Alcohol and Hepatitis C

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Alcohol and Hepatitis CPosted 11/02/2004 Kamran Safdar, M.D.; Eugene R. Schiff, M.D. Abstract and IntroductionAbstractAlcohol abuse and hepatitis C virus (HCV) infection coexist with chronic liver disease in many patients. The mechanism of injury in these patients is probably multifactorial and involves, but is not limited to, a combination of diminished immune clearance of HCV, oxidative stress, emergence of HCV quasi-species, hepatic steatosis, increased iron stores, and increased rate of hepatocyte apoptosis. In patients with HCV infection, alcohol consumption is known to cause accelerated progression of liver fibrosis, higher frequency of cirrhosis, and increased incidence of hepatocellular carcinoma (HCC). These patients also have decreased survival as compared with patients with either alcohol abuse or HCV liver injury alone. Alcohol abuse causes

decreased response to interferon treatment in HCV patients. It is therefore necessary for patients with HCV infection to abstain from alcohol consumption.IntroductionChronic hepatitis C infection and alcohol abuse account for 70 to 90% of all the cases of chronic liver diseases in the western world. About 20% of chronic alcoholics and patients with hepatitis C infection develop cirrhosis over a period of 20 to 30 years[1,2] and a portion of these patients develop HCC.[3] Hepatitis C-related cirrhosis now accounts for more than 50% of all liver transplants performed in the United States.[4]The progression to cirrhosis in patients with chronic hepatitis C is affected by several variables. Published data show that viral genotype and viral load, although important predictors of response to treatment with interferon,[5] lack association with disease severity.[6] Besides the genetic factors in the host,[7] there are three other independent variables associated with

disease progression in patients infected with hepatitis C. These are age at infection > 40 years, heavy ethanol abuse > 50 g/d, and male gender.[8-10]EpidemiologySeveral studies have shown a high prevalence of anti-HCV using first-generation immunosorbent assay among alcoholic patients with liver disease.[11-15] Testing with recombinant immunoblot assays has shown that 8 to 43% of alcoholic patients with liver disease have anti-HCV. Most alcoholics with anti-HCV and liver disease also have HCV RNA (4 to 84%).[16-19] HCV RNA is detected in some alcoholic patients with liver disease who are anti-HCV negative.[20]There is no clear-cut explanation for increased prevalence of hepatitis C infection in alcoholics. Some studies have suggested that the increased prevalence of anti-HCV in alcoholics is primarily due to a past history of intravenous drug use (IVDU).[21-23] However, others have shown that there was no significant difference between the prevalence of

anti-HCV in alcoholics with and without risk factors (IVDU and blood transfusion) for contracting HCV.[24,25]Epidemiological studies also show a difference in the severity of HCV and alcoholism along gender and racial or ethnic lines. Socioeconomic status is a known risk factor for HCV and is probably a factor among alcoholic patients. African Americans and Hispanics have a higher prevalence of alcohol abuse and HCV.[26] In addition, African Americans have a higher prevalence of genotype 1b HCV and poor response to interferon treatment.[27] Furthermore, HCV is less common in women than in men, and the liver disease is milder and responds better to interferon treatment than in men. On the other hand, women who consume alcohol are more prone to develop liver disease and cirrhosis with relatively lower amounts of alcohol consumption.[28-31]Effect of Alcohol on Liver Fibrosis ProgressionOver the past decade, several studies have shown that alcohol increases the

progression of HCV to cirrhosis and HCC. Seef et al[32] reported that more than two thirds of deaths with end-stage liver disease secondary to non-A, non-B hepatitis occurred in alcoholic patients. The threshold level above which alcohol potentiates the progression of HCV disease is unknown. Approximately 10 g of alcohol is contained in 12 oz of regular beer, 5 oz of wine, or 1 oz of distilled spirits (80 proof). Excessive alcohol intake thought to potentiate the progression of chronic hepatitis C has been reported to be between 30 and 80 g/d in different studies. It has been shown that alcohol abuse accelerated the progression of hepatic injury in patients with HCV.[33-42] In 1997, Poynard et al showed that in patients with HCV who drank more than 50 g of alcohol per day there was a 34% increased rate of fibrosis as compared with those who drank less. In one study in which HCV was contracted via IVDU, it was noted that the relative risk of end-stage liver disease was 3.6 for

