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Published in final edited form as: Clin Liver Dis. 2013 Oct 24;18(1):157–163. doi: 10.1016/j.cld.2013.09.006

The Impact of Obesity and Metabolic Syndrome on Alcoholic Liver Disease

Dian J Chiang 1, Arthur J McCullough 2
PMCID: PMC6130318  NIHMSID: NIHMS524287  PMID: 24274871

Epidemiology of Alcoholic Liver Disease

Alcoholic liver disease (ALD) is a major health burden in the US. Approximately 18 million people abuse alcohol and 10 million people suffer from ALD1–2. ALD includes a spectrum of liver pathology from alcoholic fatty liver, alcoholic steatohepatitis (AH) to liver fibrosis and cirrhosis3. In the general population, the prevalence and mortality from alcoholic liver disease closely follows per capita ethanol consumption and increases as the per capita alcohol consumption increases4. ALD remains a major cause of liver failure and contributes to more than 20,000 deaths annually in the United States2.

Spectrum of Alcoholic Liver Disease

Studies of the incidence and prevalence of different stages of ALD prior to the development of cirrhosis in the general population are difficult to conduct because patients with compensated liver disease usually do not seek medical attention5. Up to 90% of alcoholics have fatty liver, which usually resolves within 2 weeks if alcohol consumption is discontinued6. While patients with pure alcoholic fatty liver are mostly asymptomatic, they have a 10% risk of progressing to cirrhosis and an 18% risk of cirrhosis or fibrosis over a median time period of 10.5 years. Further, in those who drink more than 40 units of alcohol per week, the risk dramatically increases, with a 30% risk of cirrhosis and a 37% risk of cirrhosis or fibrosis7–8. Ten to thirty five percent of all alcoholics have changes on liver biopsy consistent with alcoholic hepatitis8. The amount of alcohol intake that puts an individual at risk for alcoholic hepatitis is unknown, but the majority of patients have a history of heavy alcohol use (more than 100 g/day) for two or more decades9. Once alcoholic hepatitis has developed, the risk of cirrhosis is increased compared with simple steatosis. In one study, over a five-year period, cirrhosis developed in 16 percent of patients with steatohepatitis and in 7 percent of patients with simple steatosis10. A subset of patients with ALD will develop severe AH, which often presents acutely against a background of chronic liver disease and has a substantially worse short-term prognosis11. The progression to cirrhosis is a leading cause of morbidity and mortality in ALD2. Hepatic decompensation is common among patients with alcoholic cirrhosis. The risk of complications including the development of ascites, variceal bleeding, or hepatic encephalopathy is about 25 percent after one year and 50 percent after five years12. Once hepatic decompensation develops, the expected five-year transplant-free survival rate is 60 percent for those who stop drinking alcohol and 30 percent for those who continue to drink alcohol13. However, only 10–15% of alcoholics develop cirrhosis. Although the amount and patterns of alcohol consumption are important, they do not fully account for the differences in cirrhosis incidence rates3. Several studies have been performed to investigate risk factors (gender, genetics, diet, type of alcohol, pattern of drinking, and HCV infection) in the progression of ALD14. Given the rising prevalence of obesity and metabolic syndrome, this review will focus on our current understanding of the potential impact of obesity and metabolic syndrome in the progression of ALD.

Obesity on the progression of ALD

The WHO and the National Center for Health Statistics define overweight as a body mass index (BMI) >25 and ≤ 29.9 and obesity as a BMI greater than 30 kg/m215. Alcohol and obesity synergistically increase the risk of liver injury as measured by elevated serum alanine aminotransferase and aspartate aminotransferase levels16. A study of 1604 alcoholic patients revealed that overweight (as determined by BMI ≥ 25 in women and ≥ 27 in men) is a risk factor for the progression of alcoholic liver disease9. Being overweight for at least 10 years is independently correlated with the presence of steatosis, acute alcoholic hepatitis, and cirrhosis. These results show that the presence of excess weight for at least 10 years is a risk factor for progression of ALD9. Another study of asymptomatic alcoholic patients revealed that higher body weight is a risk factor for more severe histological liver damage17.

