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Hepatitis C and alcohol

Hepatitis C and alcohol
Literature review current through: Jan 2024.
This topic last updated: Dec 13, 2021.

INTRODUCTION — Chronic hepatitis C virus (HCV) and alcohol are common causes of chronic liver diseases in the United States, and both are recognized as major causes of liver disease worldwide [1]. Each poses a major public and economic burden to society, and when the two coexist they appear to have a synergistic effect in the progression of chronic liver disease.

This topic will review the effect of alcohol on the natural history and treatment of hepatitis C. Other issues related to hepatitis C and alcohol-associated liver disease are discussed separately.

(See "Epidemiology and transmission of hepatitis C virus infection".)

(See "Screening and diagnosis of chronic hepatitis C virus infection".)

(See "Clinical manifestations and natural history of chronic hepatitis C virus infection".)

(See "Overview of the management of chronic hepatitis C virus infection".)

(See "Clinical manifestations, diagnosis, and treatment of acute hepatitis C virus infection in adults".)

(See "Pathogenesis of alcohol-associated liver disease".)

(See "Clinical manifestations and diagnosis of alcohol-associated fatty liver disease and cirrhosis".)

(See "Management of alcohol-associated steatosis and alcohol-associated cirrhosis".)

EPIDEMIOLOGY OF HEPATITIS C IN PATIENTS WITH AN ALCOHOL USE DISORDER — The prevalence of HCV infection in patients with a history of alcohol abuse is significantly higher than that seen in the general population. Initial reports that were based upon first-generation enzyme-linked immunosorbent assays documented a prevalence of HCV antibodies as high as 45 percent [2,3]. Subsequent studies that used more accurate tests like recombinant immunoblot assays (RIBA-I, RIBA-II) and polymerase chain reaction (PCR) found a lower prevalence (14 to 36 percent), but still substantially increased compared to the general population [4-8]. The prevalence of HCV among patients hospitalized with alcohol-related disorders is also increased (15 percent in one report) [9]. In a study of US veterans with hepatitis C, 44 percent had a history of alcohol abuse or dependence [10].

The reason for the higher incidence of HCV infection among those with an alcohol use disorder is incompletely understood. An increased prevalence of high-risk behaviors (such as intravenous drug abuse) among patients with an alcohol use disorder has been observed in some reports [11-13], although others have not detected this association [14,15]. Most of the studies did not address other potential risk factors, such as cocaine snorting, tattoos, body piercing, and a history of sexually transmitted diseases. Understanding of hepatitis C epidemiology remains elusive and there is a need to improve the tools used to measure practices that can be associated with HCV transmission and are not usually volunteered [16,17].

EFFECT OF ALCOHOL ON THE NATURAL HISTORY OF HEPATITIS C — Several studies have focused on identifying how alcohol affects the natural history of HCV and liver disease. Three observations have emerged from an increasing body of data on alcohol consumption in patients with chronic HCV. Heavy alcohol use:

Accelerates fibrosis progression and increases the risk of cirrhosis

Predicts increased mortality

Increases the risk of hepatocellular carcinoma

Acceleration of fibrosis and cirrhosis — A consistent observation has been that patients who are infected with hepatitis C and consume alcohol are at increased risk for progression to cirrhosis [18-28]. An illustrative study included 2235 patients with chronic hepatitis C in whom three independent factors were associated with increased rate of fibrosis progression [18]:

Age at infection (older than 40 years)

Male sex

Daily alcohol consumption of 50 g or more

Daily alcohol consumption of 50 g or greater was associated with a 34 percent increase in the rate of fibrosis progression, which was defined as the ratio between the histological fibrosis stage (five-point scale: 0 = no fibrosis to 4 = cirrhosis) and the estimated duration of infection in years. Other potential risk factors, such as the genotype, quantity of HCV RNA, and mode of acquisition of hepatitis C infection, were not associated with higher fibrosis progression. A standard drink contains 12 g of alcohol and is equivalent to 360 mL (12 oz) of beer, 150 mL (5 oz) of wine, or 45 mL (1.5 oz) of whiskey or other 80 proof distilled spirits.

