Alcoholic liver disease (ALD) and hepatitis C virus (HCV) infection represent, either alone or in combination, more than two thirds of all patients with liver disease in the Western world. This review discusses the epidemiology and combined impact of ALD and HCV on the progression of liver disease. ALD and HCV affect the progression of liver disease to liver cirrhosis and hepatocellular carcinoma (HCC) in a synergistic manner. Thus, the risk for HCC increases five times with a daily alcohol consumption of 80 g; in the presence of HCV it is increased 20-fold, and a combination of both risk factors leads to a more than 100-fold risk for HCC development. Alcohol consumption also decreases the response to interferon treatment which is probably due to a lack of compliance than a direct effect on HCV replication. Several molecular mechanisms are discussed that could explain the synergistic interaction of alcohol and HCV on disease progression. They include modulation of the immune response and apoptosis, increased oxidative stress via induction of CYP2E1 and the hepatic accumulation of iron. Thus, both HCV and alcohol independently cause hepatic iron accumulation in > 50% of patients probably due to suppression of the liver-secreted systemic iron hormone hepcidin. A better understanding of hepcidin regulation could help in developing novel therapeutic approaches to treat the chronic disease in the future. For now, it can be generally concluded that HCV-infected patients should abstain from alcohol and alcoholics should be encouraged to participate in detoxification programs.

Together, alcoholic liver disease (ALD) and chronic hepatitis C virus (HCV) infection are the most frequent chronic liver diseases in the Western world. In addition, they frequently coexist in the same individual. While both diseases alone have a similar progression sequence leading to cirrhosis in circa 15% of patients within 10-20 years, their coexistence dramatically enhances disease progression in a so-called synergistic manner. This synergism affects both fibrosis progression and the development of hepatocellular carcinoma (HCC). The basic molecular mechanisms of this synergism are far from being understood but may include increased production of reactive oxygen species (ROS) and deposition of iron. In the present article, we review and discuss the epidemiology of ALD and HCV infection, the synergistic impact of combined alcohol and HCV on the progression of liver disease, viral replication and response to anti-HCV treatment. We finally analyze potentially underlying mechanisms that may explain the interaction between alcohol and HCV and offer novel molecular strategies for future therapeutic interventions.

Chronic alcohol consumption causes approximately 50% of the chronic liver disease burden in Germany and the death of more than 18 000 inhabitants per year[1]. In the US alcohol is also responsible for more than 50% of liver related deaths, and ALD is a major health care cost expenditure, accounting for nearly $3 billion annually[2]. At present, the country with the fastest increase in alcohol associated health problems is the Peoples Republic of China with an annual per capita increase in alcohol consumption of 400% and more in some geographic regions[3]. The exact number of alcohol related deaths is difficult to obtain due to inaccurate reporting of ethanol use. Since patients with compensated liver cirrhosis may often die by causes not obviously related to liver disease e.g. infectious complications, official mortality tables most likely underestimate the true prevalence of ALD. If the relationship between alcohol intake and prevalence of ALD is examined on a population basis, the risk of developing ALD starts at 20-30 g ethanol per day. Liver cirrhosis develops only in 10%-20% of people consuming more than 80 g of ethanol daily[2]. Approximately 5% of the whole population in the US meet diagnostic criteria for alcoholism[4]. In Germany, more than 17.8% of the population > 18 years drink more than 20-30 g of alcohol per day[5], and a comparable number of 5% show high risk drinking behavior (> 80 g/d)[5].

In contrast to ALD, the prevalence of HCV is easier to determine based on serological studies. The worldwide seroprevalence of HCV antibodies is estimated to be 3% with marked geographic variations from 1% in North America to 10% in North Africa[6]. The prevalence is higher in males than in females (2.5% vs 1.2%) and is highest in the 30-49 years old age group[7]. Taken together, there is an estimated prevalence of high risk drinking and HCV of 1%-5% in the Western world. According to recent data from the Center of Disease Control and Prevention, the prevalence of HCV and ALD is relatively similar at 26% and 24%, respectively. Although there is a selection bias, these prevalence data are somehow reflected by large transplant centers. In our transplant center at the University of Heidelberg, liver cirrhosis due to HCV and ALD are leading causes for liver transplantation accounting for 32% and 24%, respectively, of all liver transplantations. In summary, HCV and ALD represent either alone or in combination, more than two thirds of all patients with liver disease in the Western world[8] (Figure 1).