Whether the exacerbation of ALD in overweight patients is a result of additive injury from non-alcoholic steatohepatitis (NASH), which is a hepatic manifestation of metabolic syndrome; or the metabolic derangement in obesity exacerbates ethanol-induced liver injury remain a subject of further investigation. Ethanol feeding results in more pronounced hepatic steatosis and liver injury in genetically obese mice (ob/ob), compared with control lean wild type mice18. Further, ethanol feeding augments the impairment of hepatic sirtuin 1 (SIRT1)-AMP-activated kinase (AMPK) signaling in the ob/ob mice, which is associated with altered hepatic lipid metabolism pathways18. Emerging evidence also suggests that adipose tissue has a critical regulatory function in metabolism and immunity through adipose tissue-derived bioactive substances including TNFα, IL-6, monocyte/macrophage chemo-attractant protein 1 (MCP-1), and adipokines, which may regulate insulin resistance and tissue inflammation19. Further, chronic ethanol exposure results in inflammation in adipose tissue in mice20 and alcohol intake can alter adipokines expression in adipose tissue and adipokines plasma levels21. The direct effects of alcohol on the metabolic and innate immune activity of adipose tissue likely contribute to ethanol-induced liver injury.

Obesity and metabolic syndrome on the mortality of ALD

Obesity, particularly abdominal obesity, is associated with insulin resistance on peripheral glucose and fatty acid utilization, which leads to type 2 diabetes mellitus22. Insulin resistance, the associated hyperinsulinemia and hyperglycemia, and adipokines may lead to increased risk for cardiovascular disease (CVD) due to vascular endothelial dysfunction, abnormal lipid profile, hypertension, and vascular inflammation22. The cooccurrence of metabolic risk factors for type 2 diabetes and CVD (abdominal obesity, hyperglycemia, dyslipidemia, and hypertension) suggest the existence of metabolic syndrome23. Obesity and metabolic syndrome are among the most important public health problems in the United States given the rising prevalence and comorbidities24. The prevalence of the metabolic syndrome, as defined by the 2001 ATP III criteria, was evaluated in the third National Health and Nutrition Examination Survey (NHANES III, 1988 to 1994)25. The overall prevalence of metabolic syndrome is 22% in this population25. The prevalence of obesity and metabolic syndrome in ALD patients in the NHANES III cohort are 44.5% and 32.4% respectively (Table 1)26. Further, obesity and metabolic syndrome are associated with increased liver-related mortality in ALD patients (Table 1)26. Interestingly, there is no increased overall mortality risk with either obesity or metabolic syndrome in this cohort. However, type 2 diabetes and insulin resistance are both associated with increased overall mortality in ALD patients (Table 1)26. The findings from this large population-based study suggest a detrimental effect of concomitant obesity and components of metabolic syndrome in patients with ALD.

Table 1.

Prevalence and adjusted hazard ratio for overall and liver-related mortality of obesity and metabolic syndrome in ALD patients in NHANES III

Prevalence
(%)		 Overall mortality
(aHRs and 95% CIs)		 Liver-related mortality
(aHRs and 95% CIs)
Obesity 44.56±5.9 1.58 (0.57 to 4.40) 16.22* (1.91 to 137.68)
Metabolic syndrome 32.46±5.2 2.37 (0.50 to 11.18) 2.06* (1.21 to 3.31)
Type 2 diabetes 7.46±2.4 3.00* (1.06 to 8.54) 3.60 (0.96 to 13.52)
Insulin resistance 33.76±5.1 3.21* (1.56 to 6.58) 2.43 (0.28 to 21.38)
Hypercholesterolemia 64.56±6.0 0.79 (0.25 to 2.53) 0.04 (0.01 to 0.24)
Hypertension 36.56±5.7 1.76 (0.46 to 6.70) 1.77 (0.40 to 7.72)
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*

p value for the adjusted hazard ratio (aHR) is ≤0.05.

Data from Stepanova M, Rafiq N, Younossi ZM. Components of metabolic syndrome are independent predictors of mortality in patients with chronic liver disease: a population-based study. Gut. Oct 2010;59(10):1410–1415.

Data from two Scottish prospective cohorts also reveal that obesity and alcohol consumption are strongly associated with liver disease mortality in analyses adjusted for other confounders (P=0.001 and P<0.0001 respectively)27. Drinkers of 15 or more units per week have adjusted relative rates for liver disease mortality of 3.16 (95% confidence interval 1.28 to 7.8) for underweight/normal weight men, 7.01 (3.02 to 16.3) for overweight, and 18.9 (6.84 to 52.4) for obese men. The relative excess risk due to interaction between BMI and alcohol consumption is 5.58 (1.09 to 10.1) with a synergy index of 2.89 (1.29 to 6.47), suggesting obesity and alcohol consumption synergistically increase mortality in this population27.

