Genetics and Alcohol: A Lethal Combination in Pancreatic Disease?

Authors

  • David C. Whitcomb

    1. Giant Eagle Professor of Cancer Genetics, Professor of Medicine, Cell Biology & Physiology, and Human Genetics, Chief, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh & UPMC, Room 401.4, 3708 Fifth Ave, Pittsburgh, Pennsylvania 15213.
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Reprint requests: David C. Whitcomb, MD, PhD, Giant Eagle Professor of Cancer Genetics, Professor of Medicine, Cell Biology & Physiology, and Human Genetics, Chief, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh & UPMC, Room 401.4, 3708 Fifth Ave., Pittsburgh, PA 15213; Tel.: +1-412-578-9517; Fax: +1-412-578-9537; E-mail: whitcomb@pitt.edu

Abstract

An association between alcohol consumption and pancreatic diseases has been recognized for decades, but the absolute risk for pancreatic disease for individuals who drink alcohol is low. Other than smoking, few additional environmental factors have been identified, which suggests that genetic risk factors may be important. Studies in our laboratory using the Lieber-DeCarli feeding technique demonstrate that alcohol causes oxidative stress and mitochondrial damage and alters neruohormonal regulation of the pancreas after a threshold dose is exceeded, which makes the pancreas susceptible to withdrawal hypersensitivity and acute pancreatitis. Alcohol also shifts cell death from apoptosis to necrosis and promotes fibrosis through anti-inflammatory immune mechanisms. Others have demonstrated that alcohol lowers the threshold for trypsin activation in acinar cells, which increases sensitivity to triggering pancreatitis. In addition, we used the Lieber-DeCarli diet plus recurrent acute pancreatitis insults to develop the first animal model of chronic pancreatitis that mimics human disease. Finally, our North American Pancreatitis Study 2 (NAPS2), which was built on insights from animal studies, confirmed the threshold effect predicted by Charles Lieber (>5 drinks per day and >35 drinks/week). These studies and others also defined distinctive roles of alcohol and genetics in the etiology and progression of chronic pancreatitis.

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