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Figure 1 HCV and ALD, either in combination or alone, represent the majority of liver diseases (data from the US Centers of Disease Control and Prevention 2007). HCV: Hepatitis C virus; ALD: Alcoholic liver disease; HBV: Hepatitis B virus.

ALD is the most important organ manifestation of chronic alcohol consumption. Ninety percent to one hundred percent of heavy drinkers develop alcoholic fatty liver. Ten percent to thirty-five percent of them develop alcoholic steatohepatitis and 8%-20% develop alcoholic liver cirrhosis within 10-20 years[9]. The natural course of ALD and HCV is given in Figure 2. Due to better treatment options for complications of liver cirrhosis e.g. variceal bleeding, the prevalence of HCC is increasing with an annual risk of 1%-2%. HCC represents the most common cause of death in patients with ALD. HCV shows a similar progression pattern. In a US study, the mean interval between HCV infection, chronic hepatitis, cirrhosis and HCC was circa 10, 20 and 30 years, respectively[10]. A large cohort study with long-term follow up showed that 75% of HCV-infected patients develop persistent infection while severe progressive liver disease occurred in 15%-20%[11].

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Figure 2 Natural course of ALD and HCV alone or in combination. Estimated risk and time interval for disease states are indicated (for more details see text).

Factors that contribute to progression of ALD and HCV are summarized in Table 1. For ALD, these include the amount of alcohol consumed over a life time[1213], drinking patterns, and nutritional status. Both malnutrition and obesity are associated with an increased risk for alcoholic cirrhosis[14–16]. This is especially relevant with the endemic occurrence of non-alcoholic fatty liver disease (NAFLD) in the Western World due to obesity and being overweight associated with diabetes mellitus type II and peripheral insulin resistance. Co-medication of certain drugs together with ethanol may also harm the liver by increased conversion to toxic metabolites due to induced enzyme systems. This is well known for acetaminophen[17], methotrexate[18] and the tuberculostatic drug isoniazid[17] but also occurs with retinoids such as β-carotin and vitamin A[19]. Males and females show different courses of ALD and HCV. While females are more susceptible to alcoholic damage, they progress slower in chronic HCV infection. Other important factors that contribute to disease progression in ALD are co-morbidities such as HBV, hemochromatosis, and Wilson’s disease. Factors associated with HCV progression are co-infection with HBV, HIV, schistosomiasis or conditions of immunosuppression. Finally, iron accumulation has been recognized both in ALD and HCV as an independent risk factor for the development of HCC. Pathological hepatocellular iron deposits are found in more than 50% of patients with either HCV or ALD. Underlying mechanisms and potential therapeutic options are still under investigation.

Chronic alcoholics have an increased prevalence of HCV infection, increasing with the severity of the ALD. Takase et al[20] showed that HCV prevalence demonstrated by anti-HCV positivity increases with the severity of ALD, having a prevalence of approximately 5% in alcoholic fibrosis, almost 40% in alcoholic cirrhosis and almost in 80% in HCC due to alcohol. This could be due to the lifestyle of chronic alcoholics, since many of them are also intravenous drug abusers, which is a high risk for HCV infection. It could also be due to the immunosuppressive effect of alcohol decreasing the HCV-clearance rate after infection since it has been shown that alcohol suppresses the function of various immune components including natural killer cells, neutrophils, monocytes and others[21].

A great number of studies emphasize the fact that alcoholics respond poorly to interferon therapy. More than ten years ago, Mochida et al[22] showed that almost 30% of non-alcoholics responded biochemically and virologically to interferon therapy compared to less than 10% of alcoholics. The question remained open whether this is due to a direct inhibitory effect of alcohol on interferon response or due to poor compliance of these patients. Pessione et al[23] studied serum HCV RNA in HCV patients with increasing alcohol intake (reported in gram per week). In this study a significant dose-dependent increase in serum HCV RNA was noted starting from 70 g alcohol per week. In line with this observation, a decrease of alcohol consumption prior treatment of hepatitis C significantly reduced viral load. In addition, Cromie et al[24] showed that viral load decreased highly significantly within 4 mo when patients cut down on alcohol consumption from 39-100 g/d to 0-50 g/d. More recent data, however, clearly suggest that the poor response of alcoholics towards interferon therapy is more likely due to reduced compliance. In this study, the recorded alcohol consumption during the months before HCV treatment was associated with an increased rate of therapy drop out (3% vs 26%, P = 0.002)[25] while the response rate was comparable (25% vs 23%) after correction for this confounding factor. In conclusion, poor compliance of alcoholics is probably the major cause for poor antiviral response to HCV therapy.

