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The Patient with NAFLD and Chronic HCV

Issue: July/August 2014

ByThomas C. Mahl, MD

ByAlia Hasham, MD

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Alia Hasham

Thomas C. Mahl

It is estimated that hepatitis C virus affects approximately 1.3% of the US population and is the leading indication for liver transplantation. About 20% of patients with HCV may spontaneously clear the virus; however, many will develop chronic, progressive disease that leads to cirrhosis with increased risk for hepatocellular carcinoma, at approximately 3% per year. Chronic HCV infection is associated with numerous extrahepatic manifestations, including cryoglobulinemia, and has been implicated in the pathogenesis of insulin resistance and diabetes. HCV has also been associated with dysregulation in insulin signaling and lipid metabolism, leading to excess fat accumulation in the liver in up to 86% of patients.

In the absence of significant alcohol consumption, non-alcoholic fatty liver disease is now becoming a more frequent, concomitant diagnosis in HCV patients, and insulin resistance has emerged as a key underlying pathogenic feature. NAFLD includes a spectrum of disease, ranging from nonalcoholic steatohepatitis (NASH) to steatosis, with a prevalence of approximately 10% and 30% respectively, in the general population.

The cumulative effects of HCV and NAFLD could have important clinical implications and may accelerate fibrosis progression, increase risk for hepatocarcinogenesis and impair response to antiviral therapy. However, with the introduction of newer anti-HCV agents, including direct-acting antivirals (DAAs), the presence of hepatic steatosis may have less impact on treatment response, and interventions directed at lifestyle modifications, with improvements in insulin sensitivity, could represent an important therapeutic focus.

Mechanisms of Steatosis

About 40% to 86% of patients with chronic HCV infection have hepatic steatosis of varying degrees, which likely develops through a complex interaction between various host- and viral-mediated factors. Host risk factors include those implicated in the development of NAFLD such as obesity, glucose intolerance and hyperlipidemia, which represent components of the metabolic syndrome.In the setting of obesity, visceral adipose tissue secretes various hormones and cytokines, including adiponectin and leptin, and causes dysregulation in insulin signaling. Studies have demonstrated elevated levels of leptin in patients with HCV compared with controls. This can promote insulin resistance through increase in fatty acids and/or via up-regulation of certain inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interferon (IFN)-gamma. Ethnicity also appears to influence the degree of steatosis, with a lower prevalence observed in black patients with chronic HCV infection compared with white patients. The presence of insulin resistance, as demonstrated by features of the metabolic syndrome, is central in the pathogenesis of NAFLD, and the severity is associated with likelihood of progression from simple steatosis to NASH. To diagnose concomitant NAFLD in patients with HCV, it has been proposed that individuals should have confirmed histologic presence of at least 50% steatosis, since lesser degrees of steatosis occur commonly in those with HCV. Although portal and lobular inflammation in addition to steatosis are also frequently seen in patients with HCV, the additional findings of ballooning degeneration, with or without Mallory's hyaline and perisinusoidal fibrosis, are more specific for NASH.

Figure 1. Mechanisms of steatosis. Chronic HCV infection is strongly associated with the development of insulin resistance, a key pathogenic feature in nonalcoholic fatty liver disease.

Source: Hasham A, Mahl T.

HCV and Insulin Resistance

Independent of host metabolic factors, data suggest that HCV plays a significant role in the development of insulin resistance and hepatic steatosis, likely mediated through cytokine release, HCV genotypic effects and interference with lipid metabolism. Chronic HCV infection provokes an inflammatory process associated with an enhanced intra-hepatic TNF-alpha response. Through various direct and indirect mechanisms, TNF-alpha disrupts insulin signaling by inhibiting tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 (IRS-1) in adipocytes, which can result in insulin resistance.

A study that investigated transgenic mice expressing HCV core protein showed interference of the insulin receptor-IRS-1 signaling pathway in the liver accompanied by elevation in levels of intrahepatic TNF-alpha. These abnormalities were detected before the development of steatosis, in the absence of inflammation, and improved after the administration of anti-TNF-alpha antibodies. Other potential mechanisms by which HCV infection can interfere with insulin signaling include up-regulation of suppressor of cytokine signaling (SOCS) and down-regulation of peroxisome proliferator activated receptors (PPAR-gamma), both of which can lead to IRS-1 degradation.