persons drinking > 37 g/d and 1.57 for those drinking 13 to 37 g/d.[37] In another study in which risk of developing HCV cirrhosis was evaluated after blood transfusions, it was found that the risk of cirrhosis was fourfold higher in those who drank > 80 g/d.[38]Unlike the case of heavy alcohol abuse, the effect of moderate amount of drinking and the progression of fibrosis in patients with HCV infection is not yet fully understood.[43] However a recent prospective study from France shows that both histological activity and fibrosis gradually increase with the amount of alcohol use and that even moderate alcohol consumption, as low as 31 to 50 g/d in men and 21 to 50 g/d in women, accelerates the histological lesions in chronic HCV patients.[44] In another retrospective study from Sweden, the effect of moderate alcohol consumption (< 40 g/d) on liver fibrosis progression in patients with HCV was analyzed.[45] Documented histological progression of liver disease was

most likely among those who consumed a greater amount of alcohol (5.7 g/d) and had a higher drinking frequency (drinking days per year) of 34.5 as compared with those who drank less (2.6 g/d) and had a lower drinking frequency of 8.2.Two studies from France have shown the impact of drinking on liver fibrosis progression in patients who are coinfected with HIV and HCV.[46,47] Drinking more than 50 to 80 g/d was associated with increased fibrosis progression and the risk of death from cirrhosis.Most epidemiological studies have shown that the effects of alcohol and hepatitis C on liver disease progression are synergistic.[48-51] Corrao and Arico[36] demonstrated that the relative risk for developing cirrhosis in alcohol abusers not infected with HCV was 15 as compared with 9 in HCV-infected patients who did not drink. However, the risk in HCV-infected alcohol abusers was 147. In addition, the interaction between lifetime daily alcohol intake (LDAI) and HCV was additive

at < 50 g/d and synergistic for > 50 g/d. However, one study showed that the effects of alcohol and HCV on cirrhosis were additive and not synergistic.[52]Pathogenesis of Liver InjuryThe mechanisms of advanced liver injury induced by coexisting alcohol and HCV are not fully understood. Various proposed mechanisms include immune dysfunction, increased viral replication, emergence of HCV quasi-species, apoptosis, steatosis, and hepatic iron overload. The typical histological pattern of liver injury in liver biopsies from alcoholic and HCV-infected patients is similar to that in nonalcoholic patients with chronic HCV.[21,52] Liver biopsy specimens from one study[53] showed that in 46 alcoholic patients with HCV RNA positivity lymphoid follicles were present in 34.7% and lymphoid aggregates in 93.3% of the portal tracts. These findings suggest that the hepatic injury in most alcoholics with HCV is due to hepatitis C infection rather than to alcoholic

injury.Alcohol, HCV, and Immunology. Acute alcohol ingestion results in generalized immunosuppression of the immune system.[54,55] It has also been suggested that alcohol abuse causes functional impairment of granulocytes, lymphocytes, and macrophages.[56-58] Plasma levels of proinflammatory cytokines tumor necrosis factor alpha (TNF-?), interleukin (IL)-6, and IL-8 are increased markedly in acute alcoholic hepatitis and correlate with disease severity.[59] Szabo et al[60] reported that alcohol causes decreased antigen-specific T cell proliferation because of impaired monocyte accessory function in association with raised concentrations of IL-10 and IL-13 and decreased concentrations of interferon-gamma (IFN-?). These effects in chronic HCV patients, unlike those seen in acute HCV infection, in whom there is a T helper (Th) 1 response, may in part result from a Th2 response that could explain a decrease in the clearance of the virus by the host.[61] One study in mice showed