A huge number of studies have shown that concomitant alcohol consumption in the presence of HCV increases progression of fibrosis[2326–54]. This means that fibrosis occurs at an earlier time point and its development is accelerated. A summary of selected studies on alcohol consumption and fibrosis progression is given in Table 2. Thus, it has been shown in more than 2000 HCV patients that fibrosis progression was significant (P < 0.001) if more than 50 g/d alcohol is consumed[26]. Similar results were obtained by Roudot-Thoraval et al[27] with a prevalence of cirrhosis of 35 % vs 18 % (P < 0.001). Pessione showed in more than 200 HCV patients that weekly alcohol consumption correlated significantly with fibrosis score[23]. He also showed that the relative risk for decompensated cirrhosis correlated with alcohol intake. Alcohol-driven fibrogenesis in HCV patients is dose-dependent and starts at less than 30 g/d. Overweight and obese patients as well as type II diabetics are especially sensitive to fibrosis progression[55]. HCV patients with excessive alcohol abuse have a 2-3 fold increased risk of severe liver disease compared with HCV patients without a history of drinking[56]. So far it is still unclear how long a patient has to abstain from alcohol before the negative effect of alcohol is abolished[57]. Alcoholics with HCV infection seem to stop drinking more frequently compared to alcoholics without HCV infection. This is possibly due to a higher awareness in these patients that liver disease can lead to cirrhosis and death without a change in lifestyle[58]. Finally, it has been a continuous debate whether small amounts of alcohol (< 20-30 g/d) alter progression in HCV infection. An answer may come from a Scandinavian study by Westin et al[59]. These authors investigated 78 patients with hepatitis C infection who underwent two liver biopsies in a mean interval of 6.3 years. Alcohol consumption was less than 40 g/d. The authors found progressive fibrosis with (a) increased total alcohol consumption (15.4 kg vs 3.9 kg; P = 0.007), (b) increased daily alcohol consumption (5.7 g vs 2.6 g/d; P = 0.03) and (c) increased frequency of drinking occasions (35 vs 8 d per year; P = 0.006). These results underscore that even small amounts of alcohol may increase fibrosis progression in HCV. Confirmation comes from another prospective study by Hezode et al[60] who showed an impact of mild alcohol consumption on histological activity and fibrosis starting as low as 20 g/d.

Various studies have shown that there is an increased risk of HCC in patients with HCV and alcohol abuse compared to either HCV or ALD alone[61–68]. Since these studies vary considerably in their definition of alcohol abuse, Table 3 is restricted to comparable studies that tried to identify the independent contribution of HCV and ALD to HCC development. It can be concluded from these data, that a daily uptake of > 80 g alcohol alone increases HCC risk 5-fold while the presence of HCV alone increases HCC 20-fold. A combination of both risk factors increases the risk for HCC development over 100-fold. Thus, HCV and alcohol act truly synergistic on HCC development.

The underlying molecular mechanisms of alcohol and HCV-mediated liver disease are complex and they are still incompletely understood despite intensive efforts over decades.

Both alcohol and HCV can reproduce the four sequential hallmarks of liver disease: steatosis, steatohepatitis, fibrosis and HCC. Molecular key features of ethanol and HCV mediated liver damage include direct biochemical consequences of alcohol metabolism such as the production of acetaldehyde, generation of reactive oxygen species (ROS) and oxidative damage, epigenetic modifications such as hypomethylation of histones and modulation of the signaling machinery. Some of these events lead to similar downstream effects such as fatty liver, ROS and iron accumulation but are based on different mechanisms which could well explain the synergistic effects of alcohol and HCV on the liver. Thus, steatosis in HCV is mainly caused by impairment of mitochondria preventing mitochondrial metabolism of fatty acids, while ethanol primarily stimulates lipogenesis. On the other hand, HCV and ethanol both stimulate ROS generation via distinct mechanisms and they both lead to hepatic iron accumulation, one of the most pro-fibrogenic and pro-tumorigenic factors in liver disease. For this reason, ROS generation and iron accumulation are discussed separately below. It should also be mentioned that alcohol may have direct molecular effects on HCV infection since it exerts stimulatory effects on HCV replication probably via signaling pathways[69]. The enhanced quasispecies complexity in the hypervariable region 1 of HCV in alcoholics may be one major cause that sensitizes for faster disease progression[70].