Genotypic Influences

HCV genotype appears to independently play a major role in the onset and severity of hepatic steatosis, specifically in patients with genotype 3. Although the exact mechanisms are unclear, this association may be directly related to HCV RNA viral load, as a subsequent decrease in viremia after antiviral therapy has been linked to decline or resolution of steatosis.HCV genotype 3 core protein, when strongly expressed, can also lead to increased lipid accumulation. HCV infection is associated with impairment in lipid metabolism, and the virus structurally resembles a very low-density lipoprotein (VLDL) particle. Host lipoprotein receptors, specifically low-density lipoprotein (LDL), have been shown to be involved in virus entry. Accumulation in lipid and subsequent hepatic steatosis, therefore, may occur through alterations in lipoprotein secretion by HCV inhibition of microsomal triglyceride transfer protein, which plays an important role in VLDL assembly. Furthermore, sterol regulatory element-binding proteins, a family of transcription factors involved in lipogenesis, are enhanced in patients with genotype 3. HCV core and NS4B proteins, in the setting of genotype 3, may induce proteolytic cleavage of sterol regulatory element-binding proteins and interfere with fatty acid synthesis.

In contrast, mechanisms leading to steatosis in patients without genotype 3 appear dependent on both virus and host metabolic factors such as obesity. Through the mechanisms discussed above, these patients demonstrate a pro-inflammatory response with low adiponectin levels (an anti-inflammatory adipocytokine), and up-regulation in TNF-alpha, interleukin-6 (IL-6) and SOCS3, leading to interference with insulin signaling. As shown in mice models expressing genotype 1b core protein, oxidative stress may also contribute to the development of steatosis, through increase in reactive oxygen species.

Clinical Implications

Several factors are associated with progression of HCV toward cirrhosis, including age, male gender, HCV genotype and HIV coinfection. The degree of insulin resistance and hepatic steatosis has also been linked to increased risk for fibrosis progression. Steatosis increases lipid peroxidation in hepatocytes, a marker of oxidative stress, and leads to activation of hepatic stellate cells, inducing collagen deposition and fibrogenesis. Recent studies suggest that the presence of insulin resistance represents a major independent predictor of advancing fibrosis in patients with chronic HCV, possibly mediated by various pro-fibrotic cytokines such as transforming growth factor-beta (TGF-beta), TNF-alpha and leptin, which results in hepatic stellate cell proliferation.

Furthermore, HCV infection is associated with the development of type 2 diabetes, the major sequelae of insulin resistance, which is also associated with increased risk for disease progression. Predominantly mediated by TNF-alpha, diabetes has been observed in approximately 25% of patients with HCV, in papers by Mason et al in 1999 and Knobler et al in 2003, significantly higher than patients with chronic hepatitis B virus or matched, healthy controls. Smaller papers have reported a diabetes prevalence of 23% to 50%. Interestingly, in a cohort of 201 treatment-naive patients with HCV genotype 1, fibrosis was associated with insulin resistance, not steatosis, and a higher prevalence of advanced stage of fibrosis was observed in those with diabetes. Further studies are required to better clarify the contributions of insulin resistance and steatosis to advancing liver disease; however, it is possible that, concurrently, they provide an additive effect.

The relationship between insulin resistance, hepatic steatosis and the development of HCC in patients with HCV remains unclear. Although most cases arise in patients with cirrhosis (1% to 4% per year), HCC has been reported in patients with NASH, even in the absence of cirrhosis. Interestingly, in a study published in Cancer in 2003, Ohata and colleagues showed hepatic steatosis, without NASH or cirrhosis, to be an independent risk factor for HCC in patients with chronic HCV infection (n=161), compared with patients with steatosis (relative risk, 2.81; P=.0135). In the setting of chronic HCV infection, diabetes and obesity were both found to be independent risk factors for HCC. Veldt and colleagues showed that in a large cohort of HCV patients (n=541) with advanced fibrosis, the 5-year risk for developing HCC was 11.4% in those with diabetes vs. 5% in those without diabetes.Impaired glucose tolerance and hyperinsulinemia may induce carcinogenesis through increase in oxidative stress and production of reactive oxygen species. Besides chronic inflammation induced by HCV alone, insulin resistance can promote release of certain inflammatory cytokines, such as TNF-alpha and IL-6, interfering with apoptosis regulation and increasing risk for HCC.

