Case Study: Statin Use in Chronic Hepatitis C Infection, NAFLD/NASH, Cirrhosis and Hepatocellular Carcinoma

Case Presentation:

G.S. is a 60-year-old male referred for cholesterol treatment complicated by background liver disease. He has a history of schizophrenia and chronic hepatitis C virus (HCV) diagnosed in 2016. He is asymptomatic and denied having any abdominal pain, jaundice, nausea/vomiting, fatigue or anorexia. He had no weight loss. A physical exam was unremarkable.

He was a moderate alcohol drinker who quit drinking in 2016. He smokes two packs of cigarettes a day and has no interest in quitting. His primary care provider does not want to put him on cholesterol medication because of his chronic liver disease.

Labs:

Total bilirubin, 0.4 mg/dl; direct bilirubin, 0.3 mg/dl; albumin, 4.1 gm/dl; ALT/SGPT, 70 IU/L; AST/SGOT, 68 IU/L; total protein, 7.4 g/dl; TC, 208 mg/dl; TG, 265 mg/dl; HDL, 36 mg/dl; LDL (direct), 139 mg/dl; cholesterol/HDL ratio, 5.8; Apo B, 92 mg/dl; Lp(a), 79 mg/dl; Hepatitis C viral load, 8.7 million international units/milliliter; hepatitis C virus, genotype 1A; fibrosis score, 0.47; fibrosis stage, F1-F2.

In 2015, the World Health Organization estimated that 71 million people were living with chronic hepatitis C virus (HCV) infection, a prevalence of 1%, with 1.75 million new cases that year (Global Hepatitis Report, 2017 World Health Organization). In the United States, the incidence of hepatitis C infection doubled between 2010 and 2014.(1) In 2015, the Centers for Disease Control and Prevention (CDC) estimated that from 2.7 million to 3.9 million people were living with chronic viral hepatitis C in the United States.(2) Certain investigators put the prevalence at up to 5.2 million, taking into account such specific populations as the incarcerated, the homeless, nursing home residents, people on military duty, and immigrants not included in the CDC count.(3,4,5) Chronic HCV is known to be associated with metabolic syndrome, insulin resistance and cardiovascular disease.(8,9) A Japanese study observed that a higher prevalence of patients with persistent hepatitis C infection had carotid plaque (p<0.0001) and carotid intima media thickening (p<0.05) compared to a control group.(6) Multivariate logistic regression analysis demonstrated persistent hepatitis C infection to be an independent predictor of carotid plaque with an odds ratio of 5.61 (95% CI 2.06-15.26. p<0.001). This was corroborated by another Japanese study.(7)

Chronic HCV infection is estimated to be responsible for 27% of cirrhosis and 25% of hepatocellular cancer worldwide.(10) HCV infection is one of the most common causes of chronic liver disease and the leading indicator for liver transplant worldwide.(11,12) It is estimated that from 10% to 25% of patients with chronic HCV infection will develop cirrhosis over the next 20 to 30 years and between 1% and 5% of chronic HCV patients will develop hepatocellular carcinoma (HCC).(12)

Treatment of HCV infection has evolved from a relatively affordable combination of Discuss this article at www.lipid.org/lipidspin interferon to a combination of pegylated interferon and ribavirin, to the more expensive, more effective and better tolerated direct-acting antiviral agents (DAAs).

Understanding of HCV genotype is important to decide on a suitable therapeutic strategy.(13,14) Genotype 1 is the predominant HCV in the United States and Japan.(16) However, the sustained virological response (SVR) rate of this genotype to a combination of pegylated interferon and ribavirin is less than 50%. Stratified analysis of HCV genotypes showed the addition of statin resulted in an enhanced beneficial effect in SVR in genotype 1 patients (RR=1.51; 95% CI:1.26 -1.80; P<0.001), and this benefit lost significance in HCV type 2 and HCV type 3 patients (a difference that may be a result of the small sample size of genotype 2 and genotype 3).(15) On the contrary, HCV genotype 2 and genotype 3 have higher SVR rates and cure rates compared to genotype 1.(15)

Different statins show different effects on SVR rates. Ikeda M., et al., examined five statins (atorvastatin, fluvastatin, lovastatin, pravastatin and simvastatin) and noted that fluvastatin exhibited the strongest anti-HCV activity, while atorvastatin and simvastatin displayed moderate inhibitory effects. Lovastatin exhibited the weakest activity and pravastatin had no anti-HCV activity. 16) The combination of these statins with pegylated interferon and ribavirin (with the exception of pravastatin), demonstrated strong inhibitory effects of HCV ribonucleic acid (RNA) replication.(16) Pitavastatin showed a larger beneficial effect in increasing the SVR rate than fluvastatin (RR=1.46; 95% CI: 1.23-1.74; P<0.001). (15) The combination of statins (with the exception of pravastatin) with pegylated interferon and ribavirin was shown to be associated with a 31% increase in the SVR rate in chronic HCV patients.(15) This combination also improved early virological response (EVR) and rapid virological response (RVR).(17) In vitro studies by Delang, et al., showed that statins may delay or prevent development of resistant HCV strains.(55)

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“HCV infection is one of the most common causes of chronic liver disease and the leading indicator for liver transplant worldwide.”