Role of ROS in HCV and ALD

The generation of ROS seems to be a hallmark of both ALD and HCV[91–95] (Figure 3). While location and mechanisms of their generation differ markedly between ALD and HCV, downstream events of oxidative damage are similar due to the high but rather unspecific reactivity of species such as hydroxyl radicals or lipid peroxidation products. Hepatocyte mitochondria are structurally altered in more than 50% of HCV patients and these conditions are accompanied by a significant depletion of hepatocellular and lymphocyte glutathione (GSH), an increase of oxidized GSH (GSSG) and the lipid peroxidation marker malondialdehyde[91]. ROS are either induced directly by the virus or indirectly through activation of inflammatory cells. HCV core[96] and NS5A[9697] have been implicated in generating ROS via mitochondrial damage and calcium release.

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Figure 3 Potential molecular mechanisms that explain the synergistic effect of alcohol and HCV on the progression of liver disease. Reactive oxygen species (ROS) and iron accumulation seem to be key features of both diseases.

ROS also play an important role in alcohol-induced liver injury and in hepatocarcinogenesis[87–90]. Several enzyme systems are capable of producing ROS including the mitochondrial respiratory chain, the cytosolic enzymes xanthine oxidase and aldehyde oxidase, as well as the microsomal cytochrome P450-dependent mono-oxygenases[88]. One member of the latter system, cytochrome P450 2E1 (CYP2E1), is involved in the major pathway by which ethanol generates oxidative stress. Expression of CYP2E1 has been shown to correlate well with the generation of hydroxyethyl radicals and with LPO products such as 4-HNE and MDA[98]. CYP2E1 is induced by chronic alcohol consumption within a week even at a relatively low ethanol dose (40 g/d), but the degree of CYP2E1 induction shows high variations between individuals[99]. Inhibition of CYP2E1 by chlormethiazole, a specific CYP2E1 inhibitor, improved ALD as shown in the Tsukamoto-French rat model[100]. An increase of oxidative DNA adducts and of mutagenic apurinic and apyrimidinic DNA sites has been found in chronically ethanol-treated wild- type mice but not in mice that lack functional CYP2E1[101] further stressing the importance of CYP2E1 in the generation of DNA damage following ethanol ingestion. Increased levels of Cyp2E1 also potentiate pro-apoptotic effects of TGF-β resulting in increased cell death of hepatocytes[102]. Recently, we have been able to detect etheno-DNA adducts such as εdA in the livers of patients with ALD[89103].

Kupffer cells are also an important source of ROS during ethanol exposure[93] and in response to LPS[104]. NADPH oxidase-dependent production of ROS is implicated in ethanol-induced liver injury since p47phox -/- mice which are deficient in this regulatory subunit of NADPH oxidase are resistant to chronic ethanol-induced injury[105]. Chronic ethanol feeding increases the LPS-stimulated production of ROS by Kupffer cells; this increase is primarily due to an increase in NADPH oxidase activation after chronic ethanol feeding[81]. Recently, Thakur and colleagues have specifically identified NADPH oxidase-derived ROS as an important contributor to increased TLR-4 mediated signal transduction and TNF-α expression in rat Kupffer cells, particularly after chronic ethanol exposure[81].

ALD and HCV are the most common liver diseases in the Western world either alone or in combination. Coexistence of both diseases has a true synergistic effect on fibrosis progression and HCC development. Thus, a daily consumption of more than 80 g alcohol increases the risk for HCC 5-fold, in the presence of HCV 100-fold while HCV alone increases the risk for HCC 20-fold. Alcohol abusers have an increased prevalence of HCV infection probably due to lifestyle or to immune suppression. Alcoholics also have a decreased response rate to antiviral therapy which is most probably due to poor compliance. There is obviously no safe level of drinking in patients with hepatitis C and it remains unclear how long abstinence is necessary to abolish the negative effect of alcohol on the liver. Potential mechanisms which may explain the synergistic negative effect of alcohol and HCV infection on liver disease include generation of ROS, iron accumulation, steatosis induction, immune modulation, stimulation of HCV replication and direct DNA damage. Abstaining from drinking in HCV patients who do not respond to antiviral treatment is the sole efficient treatment option to date. A better understanding of the underlying molecular mechanisms could help to develop novel targeted treatment options.