Approach to Treatment

In patients with chronic HCV infection, the presence of hepatic steatosis has been associated with adverse response to traditional antiviral therapy with pegylated interferon and ribavirin.

Poynard and colleagues showed that HCV patients with hepatic steatosis, even if mild (1% to 5% steatosis), had significantly lower sustained virologic response rates compared with those without steatosis, independent of genotype and viral load (52% vs. 66%; P<.001). Insulin resistance appears to be a major underlying factor implicated in decreasing SVR rates, as some authors have suggested that assessment of insulin resistance, such as homeostasis model assessment (HOMA) scores, be performed before treatment initiation to identify patients who may be poor candidates for treatment. It is also postulated that interactions between host lipid metabolism and HCV interfere adversely with JAK-STAT signaling, the major pathway by which interferon exerts its antiviral effects. Additionally, polymorphisms in IL28B are associated with treatment response; individuals with favorable genotypes, CC, have demonstrated lower prevalence of steatosis compared with non-CC individuals (39.6% vs. 67.4%; P=.001).

However, with the current evolution of newer anti-HCV therapies such as DAAs, treatment outcome may be less dependent on the presence of insulin resistance and steatosis. Serfaty and colleagues analyzed the metabolic response to triple therapy, including 12 weeks of the protease inhibitor telaprevir (Incivek, Vertex), in 161 treatment-naive patients with HCV genotype 1. They concluded that baseline insulin resistance, measured by HOMA-IR, was not predictive of virologic response to telaprevir, and improvements in HOMA-IR post-treatment were observed in patients who achieved SVR. Further, results of multivariate analysis revealed high LDL concentration to be predictive of SVR. Regarding the effects of insulin resistance on treatment response, Moucari and colleagues reported similar findings in patients with HCV genotype 1 treated with danoprevir (Roche) as monotherapy. Although data are limited, abnormalities in lipid profile, specifically LDL and apolipoprotein B concentrations, may still affect treatment response since viral entry and replication is associated with lipoprotein concentrations and receptor activity. Elevated LDL levels have however also been associated with the favorable IL28B CC genotype. As newer therapies emerge, further studies are needed to better elucidate the role of lipoprotein receptor activity in HCV replication and treatment response.

In view of the clinical implications of insulin resistance and steatosis on disease progression in patients with concomitant HCV and NAFLD, emphasis still remains on aggressive lifestyle modification, including strategies focused on improving insulin sensitivity and weight loss. To assess the effect of insulin-sensitizing agents on treatment response, a few studies have investigated the use of thiazolidinediones such as pioglitazone (Actos, Takeda) in addition to pegylated interferon and ribavirin. Although a reduction in insulin resistance has been observed, research has shown no consistent improvement in SVR rates across genotypes. More studies, including long-term follow-up, are awaited. Since oxidative stress appears to play an important role in HCV pathogenesis and disease progression, it is possible that antioxidants could interfere with the development of fibrogenesis. Data from earlier pilot study by Look and colleagues demonstrated reduction in viral load after use of vitamin E; however, there has been no confirmed benefit in terms of improvement in SVR.

More Data Needed

Chronic HCV infection and NAFLD are the leading causes of chronic liver disease in the Unites States and concomitantly can increase risk for fibrosis progression and HCC. Although both host- and viral-related factors affect progression of hepatic steatosis and response to treatment, underlying insulin resistance, induced by HCV alone, has emerged as a major pathogenic feature.

Data regarding the effects of insulin-sensitizers on SVR rates are limited and may be less consequential with the development of interferon-free regimens. Furthermore, studies assessing use of newer DAAs, including polymerase inhibitors, in this patient population are still awaited. In HCV patients with NAFLD, emphasis should be placed on interventions aimed at delaying disease progression through aggressive lifestyle modifications.