that ethanol-fed mice have inhibition of Th and cytotoxic T-lymphocyte (CTL) responses to HCV core protein and reduced expression of cytokines.[62] On the other hand, several studies have shown that alcohol abuse is associated with increased numbers of activated lymphocytes in the blood even without liver disease.[63,64] There have been a few animal studies that showed that, in the presence of infection, alcohol consumption causes an enhanced inflammatory response in the liver.[65-67] Therefore, the immunosuppressive effect of alcohol probably impairs the clearance of HCV, and viral persistence results in an increased nonspecificinflammatory response. This response, consisting of macrophages and lymphocytes and proinflammatory cytokines, causes nonspecific liver damage. It has been shown that the most important immune response to HCV infection is the production of CD8+ CTLs.[68-70] These cells produce IFN-?, which inhibits the HCV virus from replication and also noncytolytically

clears it from the infected cells.[71]Although alcohol causes immunosuppression, this suppression is probably not complete. The antigen-specific CTLs that are produced in response to HCV infection migrate to the liver, where they cause apoptosis of infected hepatocytes via interaction of Fas ligand expressed on activated CTL and Fas on hepatocytes.[72,73] This action may be enhanced by alcohol[74] and other proinflammatory cytokines (TNF-?) produced by CTLs.[75] In addition, hepatocyte destruction by CTL is also influenced by perforin and granzyme-mediated mechanisms.[76] Finally, alcohol causes sensitization of hepatocytes to the immune-mediated response directed at the virus, either through metabolites of alcohol-like acetaldehyde or secondary to oxidative stress.[77]Therefore, in patients with alcohol and HCV, immunosuppression by alcohol further compromises HCV clearance. The persistence of HCV continues to fuel the interactions between lymphocytes and

hepatocytes that in turn lead to chronicity of HCV infection with all its sequelae.Alcohol, HCV, and Oxidative Stress. Oxidative stress is noted to be high both in patients with HCV[78-83] and in those who are alcoholics.[84-88] An increase in the formation of mitochondrial reactive oxygen species (ROS) has been reported as a cause of alcohol-induced oxidative stress.[89] Ethanol consumption also increases the formation of ROS by cytochrome P450-2E1, which enhances lipid peroxidation in both mice[90] and humans.[91] HCV core protein also causes oxidative damage[92-94] by triggering the release of increased mitochondrial ROS in association with cytochrome c. One recent study showed that the added effects of ethanol and HCV act synergistically to increase hepatic free radical formation and alteration of liver antioxidant defenses.[95] The same study reports that both moderate alcohol consumption (< 50 g/d) and heavy ethanol use (> 50 g/d) increases the risk of developing

oxidative stress 3-fold and 13-to 24-fold, respectively. It also was noted that among alcoholic HCV-positive patients, diffuse piecemeal necrosis was four times more frequent in those patients with lipid peroxidation antibodies than it was in those without these antibodies.Another study indicated that ethanol consumption and HCV additively increase hepatic lipid peroxidation.[96] Perlemuter et al[96] also showed a synergistic effect of alcohol and HCV on hepatic transforming growth factor beta (TGF-?) and TNF-? expression. TGF-? activates hepatic stellate cells (HSC) and stimulates production of more TGF-?, which is a stimulus for overproduction of extracellular matrix. Increased expression of TNF-? causes increased formation of ROS, which in turn may increase the hepatic fibrosis. Reactive lipid peroxidation products also cause somatic mutations and chromosomal alterations.[97,98] Moreover, oxidative stress activates nuclear transcription factor-kappa ? (NF-??),[99] which

plays a role in hepatic inflammation, liver injury and regeneration, and HCC.[100-102] In addition, ethanol and HCV core protein cause activation of NF-?? in hepatic cells.[103,104]Alcohol, Anti-HCV, and HCV RNA. There are several studies that show that alcoholic patients with anti-HCV have more severe liver damage than do antibody-negative patients.[19,20,105-109] There are conflicting reports about the effects of alcohol on serum HCV RNA. Some have suggested that chronic ethanol consumption leads to a higher viral load,[8,18-20,35,110] whereas others have not found a relationship between HCV RNA and the amount of drinking.[30,34,52,111,112] A study from Japan showed that patients with alcoholic cirrhosis and HCV RNA had higher alanine aminotransferase levels and histological indices of severe liver disease than did those without HCV RNA.[20] In another study from Japan[19] among patients with alcoholic liver disease, HCV RNA detection was highest in those with chronic

