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From the Townsend Letter
April 2014

Nonalcoholic Fatty Liver Disease
in Chronic Hepatitis C

by Lyn Patrick, ND
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Nonalcoholic fatty liver disease (NAFLD) is epidemic among overweight and obese individuals in developing nations and affects approximately 30% to 46% of all adults in the US.1 Insulin resistance is the main risk factor for this condition, and NAFLD is considered the hepatic manifestation of cardiometabolic syndrome.
Another risk factor for NAFLD is chronic hepatitis C virus infection (HCV). It is considered an epidemic for a reason: 200 million people in the world have chronic hepatitis C, including up to 5 million in the US.2,3 Fatty liver in chronic hepatitis C is an epidemic within an epidemic: up to 70% of those with chronic hepatitis C will have steatosis.4
Fatty liver is important in HCV for a number of reasons: steatosis increases risk for failing standard antiviral therapy, and the more severe form of nonalcoholic steatotic hepatitis (NASH) increases risk for progression to cirrhosis and hepatocellular carcinoma.5-7
Insulin resistance is also the main mechanism in the genesis of NAFLD in HCV, and the virus itself increases risk for insulin resistance and type 2 diabetes; up to 70% of HCV-infected individuals over age 40 in a recent NHANES study had type 2 diabetes.8
So, the logical question arises for clinicians, should all patients with diagnosed NAFLD be screened for chronic hepatitis C? And should all chronic hepatitis C patients be screened for NASH, the progressed form of NAFLD? And, as importantly, what are the treatment approaches for this epidemic within an epidemic?
To address the first question: should a patient with fatty liver disease not caused by drugs; alcohol; metabolic disease; environmental exposure to solvents, PCBs, and so on; or bariatric surgery be tested for hepatitis C? The answer is yes, unless you can pinpoint another cause. And even then, if the patient is between ages 47 and 67, the answer is doubly yes. The American Association for the Study of Liver Disease Practice Guidelines for NAFLD, published June 2012, agrees that HCV testing is appropriate and so does the Centers for Disease Control, whose guidelines for testing were recently published in August 2012.9,10
And the second question, do all HCV-infected individuals need to be screened for NAFLD? There are no guidelines for screening or treatment specifically for HCV-infected persons, only the suggestion that measures to improve insulin sensitivity and reach a body mass index under 25 would increase chances of sustained viral responses (the definition of successful standard treatment).11 This recommendation may stem from the fact that steatosis is common in HCV; but, aside from successful antiviral therapy, there is no clear strategy for how to intercept the fibrosis process.12
Steatosis in HCV infection follows the same ethnic risks as it does in the general population. It is more common in Latinos than in Caucasians, and more common in Caucasians than in African Americans. Interestingly, African Americans are for the most part spared from HCV-related steatosis. And, as in the general population, alcohol, obesity, diabetes, and hyperlipidemia are major risk factors for steatosis in those who are HCV infected.13 Weight loss and exercise, the only approved treatment strategies for NAFLD, are specifically relevant in the above risk groups, particularly if standard treatment is suggested.
HCV-infected individuals, though, are different than their HCV-negative counterparts, as they could be considered "doubly blessed": the virus itself affects insulin signaling pathways even in the absence of obesity, leading to insulin resistance. Lifestyle modification in not always enough to reverse the inflammatory effects of the viral infection, because the infection itself leads to the production of free radicals that drive steatosis. This is particularly important in genotype 1 (the majority of HCV in the US) patients, in whom even successful antiviral treatment does not improve fatty liver, since the signaling turned on by the virus cannot be turned off in its absence.14,15 With genotype 3 patients, who are at the highest risk of fatty liver, this does not appear to be the case. In these patients, the virus itself appears to affect lipid synthesis in the liver, and viral clearance improves steatosis posttreatment.12
The mechanisms involved in virally induced steatosis and fibrosis include interactions between oxidative stress, inflammation, and altered cell signaling – resulting in increased liver cell apoptosis and likelihood of both fat accumulation and lipid peroxidation in hepatocytes.16

The actual diagnostic criteria for NAFLD in HCV are essentially the same as in individuals who are HCV negative. But because serum ALT/AST levels and imaging tests (abdominal ultrasound, CT, and MR) cannot reliably assess steatohepatitis and fibrosis in NAFLD, there is increasing interest in using fibrosis scoring to evaluate the need for liver biopsy, the gold standard in diagnosis of NAFLD and NASH.9 The American Association for the Study of Liver Disease (AASLD) guidelines include the formula-based NAFLD Fibrosis Score, which is based on six readily available variables (age, BMI, hyperglycemia, platelet count, albumin, AST/ALT ratio). It is calculated using the published formula ( In a meta-analysis of 3064 patients in 13 studies, NAFLD Fibrosis Score could effectively predict and exclude advanced fibrosis and may be helpful along with other blood work (FibroSure or FIBROSpect) in determining the need for liver biopsy when ultrasound is not definitive.17 Elevated ferritin, as in the general population, is also a risk factor for steatosis in those with HCV infection.
Screening for NAFLD simply using the symptoms of metabolic syndrome used for the general population may not be effective for HCV-infected individuals, at least those with genotypes 1 and 2. While metabolic syndrome occurs in 28% of the HCV-negative population with NAFLD, Italian researchers found that metabolic syndrome was only present in 6% of those with both NAFLD and genotype 1 or 2 HCV infection.18 Those with HCV/NAFLD were more likely to be insulin resistant (elevated fasting glucose and elevated fasting insulin), be male, and have fibrosis on liver biopsy than their NAFLD counterparts without HCV. For those with genotype 3, central obesity and metabolic syndrome are more prevalent. Because up to 80% of individuals with genotype 3 virus have moderate to severe steatosis, it should be presumed, especially in patients with fibrosis.12