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The inhibitory effects of statins on HCV RNA replication occurs via a mechanism different from induction of the type 1 interferon signaling pathway.(18) HCV replication is dependent on lipid rafts present on endoplasmic reticulum and golgi membranes, which are involved in cell signaling and intracellular trafficking. HMG-CoA reductase (3-hydroxy-3-methylglutaryl-coenzyme A reductase) leads to intracellular mevalonate and isoprenoid geranylgeranyl pyrophosphate production. This is attached on specific G proteins by means of protein prenylation, which subsequently regulates a wide array of cellular functions. Geranylgeranyl pyrophosphate is required for HCV RNA replication. By blocking mevalonate and geranylgeranyl pyrophosphate production, HMG-CoA inhibitors disrupt HCV RNA replication.(19,20) Ikeda M., et al., developed a genome-length HCV RNA (strain O, of genotype 1b) replication reporter system and observed that the addition of mevalonate and geranylgeraniol to ORG cells restored HCV RNA replication.(16)

It also is thought that activation of Peroxisome proliferator-activated receptor alpha (PPAR-α) is another possible antiviral mechanism. PPAR-α activation results in the downregulation of nuclear factorkappa B (NF-ΚB), which has been shown to potentiate HCV RNA replication. (21) It therefore is thought that PPAR-α activation with resultant inhibition of NF-κB leads to decreased HCV replication in hepatocytes.(22) This also may explain why bezafibrate, which upregulates PPAR-α expression, caused 0.5 log reduction in serum HCV RNA titer and significant decrease in HCV RNA that is bound to low-density lipoprotein (LDL) in the blood.(22) It also has been suggested that targeting host lipid metabolism may be a potential, if novel, approach to improve response to HCV infection. This is based on the fact that HCV infectivity is partially dependent on LDL receptor.(23) Direct LDL receptor (LDL-R) involvement in early HCV infectivity is supported by the ability to inhibit HCV RNA accumulation with antibodies against LDL-R.(23) The participation of LDL-R in HCV infectivity also is indirectly supported by a direct relationship between a higher serum lowdensity lipoprotein cholesterol (LDL-C) and the likelihood of achieving a sustained virological response.(24,25)

Paradoxically, inhibition of HMG-CoA reductase by statins will result in the upregulation of LDL receptors, thereby causing increased clearance of LDL-C from the plasma and, consequently, increased hepatocyte infectivity.(26) It therefore is suggested that statins exert their antiviral effect through their non-receptor mechanisms.(26)

Although the benefits of statin use in cardiovascular disease (CVD) morbidity and mortality far outweigh the risks of

Table 1: Statin Effects and Mechanisms in Chronic Liver Disease

SVR, Sustained virological response; EVR, early virological response; RPR, rapid virological response; HCV, hepatitis C virus; SREBP, sterol regulatory element binding protein; NASH, non-alcoholic steatohepatitis; NAFLD, non-alcoholic fatty liver disease; HSC, hepatic stellate cell; NO, nitric oxide; eNOS, endothelial nitric oxide synthase; HMG-CPoA, 3-hydroxy-3-methyl-glutaryl-coenzyme A; PPAR, peroxisome proliferator-activated receptor

statin use, there remains a lingering safety concern among some healthcare professionals, especially with respect to hepatotoxicity, presence of baseline elevation of liver enzymes, or use in chronic liver disease. These concerns probably are a result of (i) the initial U.S. Food and Drug Administration labeling of statins as unsafe in liver disease, (ii) the executive summary of the National Cholesterol Education Program (NCEP) Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults (ATP III) recommendations on statin in liver disease and (iii) the occasional elevated aminotransferase levels associated with statin therapy.(33,34)

The Third National Health and Nutrition Survey (NHANES III) noted that, between 1988 and 1994, between 7% and 9% of the U.S. population had asymptomatic elevations of aminotransaminase attributable to non-alcoholic fatty liver disease (NAFLD), which includes fatty liver disease and non-alcoholic steatohepatitis, and HCV infection – representing the two most common causes – followed by alcoholic liver disease, viral hepatitis B infection and hemochromatosis.(32) These usually are followed by pathologic changes in the liver. Asymptomatic transaminitis – a term adopted to define this condition in which there is no accompanying pathological changes in the liver – is not uncommon during statin use. It usually is transient, reversible (even in the setting of continued statin use), often occurring within the first 12 weeks of statin use, and usually without associated histopathological changes.(27-30)

The mechanism of transaminitis arising from statin use is uncertain. However, it has been postulated that this may be from leakage of liver enzymes as a consequence of increased permeability stemming from changes in the lipid components of hepatocyte cell membranes.(29,31,35) Severe hepatotoxicity as a result of statin therapy is extremely rare.(29)