hepatitis (84%) and HCC (100%). An association between HCV RNA level and degree of hepatic damage was shown by Fanning et al,[113] but others have not confirmed it.[114,115] Two studies have tried to find a correlation between intrahepatic HCV RNA and level of alcohol consumption. One study found a relationship between daily ethanol use and intrahepatic HCV RNA but did not find a correlation between levels of intrahepatic HCV RNA and degree of hepatic injury.[116] The other study found that alcohol abuse did not alter intrahepatic HCV RNA.[117] A reduction in intake of ethanol has been shown by some,[18,111,118] but not by others,[112,117]to cause a decrease in serum HCV RNA. Last, alcohol may potentiate the HCV replicon expression via activation of NF-?? and the endogenous opioid system.[119]Alcohol and HCV Quasi-Species. Two studies have shown the effect of alcohol on HCV quasi-species. One study has shown that HCV quasi-species complexity increased in patients with

alcoholic liver disease.[120] Another study has suggested that alcoholics have increased quasi-species complexity in hypervariable region 1 of HCV.[121] Alcohol immunosuppression probably promotes the accumulation of multiple variants (quasi-species), which in turn causes viral escape from the immune onslaught.Hepatic Iron Overload. Hepatic iron concentrations were found to be significantly higher in HCV-positive patients with a history of alcohol abuse as compared with nonabusers.[122,123] Because increased hepatic iron stores enhances HCV disease progression,[124] the superimposed alcohol-induced iron deposition is likely to promote further hepatic fibrosis.Hepatocyte Apoptosis. As stated earlier, hepatocyte apoptosis occurs more frequently in HCV infections than in normal controls and is further enhanced by active ethanol consumption.[74] Binding of Fas ligand on CTLs to Fas receptor on hepatocytes results in caspase 8 activation, causing mitochondrial dysfunction

that leads to cell death.[125] A recent study indicated a higher rate of hepatocyte apoptosis and absent bcl-2 (inhibitor of apoptosis) expression in HCV patients who consumed more than 30 g/d of ethanol.[126] In contrast, patients who drank smaller amounts of alcohol had lower rates of apoptosis and more frequent expression of bcl-2. It has also been shown that cells expressing HCV core protein were sensitized to TNF-?-induced apoptosis.[127]Hepatic Steatosis. Steatosis is a common histological finding in patients with HCV.[128-132] Comorbidity with nonalcoholic steatosis or viral-induced steatosis as observed with HCV genotype 3 is often present. In some cases, alcohol has been identified as an independent risk factor in the pathogenesis of HCV-associated steatosis.[133] Alcohol-induced steatohepatitis potentiates liver fibrosis in HCV-infected patients.[134,135] In a recent study of patients with chronic HCV infection, extensive fibrosis or cirrhosis occurred in those

with moderate or severe steatosis independent of alcohol intake as well as in those with piecemeal necrosis.[136] The median progression rate of fibrosis was twice as high among drinkers with steatosis than it was among drinkers without steatosis or nondrinkers with or without steatosis.Alcohol and HIV/HCV Coinfection. Patients coinfected with HIV and HCV have increased rates of liver fibrosis.[46,47] Most coinfected patients have a past history of either IVDU or significant ethanol abuse. It has been suggested that coinfected patients who drank ethanol are more likely to die of end-stage liver disease.[137] Another study showed that coinfected patients who drank ethanol had a higher incidence of cirrhosis than did HCV-positive alcoholic patients who were HIV negative.[138]Alcohol, Hepatitis C, Cirrhosis, and SurvivalAll of these studies cited make it abundantly clear that alcoholic and HCV-positive patients have demonstrable increased rates of progressive