Similar conclusions were reached in another report that focused on 1667 HCV-positive injection drug users who were followed for a median of nine years [27]. The relative risk of end-stage liver disease was increased almost fourfold for those who drank more than 260 g of alcohol per week (RR 3.6, 95% CI 1.73 to 7.52).

A meta-analysis pooled data from 16 studies involving more than 15,000 patients looking at the impact of alcohol on those with HCV. With regard to the combined outcome (cirrhosis or decompensated cirrhosis), heavy alcohol use (>240 to 560 g/week) was associated with an increased risk when compared to those with less than heavy use (RR 2.33, 95% CI 1.67-3.26) [29].

A prospective study of United States veterans compared with non-veterans with hepatitis C infection found that veterans were older and had higher lifetime alcohol consumption than non-veterans, but their median fibrosis scores did not differ from non-veterans [30]. However, fibrosis in non-veterans was significantly associated with increased alcohol consumption (men >150 kg lifetime: four to five drinks per day for >10 years; women >100 kg lifetime: >3 drinks per day for >10 years) [30].

The exact amount of alcohol that increases the risk of HCC in patients with HCV is unknown but it appears that even modest alcohol use can accelerate fibrosis [31]. This was illustrated in a study of 800 patients with HCV who underwent liver biopsies and in whom a detailed alcohol history was assessed. A spectrum of fibrosis was observed for each category of alcohol intake (none, light, moderate, and heavy).

Another study of 3404 newly referred patients with hepatitis C identified factors associated with severe liver disease (ie, cirrhosis or liver cancer) [32]. Patients with severe liver disease were more likely to have past excessive alcohol consumption defined as >21 glasses per week for women, >28 glasses per week for men (adjusted OR 2.6, 95% CI 1.9-3.5). While this observation was significant in those with >5 years of excessive alcohol use, it was not seen in those with <5 years of excessive alcohol use.

Increase in mortality — Concomitant alcohol abuse has been associated with increased mortality in patients with HCV [28,33-35].

One study in a referral center found significantly increased five-year mortality in patients with HCV and alcohol abuse compared with HCV alone (28 versus 10 percent) [33].

Another study evaluated more than 7 million death records in the United States from 2000 to 2002 [34]. Patients were categorized as having HCV without heavy alcohol use (HAU), HAU without HCV, HCV plus HAU, and all others. Among men, those with HAU and HCV had a significantly lower mean age of death when compared with those with HCV alone (50 versus 55 years). A similar observation was seen in women (49 versus 61 years).

Risk of hepatocellular carcinoma — A growing number of studies have demonstrated that patients with alcohol-associated liver disease who are infected with HCV are at increased risk for the development of hepatocellular carcinoma (HCC) compared with those with HCV alone [36-42] (see "Epidemiology and risk factors for hepatocellular carcinoma"). The mechanisms underlying this interaction are poorly understood. The following examples illustrate the range of findings:

A case control study included 305 patients with newly diagnosed HCC (of whom 122 were HCV RNA positive) who were compared to 610 controls without liver disease [38]. The risk of HCC was increased 26-fold in patients who were HCV RNA positive (Odds ratio 26.3, 95% CI 15.8 to 44). The risk was increased 126-fold among patients who were HCV RNA positive who consumed more than 80 g/day of alcohol (Odds ratio 126, 95% CI 42.8 to 373). An additional finding from this study was an increased risk of HCC in patients with concomitant infection with hepatitis B (Odds ratio 132, 95% CI 15.3 to 54.0), a finding that has been confirmed in several other studies [39-41].

A prospective cohort study included 290 consecutive patients with cirrhosis (69 percent of whom were positive for HCV antibodies) who were followed with periodic ultrasound examinations [40]. During an average follow-up of 46 months, HCC developed in 32 patients (11 percent), including 20 percent of those who were HBsAg positive, 12 percent of those who were HCV antibody positive, and 14 percent of those with a history of alcohol abuse. On multivariate analysis, independent predictors of the development of HCC included positivity for HBsAg and HCV antibodies, male sex, and alcohol abuse. These results were comparable to an earlier prospective study with a similar design [41].

A case-control study included 115 cases who were compared with 230 controls with non-liver cancer [42]. On multivariate analysis, independent predictors of HCC included antibodies against HCV or HBV, heavy alcohol consumption, and diabetes mellitus. The risk appeared to be synergistic.

