Studies on Alcoholic Liver Disease

The overall aim of this thesis was to explore the impact of alcoholic cirrhosis in Sweden, and the relation between drinking patterns and beverage types and alcoholic cirrhosis, and to evaluate the possible role of autoantibodies in the pathogenesis of alcohol related liver disease. We found that rats had appearance of IgG against rat CYP3A1 and CYP2E1 during chronic ethanol feeding We found that patients had reactivity against CYP3A4 and CYP2E1 in about 20 to 30% and 10 to 20% of the alcoholic sera. Western blotting confirmed anti-human CYP2E1 reactivity in 8 of 85 alcoholic sera, and 3 of 58 control sera. Anti-CYP3A4 reactivity was detected in 18 of 85 alcoholic sera and 4 of 58 control sera. The results suggest that autoantibodies toward both CYP2E1 and CYP3A could be generated after exposure to alcohol in both humans and experimental animals and it may contribute to the development of liver cirrhosis. We found that the liver disease mortality increase from 1969 to 1976 coincided with the increase in spirit sales. Both mortality and spirit sales decreased thereafter, whereas there was no decrease in beer or wine sales. Hospitalization rates were reduced after 1987. Depending on age and sex there was a 30-80 percent five-year mortality following discharge. The same patients could be diagnosed as having both alcoholic and non-alcoholic liver diseases in the Hospital Discharge Register and the Cause of Death Register. This was most often found among men. The results suggest that liver diseases in Sweden during the last thirty years have a reduced mortality that may be associated with the reduction in spirit consumption on the aggregate level of the Swedish population. There are difficulties in differing between alcoholic and nonalcoholic liver disease using register data. We investigated and followed up 12 281 patients who were hospitalized with esophageal varices. There was an increase in five-year survival between 1990 and 2002 compared to the years between 1969 and 1979 for all patients. There was a better survival for women than men, for younger patients compared to older and for patients hospitalized in the latest decade compared to the earlier decades. We found a significant decrease in mortality due to esophageal varices during the years studied but no decrease due to other causes. An improved prognosis for patients with esophageal varices may be related to improvement in therapeutic strategies towards acute variceal bleeding and secondary prophylactic treatment. We interviewed 140 patients (50 with alcoholic cirrhosis, 50 with alcohol dependence without cirrhosis and 40 with non-alcoholic cirrhosis). We found that women drank less than men, and patients with alcoholic cirrhosis did not drink more than patients with alcohol dependence without cirrhosis. Women with alcoholic cirrhosis drank 14 009 drinks of alcohol during their lifetime compared to 45 658 drinks consumed by men with alcoholic cirrhosis. Women with alcoholic cirrhosis reported 9 198 drinks consumed as binge drinking compared to 25 890 drinks for women with alcohol dependence. Women with alcoholic cirrhosis drank less beer compared to women with alcohol dependence. The results suggest that patients with alcoholic cirrhosis seem to be predisposed to the hepatotoxic effects of alcohol with a more pronounced sensitivity in women. LIST OF PUBLICATIONS I. Lytton SD, Helander A, Zhang-Gouillon ZQ, Stokkeland K, Bordone R, Arico S, Albano E, French SW, Ingelman-Sundberg M. Autoantibodies against cytochromes P-4502E1 and P-4503A in alcoholics, Molecular Pharmacology