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"Dietary factors are important and probably causative risk factors for obesity, insulin resistance, and diabetes, which are the most important, known risk factors for hepatic steatosis," write George N. Ioannou, MD, MS, from the Division of Gastroenterology, Department of Medicine and Research Enhancement Award Program, Veterans Affairs Puget Sound Health Care System and University of Washington in Seattle, and colleagues. In addition, "It is possible that the quantity and composition of dietary lipid can either promote or protect against the development or progression of hepatic steatosis."

The authors write that if dietary composition affects the development or progression of hepatic steatosis, it is likely to play a part in the natural history of the 3 most important liver conditions in the United States: nonalcoholic fatty liver disease, hepatitis C virus (HCV) infection, and alcoholic liver disease.

Previous research has shown that a high-cholesterol diet in rabbits and mice induced profound steatosis, inflammation, and cetrilobular fibrosis, whereas a diet low in animal protein for hepatitis B virus transgenic mice was associated with decreased liver injury and decreased incidence of hepatocellular carcinoma.

In this study, the investigators sought to determine whether dietary intake was associated with the subsequent development of cirrhosis-related or liver cancer–related death or hospitalization in the US population.

They examined data from the first National Health and Nutrition Examination Survey (NHANES I), a cross-sectional study of 14,407 participants conducted between 1971 and 1975 by the National Center for Health Statistics. It ascertained dietary intake at baseline using a 24-hour dietary recall questionnaire and then used a Nutrient Composition Data Bank to calculate grams of protein, carbohydrate, and fat consumed. The NHANES I Epidemiologic Follow-up Study then collected data on specific health conditions that developed in the intervening years, through personal interviews, hospitalization records, and death certificates.

For this study, Dr. Ioannou and his team evaluated a cohort of 9221 adults (aged 25 – 74 years, 82.9% white) from the NHANES I Epidemiologic Follow-up Study who were without evidence of cirrhosis at entry into the original study.

Potential confounders identified included daily consumption of protein, carbohydrate, fat, tea or coffee, and alcohol; sex; race; age; educational attainment; geographical region; diabetes; body mass index; and subscapular-to-triceps skin fold ratio. In addition, as hepatitis B and HCV RNA testing was not available when the NHANES I participants were recruited, the investigators used data from NHANES III, a cross-sectional study from 1988 to 1994 that included measurements of viral hepatitis serologies.

During an average follow-up of 13.3 years, the investigative team found that 118 of the 9221 participants had a new diagnosis of cirrhosis and 5 had a new diagnosis of liver cancer.

After adjusting for the potential confounders, the investigators found that patients who reported a diet high in protein were at higher risk for hospitalization or death because of cirrhosis or liver cancer (P = .0001), whereas those reporting a diet high in carbohydrates were at a significantly lower risk (P = .003).

In addition, cholesterol consumption was associated with a higher risk for cirrhosis or liver cancer (P = .007), whereas total number of calories, total quantity of fat consumed, and serum cholesterol level were not. The authors write that because cholesterol has never before been linked to human liver disease, this strong association "is potentially our study's most important finding."

Using the NHANES III data, the investigators found no association between any dietary composition and HCV infection. They write that this lack of association "strongly suggests that the presence of underlying liver disease does not cause a change in dietary intake and instead makes it more plausible that differences in dietary intake of proteins, carbohydrates, cholesterol, and perhaps other lipid components contribute to the development of cirrhosis or liver cancer."

Study limitations include the 24-hour dietary recall, which may not accurately reflect long-term dietary intake, and the absence of data on HCV infection, a major cause of cirrhosis and liver cancer in the United States. However, the authors explain that because of the NHANES III study data, "HCV infection is unlikely to be an important source of uncontrolled confounding."

They conclude, "Our study raises the possibility that dietary factors may be important, modifiable, and hitherto unrecognized determinants of liver disease progression."

This study was supported by the American Liver Foundation and American Association for the Study of Liver Diseases Jan Albrecht Award. The authors have disclosed no relevant financial relationships.

Hepatology. 2009;50:175–184.