further assessed. Moreover, HCV exerts its pathogenetic role in a multifactorial context that includes several co-factors such as genetics and environment. A better knowledge of all co-factors involved and the use of IFN-free direct acting antiviral drugs could considerably improve not only SVR but also HCV-associated endocrinopathies outcome.
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TABLE I. Principal extra-hepatic manifestations of chronic HCV infection and related strength of association.
Organ/system involved Manifestation Association
Hematologic disorders B-cell non-Hodjking lymphomas Monoclonal gammopathies Autoimmune hemolityc anemia
1 2 4 Rheumatic disorders Mixed cryoglobulinemia
Croglobulinemic vasculitis Glomerulonephritis Sicca syndrome Rheumatoid arthritis 1 1 2 3 4 Dermatologic disorders Porphyria cutanea tarda
Lichen planus Pruritus Psoriasis 2 2 3 4 Endocrine disorders Type 2 diabetes
Autoimmune thyroidopathies Growth hormone insufficiency Vitamin D deficiency
2 2 4 4 Central nervous system
disorders Chronic fatigue Depression Neurocognitive disorders 2 2 3 Miscellaneus Idiopatic pulmonary fibrosis
Fibromyalgia Cardiomiopathies Erectile dysfunctions 3 3 4 4 1) Associations with strong epidemiological evidence and clear pathogenetic mechanisms. 2) Associations defined on the basis of higher prevalence compared to general population. 3) Associations to be confirmed. 4) Anecdotal observations.
FIGURE I. Regulation mechanism of CXCL10 thyrocytes up-regulation by HCV. Adapted from Antonelli et al.21
HCV up-regulates thyrocytes chemokines secretion. Chemokine CXC ligand 10 (CXCL10) is responsible for Th 1 lymphocytes recruitment that in turn enhance interferon (IFN)-γ and tumor necrosis factor (TNF)-α production and consequently induce CXCL10 secretion stimulation, thus perpetuating the immune cascade.
Abbreviations: CXCL10, chemokine ligand 10; HCV, hepatitis C virus; IFN-γ, interferon-γ; TNF-α, tumor necrosis factor-α.
FIGURE II. Molecular pathways involved in the development of insulin resistance in HCV infection.
The HCV core protein impairs the insulin-dependent tyrosine phosphorylation of hepatic IRS through the up-regulation of SOCS and mTOR factors resulting in reduced Akt activation and leading to the development of IR and eventually T2D. HCV may also disrupt Akt pathway inducing the ER stress in turn enhancing the expression of PP2A.
Abbreviations: Akt, protein kinase B; ER, endoplasmic reticulum; HCV, hepatitis C virus; IR, insulin resistance; IRS, insulin receptors substrate; mTOR, mammalian target of rapamycin; PP2A, protein phosphatase 2A; SOCS, suppressor of cytokine signaling; T2D, type 2 diabetes.
