Alcohol and Hepatitis C

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Alcohol and Hepatitis C

Posted 11/02/2004

Kamran Safdar, M.D.; Eugene R. Schiff, M.D.

Abstract and Introduction

Abstract

Alcohol 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.

Introduction

Chronic 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]

Epidemiology

Several 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 Progression

Over 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 Injury

The 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 Survival

All 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 HCC

Alcoholic 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 HCV

Continued 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]

Conclusion

Excess 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 Information

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Reprint Address

Eugene R. Schiff, M.D., Center for Liver Diseases, University of Miami, 1500 NW

12th Avenue, Suite 1101, Miami, FL 33136. E-mail: eschiff@...

Abbreviation Notes

CTL = 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 beta

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