Clinical Liver Disease
Special Issue: Alcoholic Liver Disease
Volume 2, Issue 2, pages 72–75, April 2013
Jose Altamirano*, Javier Michelena
Article first published online: 24 APR 2013
Copyright © 2013 the American Association for the Study of Liver Diseases
† CIBERehd is funded by Instituto de Salud Carlos III. Javier Michelena received “Formación del Profesorado Universitaro” grant from the Ministerio de Educación of the Spanish Goverment.
‡ Potential conflict of interest: Nothing to report.
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Alcohol has been shown to cause synergistic injury in combination with other chronic liver diseases, such as nonalcoholic fatty liver disease (NAFLD), chronic viral hepatitis B and C, hemochromatosis, and autoimmune liver diseases. Abusive alcohol consumption rapidly accelerates the development of hepatic fibrosis and cirrhosis and also increases the risk of liver cancer and death from liver disease. The negative impact of alcohol consumption is dose- and time-dependent and varies depending on the underlying liver disease and may occur at much lower alcohol intake compared with an alcohol dose necessary to initiate alcoholic liver disease itself. There is not a clear “safe” limit for alcohol consumption in the setting of chronic liver disease. Thus, alcohol consumption should be avoided or at least limited in any patient with underlying liver disease.
Abusive alcohol intake is a major risk factor for chronic liver disease (CLD). In addition, alcohol consumption in the presence of other liver diseases may result in progression of the disease. Alcoholic liver disease is prevalent among patients with chronic hepatitis C (HCV) and B (HBV) virus infection, influences the progression of the disease and has a stimulation effect on viral replication.1, 2 Alcohol may negatively impact the course of NAFLD increasing the fibrosis rate in patients with non-alcoholic steatohepatitis3 and of hereditary hemochromatosis (HH).4 Finally, alcohol may interact with the metabolism of certain drugs5 and can also contribute to the development and worsening of some autoimmune liver diseases.6
Alcohol and Chronic Hepatitis C
Chronic HCV infection is the leading cause of advanced liver disease in the United States; an estimated 3.2 million people have active chronic HCV infection.7 Alcohol consumption is a common comorbidity in these patients, and multiple studies have shown that it may result in synergistic injury, with accelerated rates of fibrosis and the development of cirrhosis and liver cancer.8–11 Various mechanisms have been proposed, including: alcohol's effect on HCV viral replication, HCV-related cytotoxicity, hepatic oxidative stress, and immune modulation.
There is evidence that HCV RNA levels increase in concert with a more pronounced alcohol intake (Fig. 1a).12 Conversely, it has been shown that serum HCV RNA decreases with a reduction in alcohol intake (Fig. 1b).2 Alcohol consumption is also associated with HCV progression, and there is extensive evidence showing that chronic alcohol consumption leads to disease progression (Table 1). Even small doses of alcohol intake (below 30 g/day) can promote liver fibrogenesis.13 Thus, it appears that there is no “safe alcohol consumption” among patients with HCV infection. Chronic alcohol consumption in HCV-infected patients stimulates not only fibrogenesis but also hepatocarcinogenesis. Patients with chronic HCV infection who actively consume alcohol have a higher relative risk of hepatocellular carcinoma (HCC) compared with abstainers (54 versus 19, respectively).14 This risk also appears to be dose-dependent. In one study, alcohol consumption >80 g/day increased the risk for HCC significantly by a factor of 7.3 when compared with <40 g/day.11 Finally, there are data showing that alcoholics have inferior rates of response to HCV therapy.15 However, the question about a possible inhibitory effect of alcohol on therapy rather than patient noncompliance requires further research.
Figure 1. Impact of alcohol consumption and effect of alcohol reduction on serum HCV RNA levels. Abbreviations: HCV, hepatitis C virus; SRAC, self-reported alcohol consumption. (a) Adapted with permission from Hepatology.12 Copyright 1998, Wiley. (b) Adapted with permission from the Journal of Hepatology.2 Copyright 1996, Munksgaard International Publishers.