In one small study, bile duct dysplasia was found to be associated with chronic HCV and alcohol cirrhosis. Of 19 cases of dysplasia, 19 were in the setting of HCV and 4 out of 19 were in the setting of combined HCV and alcohol use [43].

PATHOGENESIS OF ACCELERATED INJURY — The mechanisms underlying the interaction between alcohol, hepatitis C, and liver disease are incompletely understood and are likely beyond that of just additive injury. There are several theories regarding the interaction of alcohol and hepatitis C (algorithm 1):

Alcohol increases HCV replication

Alcohol and HCV affect host cellular immunity

Alcohol and HCV increase oxidative stress

Alcohol increases HCV quasispecies

Effect of alcohol on HCV replication — One possible explanation for worsened outcome in alcohol consuming patients is that alcohol may increase HCV replication. Several in vitro studies have demonstrated upregulation of HCV replication (about a threefold increase at 96 hours) and protein expression in cells treated in an alcohol rich environment [44-46]. Disparate data have also been published, although differences in experimental techniques may have accounted for the varying results [47].

Several studies have also suggested that HCV RNA is increased in drinkers compared with nondrinkers [10,18,30,48]. However, the strength of this association is unclear. A meta-analysis of 14 studies found no significant association between HCV RNA levels and the amount of alcohol consumption [49].

Other authors have looked at the acute effect of alcohol on HCV levels in patients. One such report included 21 patients with chronic hepatitis C who were randomly assigned to receive a single dose of alcohol (50 g) versus placebo [50]. No significant effects on HCV RNA were detected.

Alcohol affects host cellular immunity — Several studies have evaluated the interaction of HCV and alcohol on host cellular immunity [47,51-55]. The following general observations have been made:

Alcohol influences hepatocyte transduction pathways possibly acting with HCV to induce alterations in cellular responses to HCV.

Host dendritic cells are modulated by HCV infection and by alcohol. The presence of HCV proteins (core and NS3) reduced dendritic cell differentiation in vitro while alcohol further reduced dendritic cell function by decreasing T cell stimulation and interferon production [53,55]. These effects inhibited the antiviral response. Animal models of long-term alcohol consumption have also demonstrated an impaired cellular immune response to HCV infection attributable to altered dendritic cell function [53].

The presence of alcohol inhibits the antiviral actions of exogenous interferon [49].

Alcohol consumption did not influence T cell immune responses (interferon gamma and IL-10 production) in HCV or HCV/HIV coinfected patients [54].

Alcohol and HCV increase oxidative stress — Alcohol intake increases oxidative stress in patients with HCV. An illustrative study compared measures of oxidative stress in 145 patients with chronic hepatitis C virus, 20 heavy drinkers without HCV, and 50 controls [56]. The risk of developing oxidative stress during chronic hepatitis C infection was increased threefold by moderate alcohol intake (<50gm ethanol/day) and 13- to 24-fold in chronic hepatitis C patients with heavy alcohol intake (>50 gm ethanol/day). The authors conclude that HCV and alcohol act synergistically in stimulating free radical generation as well affecting antioxidant defenses.

In vivo observations are further confirmed with in vitro studies. In studies of hepatoma cells, HCV protein, enhanced CYP2E1 expression, and alcohol acted synergistically to enhance reactive oxygen species and sensitize cells to mitochondrial depolarization and cell death by TNF or oxidative stress [57].

HCV alters the redox state of hepatocytes leading to changes in mitochondrial structure and function. As an example, the HCV NS5a protein appears to contribute to development of reactive oxygen species in mitochondria and endoplasmic reticulum (ER). HCV core protein induces ER stress, an effect exacerbated by alcohol, thereby further oxidizing the mitochondrial antioxidant (glutathione) pool [58]. Oxidative stress may contribute to liver injury and impair liver regeneration [56,59].

Alcohol increases HCV quasispecies — Hepatitis C exists as closely related "quasispecies". Alcohol increases the diversity of HCV quasispecies by mechanisms that are poorly understood. One theory is that the generation of reactive oxygen species (see above) increases the mutation rate of the HCV genome, thereby driving viral evolution [60].