Obesity and alcohol on hepatic carcinogenesis

Hepatocellular carcinoma (HCC) is one of the complications of ALD and cirrhosis. Several epidemiologic studies have suggested that both alcoholic and nonalcoholic fatty liver disease are associated with increased risk of HCC28–30. Given the enhanced liver injury and fibrosis from concomitant alcohol consumption and obesity16, it is plausible that alcohol and obesity may enhance hepatic carcinogenesis. In a population-based study of 23,712 Taiwanese residents from January 1, 1991 to December 31, 2004, there was an association betweem alcohol use (defined as those who consume alcohol at least 4 days per week for at least a year) and obesity (BMI ≥ 30) with the risk of HCC incidence in an unadjusted analysis (hazard ratio = 7.19, 95% confidence interval: 3.69, 14.00; P < 0.01) and a multivariable-adjusted analyses (hazard ratio = 3.82, 95% confidence interval: 1.94, 7.52; P < 0.01)31. Further, the data suggests a multiplicative interaction between alcohol use and obesity and that obesity and alcohol synergistically increase the risk of HCC incidence31. In addition, alcohol consumption is associated with increased risk of HCC in a cohort of patients with NASH cirrhosis from a tertiary referral center in the US32.

Diabetes on the progression of ALD

Concomitant diabetes mellitus in alcoholics includes a wide spectrum of etiologies including insulin insufficiency due to alcoholic pancreatitis33, hyperinsulinemia and insulin resistance associated with liver cirrhosis34 and type 2 diabetes mellitus associated with the metabolic syndrome. The presence of diabetes is a significant risk factor for mortality in a Japanese cohort of alcoholic patients, in both cirrhosis and noncirrhosis groups35. Further, diabetes is an independent risk factor for hepatic carcinogenesis in patients with alcoholic cirrhosis36. Autonomic nerve dysfunction occurs in both alcoholics and diabetics. It is generally reversible in alcoholics if they abstain37, but is irreversible in diabetics38.

Clinical management and future direction

The corner stone of clinical management of ALD is alcohol cessation14. Since obesity and metabolic syndrome may exacerbate progression of ALD, it is critical for physicians to counsel patients with concomitant metabolic syndrome on their increased risk of ALD progression. Treatment options for patients with concomitant obesity, metabolic syndrome and advanced ALD remain limited. Therefore, detection of early stage disease and prevention of progression are critical in addressing this issue. Both obesity and alcohol use are modifiable risk factors, life style interventions should be undertaken to reduce the risks of disease progression. Early referral to alcohol rehabilitation program should be considered in these patients prior to the development of cirrhosis or severe AH to avoid disease progression. Further, treatment of components of metabolic syndrome may improve the outcomes in these patients. Prospective studies will be instrumental to demonstrate the clinical efficacy of such intervention. Further understanding of the mechanistic link of synergism among alcohol, obesity and metabolic syndrome in the progression of ALD may provide novel targets of intervention in this high risk population.

Conclusion

The intersection of the obesity epidemic and ALD poses a challenging health care issue with significant morbidity and mortality. Obesity and metabolic syndrome exacerbate progression of ALD, increase mortality and HCC incidence. Further, alcohol may modulate the metabolic and innate immune activity of adipose tissue and thus contribute to ethanol-induced liver injury. Recognition of these increased risks is crucial in patient counseling and disease management. Detection of early stage of liver injury in asymptomatic patients may offer the opportunity to prevent disease progression. Life style modifications including alcohol cessation and weight loss should be pursued along with the management of components of metabolic syndrome.

Synopsis.

Alcoholic liver disease (ALD) remains a major cause of chronic liver diseases and liver failure. Population-based prospective studies and patient cohort studies have demonstrated that obesity and the metabolic syndrome exacerbate progression of ALD, increase HCC incidence and mortality. Emerging evidence also suggests a synergism between alcohol and obesity in mortality and HCC incidence. Recognition of these increased risks and detection of early-stage liver disease may offer the opportunity to address these modifiable risk factors and prevent disease progression in these patients.

Key points.

  • Obesity and metabolic syndrome are common in ALD patients and increase the risk of liver-related mortality.

  • Obesity is an independent risk factor for steatosis, acute alcoholic hepatitis and cirrhosis in ALD.

  • Obesity and alcohol synergistically enhance hepatic carcinogenesis.

  • Diabetes is an independent risk factor for hepatic carcinogenesis in alcoholics and increases mortality in both cirrhosis and pre-cirrhosis patients.

Acknowledgments

This work was supported in part by grant from ABMRF/The Foundation for Alcohol Research to DJC and AA021893 grant from the National Institute of Alcohol Abuse and Alcoholism to AJM.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

The authors have nothing to disclose.

Contributor Information

Dian J. Chiang, Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic, A51, 9500 Euclid Avenue, Cleveland OH, 44195, (216) 445-7841, (216) 445-5477 (fax), chiangd@ccf.org.

Arthur J. McCullough, Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic, A31, 9500 Euclid Avenue, Cleveland OH, 44195, (216) 444-2766, (216) 445-5477 (fax), mcculla@ccf.org.

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