|Study||Alcohol Intake Evaluation||No. of Patients||Results|
|Roudot-Thoraval et al.33||Excessive alcohol intake defined as >5 drinks/day for women and 6 drinks/day for men for >1 year||6,664||Excessive alcohol intake was also associated with a higher risk of cirrhosis (34.9% versus 18.2%; P < 0.001).|
|Poynard et al.34||Abstinent/Moderate, <50 g/day; high, ≥50 g/day||2,235||Fibrosis rate progression increased from 0.125 to 0.167 in patients with consumption ≥50 g/day|
|Pessione et al.12||Weekly self-reported alcohol consumption||233||Significant correlation between self-reported alcohol consumption and serum HCV RNA levels (r = 0.26; P = 0.001)|
|Corrao et al.35||Lifetime daily alcohol intake||702||Alcohol intake + HCV infection multiplies the alcohol-associated risk of cirrhosis (odds ratio: 9.0 for 50 g/day, 26.1 for 100 g/day, 133 for >125 g/day)|
|Harris et al.36||Heavy drinking defined as >80 g/day||836||Heavy drinking exacerbates the risk for cirrhosis among patients with HCV infection (odds ratio: 7.8 versus 31.1 in HCV and HCV heavy drinkers, respectively)|
Alcohol and Chronic Hepatitis B
The interaction of alcohol consumption with HBV infection has been studied less extensively. Alcohol stimulates carcinogenesis in patients with HBV. This effect was shown in the seminal study of Ohnishi et al.,16 in which patients with HBV infection and active alcohol consumption developed HCC approximately 10 years earlier than patients who did not drink at all. Additionally, a dose-dependent effect of alcohol consumption has been demonstrated. Patients with heavy alcohol consumption (>80g/day) had a significantly increased risk of HCC in HBV-related cirrhosis.17
Alcohol and NAFLD
NAFLD is increasingly recognized as the downstream hepatic consequence of the metabolic syndrome. Well-known risk factors for NAFLD include obesity (especially with increased waist circumference), insulin resistance, and hypertriglyceridemia. Small amounts of alcohol may improve peripheral insulin resistance that take place in NAFLD.18 In addition, some studies have shown a paradoxical association between modest alcohol consumption with a lesser degree of severity in NAFLD patients.19, 20 However, additional alcohol consumption worsens NAFLD at various stages of the disease, both in animals5 and in humans.21–23
There is evidence that the impact of alcohol consumption on the development of NALFD is dose-dependent. Studies from Europe have shown that alcohol consumption of more than 60 g/day increases the rate of fatty liver by echography to 46% compared with 16% in control subjects.24 Alcohol consumption has also shown an additive risk for NAFLD development in obese patients. In one study, individuals with a body mass index of more than 25 kg/m2 had a further increase in fatty liver to >70%, and if both alcohol consumption and overweight were factors, steatosis was present in >90%.22
On the other hand, liver fibrosis in NAFLD also increases with alcohol consumption. Patients with high-risk alcohol consumption and obesity have an almost two-fold risk of developing cirrhosis21 (Fig. 2).
Figure 2. Obesity is a risk factor for alcoholic liver disease progression. Abbreviation: BMI, body mass index. Adapted with permission from the Journal of Hepatology.2 Copyright 1996, Munksgaard International Publishers.
Finally, recent evidence shows that even social drinking in patients with nonalcoholic steatohepatitis results in a significantly increased risk of HCC.25 This observation is in keeping with animal studies showing that alcohol administration is associated with deterioration of experimentally induced fatty liver disease in rodents and may also enhance the generation of carcinogenic DNA lesions.26
Alcohol Consumption and Hereditary Hemochromatosis
HH is an autosomal recessive gene disorder in which HFE gene mutations cause chronic intestinal hyperabsorption of iron, resulting in iron overload in various organs.27, 28 Iron overload is a negative prognostic factor for the development of liver disease.4 Alcohol consumption increases reactive oxygen species by producing H2O2, which leads to iron hyperabsorption and iron release due to a decrease in hepcidin. This leads to iron accumulation in the liver, resulting in increased toxicity (Fig. 3). One observational study showed that hemochromatosis subjects who drank >60 g/day of alcohol were approximately nine times more likely to develop cirrhosis than those who drank <60 g/day.29 Thus, patients diagnosed with HH should avoid alcohol consumption.
Figure 3. Iron overload due to alcoholic liver disease. Abbreviations: EtOH, ethanol; ROS, reactive oxygen species; TfR1, transferrin receptor 1.
Alcohol, Drug Interactions and Autoimmune Liver Diseases
Toxicity of various drugs may be increased by concomitant alcohol consumption. This is especially well known for methotrexate, paracetamol, and antituberculosis drugs. First, prolonged high-dose methotrexate intake results in stellate cell activation leading to zone 3 fibrosis, which is further enhanced by alcohol consumption, since alcohol by itself leads to an activation of stellate cells.30 Second, alcohol consumption induces cytochrome P450 2E, which is also responsible for the metabolism of various drugs (e.g., paracetamol and antituberculosis drugs such as isoniazid). An induction of CYP2E1 by alcohol results in enhanced metabolism of paracetamol with an increased generation of highly toxic intermediates that are not normally detoxified due to the decreased hepatic glutathione levels presented in alcoholic patients. Isoniazid toxicity depends on two factors: (1) the speed of isoniazid acetylation and (2) the speed of the metabolism of the intermediate acetylhydrazine by CYP2E1.31 Finally, it should be pointed out that vitamin A and beta-carotene taken in excess may also lead to hepatic fibrosis and cirrhosis.
The effect of alcohol consumption in patients with autoimmune liver diseases has not been studied extensively, though there is some clinical evidence in patients with primary biliary cirrhosis (PBC). In a study of 274 patients with untreated PBC, moderate alcohol consumption (30 g/day) was an independent predictor of advanced PBC stage.32 In these patients, moderate alcohol consumption was also significantly correlated with increased oxidative stress and steatosis on liver biopsies, which was thought to contribute to worsening of PBC stage.
Alcohol has been shown to cause synergistic injury in combination with other forms of CLD, particularly chronic HCV and HBV infection, NAFLD, HH, and autoimmune liver disease. Alcohol consumption, particularly in high doses, accelerates to liver fibrogenesis and the development of cirrhosis and also increases the risk of HCC and death from liver disease. Despite the effect of light alcohol consumption on decreasing insulin resistance and cardiovascular mortality, there does not seem to be a “safe” limit for alcohol consumption in the setting of combined CLD.