The importance of fat and alcohol for progression and prognosis in chronic liver disease

Abstract: Chronic liver disease is an increasing cause of global morbidity and mortality. The popular belief is that liver disease is caused mainly by alcoholic liver disease or viral hepatitis. However, the most common cause of chronic liver disease today is non-alcoholic fatty liver disease (NAFLD), which is associated with obesity and insulin resistance rather than alcohol. NAFLD is considered to become the most common cause for need of liver transplantation in the coming years. Today, the most common cause of liver transplantation in Sweden is primary sclerosing cholangitis (PSC) - a rare but very serious disease of the bile ducts that become inflamed and obliterated, and is associated with a high risk of development of cholangiocarcinoma. The role of concurrent use of alcohol in NAFLD and PSC is controversial. Part of this thesis explores the effect of alcohol on the degree of liver damage in these two diseases. We found that a low consumption of alcohol, around one unit per day, is not associated with a higher stage of fibrosis in the liver in PSC and should be safe in these patients. For NAFLD, we found that a low to moderate consumption of alcohol was associated with a lower risk for a higher fibrosis stage, up to thirteen units of alcohol per week. However, patients who had biochemical evidence of high alcohol consumption had a higher risk of more severe liver damage. This is well in line with other studies and indicates a J-formed risk profile for alcohol consumption in NAFLD. In another part of the thesis we studied the long-term risk of having fat accumulation in the liver and if overweight per se can predict development of severe liver disease. We found that the strongest histological marker for disease-specific mortality in NAFLD after a follow-up of in mean 26 years was the stage of fibrosis, and found no excess mortality in patients with signs of inflammation in the liver after adjustment for the stage of fibrosis. The risk of being overweight was studied in close to 45.000 men in their late adolescence who were conscribed to military service in 1969-1970 after adjustment of potential confounders, such as alcohol consumption. Body mass index (BMI) was found to be an independent predictor of development of severe liver disease after a mean follow-up of 39 years. Taken together, this thesis indicates that a low to moderate consumption of alcohol is safe in PSC and possibly protective in NAFLD. Furthermore, we found that the strongest predictor of disease-specific mortality in NAFLD is the stage of fibrosis, which can have implications for the design of endpoints in future clinical studies. Also, the finding that overweight per se is a predictor for development of severe liver disease is important for public health decisionmaking.