However, the clinical implications of alcohol and HCV quasispecies diversification are unclear. On the one hand, increased quasispecies complexity has been associated with poor responsiveness to interferon-alfa, possibly contributing to the decreased responsiveness of patients with an alcohol use disorder and HCV to interferon treatment [61]. (See 'Effect of alcohol on treatment of hepatitis C' below.)

On the other hand, low quasispecies diversification has been associated with more severe disease [62]. This may reflect immune failure and/or selective outgrowth of aggressive viral variants. In one such report, alcohol had no significant association between the degree of quasispecies diversification and the severity of liver disease [62].

HISTOPATHOLOGIC CORRELATES — Liver histology in patients with alcohol-associated liver disease and HCV may demonstrate the typical histologic features of alcohol-associated liver disease, such as macrovesicular steatosis, polymorphonuclear infiltrate, hepatocyte ballooning, and Mallory bodies. Superimposed features of chronic hepatitis, such as periportal necrosis, portal inflammation, lymphoid aggregates in the portal tracts, and lymphocytosis in the sinusoids, are also commonly present [14,63,64]. As expected, there is a higher risk of fibrosis seen in consumers of alcohol (>50 g/day) versus those with lower intakes of alcohol on liver biopsy (figure 1). (See 'Acceleration of fibrosis and cirrhosis' above.)

EFFECT OF ALCOHOL ON TREATMENT OF HEPATITIS C — With the advent of new oral direct-acting antiviral (DAA) combination therapy for HCV treatment, HCV eradication became a reality for most patients, regardless of HCV genotype or liver fibrosis stage. Clinical studies that defined the current doses and lengths of effective HCV DAA therapies required no or negligible alcohol use during treatment. Thus, to date, there are no data as to how the oral anti-HCV therapies would perform in patients with ongoing alcohol use [65]. Given that the action of the serine protease inhibitors involves enabling the host endogenous type I interferon pathways that can be inhibited by alcohol use itself, patients most likely should avoid alcohol use during anti-HCV therapy, even with the new oral agents.

Ongoing alcohol use decreases the efficacy of interferon-based treatment of HCV [44,48,66,67]. The reason for the decreased responsiveness is incompletely understood. It may in part be due to decreased compliance, although several biological mechanisms have also been hypothesized, such as potentiation of HCV replication [44,45,68,69]. (See 'Pathogenesis of accelerated injury' above.)

By contrast, data regarding the impact of past alcohol use (more than six months prior to therapy) are conflicting. Considered together, the studies suggest that past alcohol use has no impact on treatment [68,70-72].

HOW MUCH ALCOHOL IS TOO MUCH? — The amount of alcohol required to increase the risk of disease progression in patients with HCV has not been well defined. Although most of the studies discussed above included patients with alcohol intake of >50 g/day, more modest alcohol intake (<140 g/week) has been associated with increased HCV viremia and hepatic fibrosis [21]. Even modest alcohol intake is associated with increased oxidative stress [56].

A standard drink contains 12 g of alcohol and is equivalent to 360 mL (12 oz) of beer, 150 mL (5 oz) of wine, and 45 mL (1.5 oz) of whiskey or other 80 proof distilled spirits. Thus, modest alcohol intake translates into approximately two standard size beers per day, an amount that can easily be considered social drinking. Thus, a conservative recommendation that can be unambiguously interpreted when counseling patients is that alcohol should be avoided altogether, particularly prior to antiviral treatment.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hepatitis C virus infection".)

SUMMARY AND RECOMMENDATIONS

Chronic hepatitis C and alcoholism are common causes of liver diseases in the United States and in many other countries. (See 'Epidemiology of hepatitis C in patients with an alcohol use disorder' above.)

Alcohol and HCV appear to act synergistically in promoting progression to cirrhosis and increasing the risk of hepatocellular carcinoma. (See 'Effect of alcohol on the natural history of hepatitis C' above.)

Clinical studies of direct-acting antivirals required no or minimal alcohol use, so the effect of alcohol on the efficacy of such regimens is uncertain. (See 'Effect of alcohol on treatment of hepatitis C' above.)

A safe threshold of alcohol consumption has not been established to date. As a result, we suggest total abstinence of alcohol in patients with chronic HCV, particularly before initiation and during antiviral therapy (Grade 2C). (See 'How much alcohol is too much?' above.)

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Topic 3585 Version 25.0

References

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