hepatitis and fibrosis, as compared with appropriate controls. The "Dionysos" study showed that alcoholics who drank more than 30 g/d of ethanol for more than 10 years had a threefold higher incidence for development of cirrhosis in both HCV-negative and -positive patients.[30] However, HCV-positive patients who drank more than 30 g/d had a 32% higher risk of developing cirrhosis as compared with those who drank less than 30 g/d. In their study, et al[139] proved that patients with HCV who drank more than 30 g/d of alcohol had an increased risk of fibrosis and a lower survival rate than did with those who drank less than 30 g/d. One report suggested a twofold to threefold increased risk of liver cirrhosis and decompensated liver disease in patients with HCV and a history of heavy alcohol abuse (women > 40 g/d, men > 60 g/d) for more than 5 years.[34] By the second decade, 58% were cirrhotic, compared with 10% in alcohol-free patients. Another study in patients with HCV

and alcohol excess demonstrated that patients who developed cirrhosis had a greater total and daily lifetime alcohol use.[10] The odds ratio was 1.16/100,000 g of ethanol consumed during life. Cirrhotic patients were also older both at the time of study and at the time of infection and had a longer duration of infection than did those who did not have cirrhosis.In a study by Niederau et al,[39] 838 HCV patients were followed for a period of 50 ± 27 months. During that time, survival was decreased by the presence of four factors: (1) cirrhosis, (2) long disease duration, (3) history of IVDU, and (4) excessive alcohol consumption. In patients who consumed > 80 g/d of ethanol, the risk ratio for death, liver transplantation, and clinical complications of liver disease was 2.3. A recent analysis showed a higher risk of death with an odds ratio of 1.14 in patients with HCV and alcohol abuse.[140] Patients were also younger at the time of hospitalization and had a higher death

rate compared with those who had either HCV or alcoholic liver disease alone.Alcohol, HCV, and HCCAlcoholic liver disease and HCV infection are both considered as risk factors for the development of HCC. The prevalence of anti-HCV in alcoholics with HCC range from 35 to 85%;[17,141-143] one Japanese study revealed that 100% of alcoholics with HCC were positive for HCV RNA.[19] Several authors have shown that the probability of developing HCC was significantly higher in alcoholics who were anti-HCV positive in contrast to those who were anti-HCV negative.[24,144,145] There is an increased incidence of HCC in patients with HCV and alcoholic liver disease.[50,51,146-156] Most of these studies have shown alcohol to be an independent risk factor for HCC in HCV-positive patients. In one study there was a 1.5- to 2.5-fold increased risk of cirrhosis and HCC in HCV-infected patients who consumed > 80 g/d of alcohol.[50] A later study found that HCV-infected patients who drank

ethanol heavily had a twofold greater risk of developing HCC than did those who were abstinent or light drinkers.[51]The time for the development of HCC was shorter in HCV-infected patients who drank alcohol excessively than it was for those who did not drink. Among HCV-positive patients who drank more than 46 g/d of ethanol, HCC developed in an average of 26 ± 6 years as compared with 31 ± 9 years for those who consumed less than 46 g/d.[154] The risk of HCC in HCV-infected patients with alcohol abuse was 8.3 times higher than it was in HCV-negative alcoholic patients. Heavy alcohol abuse results in the development of HCC at a younger age in HCV-infected patients.[157]The cumulative ratio of HCC in alcoholic cirrhosis without hepatitis B surface antigen or anti-HCV was 7 and 15% versus 20 and 50% in those with hepatitis B surface antigen or anti-HCV-positive patients at the end of the 5th and 10th year, respectively.[158] Kubo et al[159] showed that in HCC patients