In the rare cases of statin-related hepatotoxicity, non-specific hepatocellular, cholestatic or mixed histologic findings have been observed. Consequently, it is suggested that the possible mechanism is an idiosyncratic or immunologic reaction. (29,30) Autoimmune hepatitis also may occur during statin therapy and should be suspected when aminotransferase levels remain persistently and significantly elevated – even after discontinuation of statin – especially when the markers of autoimmune disease such as autoantibodies and immunoglobulins are present.(38,39) Liver failure because of statin use is extremely rare – 1 per 114,000 patient years had been reported with lovastatin, which is similar to the incidence of idiopathic liver failure in the general population of 1 per 130,000 patient years.(31,40) Fulminant liver failure occurred in 3 of 51,741 cases of liver transplant patients on statin in the U.S, between 1990 and 2002.(41)

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“A statin prescription should be considered standard practice in the management of chronic liver disease.”

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Numerous statin trials – including the Scandinavian Simvastatin Survival Study (SSSS), the Prospective Simvastatin Pooling (PPP) project, the Heart Protection Study (HPS), and Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) – did not find any significant differences in aminotransferase levels between patients on statin compared with placebo. (30, 42-46) There is a direct relationship between statin dose and percentage rise in transaminitis.(47-49) Among those receiving low to moderate doses of statin, incidence of serum aminotransferase levels of more than 3 times the upper limit of normal was 1%, which is no different from placebo.(47) The incidence increases up to between 2% and 3% in patients receiving high doses of statins.(49-51) All statins of similar intensity have been observed to produce similar incidence of transaminase elevations, their different pharmacokinetics notwithstanding. Several trials have demonstrated spontaneous improvements of transaminitis in 70% of cases, even with continued statin use – an observation thought to be secondary to development of adaptation or tolerance. (37,52)

After reviewing post-marketing data regarding clinically serious hepatotoxicity during statin therapy between 2000 and 2009, and using data from the Adverse Event Reporting System (AERS) database and the Drug Induced Liver Network (DILIN), the FDA in 2012 made “important” safety label changes to cholesterol-lowering statin drugs and stated that because serious liver injury with statins is rare and unpredictable in individual patients, periodic monitoring of liver function is ineffective in detecting or preventing serious liver injury. The agency recommended that liver enzymes should be obtained before starting therapy with statin, and repeat liver enzymes may be obtained during treatment with statin if clinically indicated.(53)

Statins have been demonstrated to confer lower risk of decompensation and mortality in patients with compensated cirrhosis(65), (Table 1.) The development of the following forms of decompensation – including ascites and ascites-related compensations, hepatic encephalopathy and variceal bleeding – was decreased during concomitant statin use. However, statins have borderline beneficial effects on the decompensation of alcohol-related ascites.(81). Statins reduce interleukin 6 (IL-6) and C-reactive protein (CRP) levels. Higher levels are a marker of poor prognosis in cirrhosis.(80)

Several small-scale studies with simvastatin showed significant improvement in liver function and hepatic vascular resistance in cirrhotic portal hypertension. This was in addition to the extrahepatic effects of beta-blockers on portal hypertension(See table).(86) Statins also have been found to be beneficial in cases of cirrhotic portal hypertension that have not responded to beta-blockers.(87)

In small-scale studies, statin monotherapy showed mild antiviral effect. Direct antiviral agents achieve efficacy of up to 95%. Statins in combination with direct-acting antiviral agents have demonstrated increased antiviral efficacy. (88) The limiting factor is the potential for significant drug interactions with DAAs. (89) For instance, the combination of lovastatin and simvastatin with boceprevir and telaprevir should be avoided, while rosuvastatin can be used with these agents. (90) Atorvastatin should be avoided in HCV patients on telaprevir.(90) There is a potential risk in using pravastatin and boceprevir.(90) The interaction between pitavastatin and DAAs is not known.

In conclusion, a statin prescription should be considered standard practice in the management of chronic liver disease. Statins are relatively low-priced, have satisfactory safety profiles and proven benefits in decreasing cardiovascular events. Increased cardiovascular (CV) risk is seen in patients with chronic HCV infection, and there is evidence of benefit in lowering the incidence of progression of chronic HCV infections to cirrhosis of the liver, decompensation of compensated cirrhosis or HCC. Given the expected benefit and improved morbidity and mortality data, statins should be considered as attractive options in patients with abnormal liver function test, chronic HCV infection and chronic liver disease, in accordance with the current monitoring protocols by the Food and Drug Administration, National Lipid Association and NCEP ATP III. Clinically significant statin-associated adverse events are extremely rare. When a patient on statin develops transaminase >10x upper limit of normal, it is incumbent on the clinician to look for underlying causes by taking a complete medication history and a thorough medical history to exclude autoimmune hepatitis and immunologic or idiosyncratic reactions.(28,29,36,37)

Disclosure Statement: Dr. Nwizu has received honoraria from Medscape.