Treatment Options
In most HCV patients with nonalcoholic fatty liver, overnutrition and excessive carbohydrate intake, particularly fructose, can lead to elevated glucose and/or free fatty acids in the liver. These free fatty acids are subject to oxidation, resulting in stellate cell activation, mitochondrial dysfunction, and subsequent fibrosis.19
There is a consensus that the inclusion of omega-3 fatty acids, high monounsaturated fatty–acid containing food, fresh fruit and vegetables, and low–glycemic index, high-fiber foods and reduction of saturated fats, simple carbohydrates, and sweetened drinks are universally recommended.20 Because dietary conditions contributing to insulin resistance may play an active part in HCV fatty liver, caloric restriction, weight loss, and exercise have been studied as therapeutic interventions. One study looking at 19 HCV overweight or obese patients with before-and-after liver biopsies showed that exercise-induced weight loss with as little as 2.6% body weight resulted in a reduction in steatosis. In two lean patients with genotype 3 in this trial, weight loss was also accompanied by a significant reduction in steatosis.21 In a trial of obese HCV patients with steatosis, physical activity and dietary–intervention induced weight loss (as little as 5%) resulted in a reduction of both ALT and fasting insulin that was sustained after the weight loss plateaued.22 The significant effect of such modest amounts of weight may be the influence of exercise and calorie restriction on adipocytokines, particularly adiponectin, which is reduced in insulin resistance and obesity.

Adiponectin has strong anti-inflammatory and insulin-sensitizing properties, and has been shown to reduce hepatic steatosis, prevent liver fibrosis, and reduce insulin resistance. Along with exercise-induced weight loss, omega-3 fatty acids, thiazolidinediones, and testosterone replacement have all been shown to normalize adiponectin synthesis and secretion.23 Men with low testosterone are 5 times more likely to have NAFLD than men with high normal testosterone, even after adjusting for BMI and blood lipids.24 And men with HCV who are undergoing standard treatment with interferon, or who already have advanced disease, are at risk for low testosterone levels.25,26

Depressed levels of antioxidants have been found in HCV; blood levels of glutathione, vitamins A,C, and E and selenium were found to be significantly lower than in matched HCV-negative controls.27 These levels were accompanied by elevated levels of oxidant stress markers that correlated with steatosis and fibrosis in these patients. Evidence of oxidant stress is also seen in HCV patients with minimal fibrosis. Impaired oxidation of free fatty acids causing oxidant stress in the liver is one of the mechanisms for steatosis in HCV, and hyperactivity of nitric oxide synthase, impaired mitochondrial function, and net depletion of antioxidants such as glutathione are all thought to contribute as triggers for steatosis.28
Vitamin E specifically quenches free radicals found in hepatic tissue. A small study in HCV patients with 1200 IU alpha-tocopherol for 8 weeks resulted in blockage of the pathway for stellate cell activation, preventing steatosis and fibrosis progression and an improvement in liver biopsy.29 Other antioxidants, including zinc, N-acetylcysteine, and betaine, are under study for their ability to inhibit steatosis and subsequent fibrosis in HCV.30,31 Low serum zinc levels are observed in hepatic fibrosis and hepatic encephalopathy and recently have been shown to correlate with insulin resistance in HCV.32 Serum zinc is also inversely correlated with serum ferritin, and high ferritin levels are a common finding in both HCV NAFLD and NAFLD in the general population. Historically, dosing studies with zinc have been limited to extremely high doses of 400 to 600 mg zinc oxide in alcoholic cirrhosis-related hepatic encephalopathy. Recent studies, however, using 35 mg elemental zinc (as zinc L-carnosine) have shown dramatic improvements in necroinflammation, particularly in HCV patients with iron overload.33

Vitamin D
Vitamin D deficiency has been commonly reported in HCV patients, and low vitamin D in HCV infection is correlated with liver fibrosis.34,35 Vitamin D has also been shown to reduce the extent of hepatic lipid peroxidation in animal models, which suggests that it modulates oxidative stress in viral hepatitis.36 Because low blood vitamin D has been shown to impair ability to respond to standard treatment and supplementation during treatment to improve chances of response to standard treatment, assessing D levels and supplementation D in HCV is becoming more accepted.37

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