with HCV and heavy ethanol abuse, the tumors were more anaplastic, with increased capsular, extracapsular, and portal vein invasion as well as intrahepatic metastasis. The survival time was shortened in these patients too. Heavy ethanol use also affected the long-term results of resection of HCV-related HCC. One study from Japan found the median disease-free survival time after HCC resection was 12.6 months in patients with HCV who consumed > 80 g/d of alcohol as compared with 25.4 months in patients who consumed < 80 g/d.[160] The exact mechanisms that promote the development of HCC in patients with HCV and alcohol are clearly not known.[161] Putative mechanisms include accelerated progression of fibrosis, oxidative stress, and potentiation of NF-?? activation by alcohol and HCV core protein. The binding of acetaldehyde to DNA, impaired DNA repair, activation of environmental precarcinogens, and dietary deficiencies have also been implicated in the pathogenesis of HCC in

alcoholic liver cirrhosis.[162]Effect of Alcohol on Interferon Treatment for HCVContinued alcohol consumption has been shown to decrease the response to interferon in patients with HCV infection.[163-165] Alcohol negatively influences the IFN-based therapy for HCV by decreasing the compliance to treatment regimen and adversely affecting antiviral actions of IFN. Concurrent alcohol use has been considered as a contraindication during the treatment for HCV. Preferably, the patient should be abstinent for at least 6 to 12 months before initiation of treatment with interferon. Studies from Japan showed that patients with HCV infection and heavy ethanol abuse had the highest levels of HCV RNA,[18] lower efficacy of IFN,[166] and partial benefit from abstinence before treatment initiation.[167] During IFN treatment, HCV RNA clearance is related to cumulative alcohol consumption and HCV RNA levels.[168] In this study, 56% of the patients discontinued ethanol for at least 1

month before the initiation of IFN treatment.Loguercio et al[110] showed that there was a direct relationship between alcohol use (< 40 g/d or > 80 g/d) and response to IFN treatment. They found that the number of sustained responders decreased as alcohol consumption increased.An Italian study examined the effects of IFN treatment in HCV-positive patients whose alanine aminotransferase levels remained twice the upper limit of normal despite 6 months of complete alcohol abstinence.[169] The relapse rate was higher in patients with a prior history of mild or heavy ethanol use, than it was for nondrinkers (52, 59, and 36%, respectively). The sustained virological response was 33% in nondrinkers, 20% in mild drinkers, and 9% in those who drank heavily. Age, previous alcohol intake, and genotype 1 were found to be independent predictors of nonresponse to IFN treatment. Six months of alcohol cessation before initiation of IFN treatment seems insufficient to negate

the negative influence of lifetime daily intake of alcohol. Several proposed mechanisms of decreased responsiveness to IFN treatment in alcoholics include, but are not limited to, impaired cellular immunity, high HCV RNA levels, lipid peroxidation products, emergence of quasi-species,[170,171] and increased hepatic iron stores.[122,172-174] However, few data exist regarding the effect of alcohol on the combined use of IFN and ribavirin.[175]ConclusionExcess alcohol consumption accelerates the progression of chronic hepatitis C toward increased fibrosis, cirrhosis, and HCC. Furthermore, alcoholism compromises the success of antiviral therapy in hepatitis C. Although the prudent approach in most patients with chronic hepatitis C is to avoid alcohol altogether, among those with mild hepatitis C who are not on antiviral therapy 10 g/d among women and 10 to 20 g/d among men is unlikely to adversely affect the natural history and ultimate treatment of the disease and may

have beneficial effects for the risk of myocardial infarction.CE InformationThe print version of this article was orginally certified for CME credit. For accreditation details, please contact the publisher, Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001Reprint AddressEugene R. Schiff, M.D., Center for Liver Diseases, University of Miami, 1500 NW 12th Avenue, Suite 1101, Miami, FL 33136. E-mail: eschiff@...Abbreviation NotesCTL = cytotoxic T-lymphocyte; HCC = hepatocellular carcinoma; HCV = hepatitis C virus; HSC = hepatic stellate cells; IFN = interferon; IL = interleukin; IVDU = intravenous drug use; LDAI = lifetime daily alcohol intake; NF-?? = nuclear transcription factor-kappa ?; ROS = reactive oxygen species; Th = T helper; TNF = tumor necrosis factor; TGF-? = transforming growth factor betahttp://www.medscape.com/viewarticle/488940[Non-text portions of this message have been

removed]Kathy Brunow