• The Same Path to Pancreatitis From Alcohol Abuse or Cystic Fibrosis?

The Same Path to Pancreatitis From Alcohol Abuse or Cystic Fibrosis?

Excessive alcohol consumption disrupts expression and localization of the cystic fibrosis transmembrane conductance regulator (CFTR), researchers report in the February issue of Gastroenterology. People with loss-of-function mutations in the CFTR develop cystic fibrosis and are at risk for pancreatitis—the finding that alcohol intake also alters this protein could provide insight to the relationship between alcoholism and pancreatitis, and lead to new treatments.

Excessive alcohol consumption is one of the most common causes of acute and chronic pancreatitis. Alcohol-induced chronic calcifying pancreatitis is characterized by the formation of muco-protein plugs in the small pancreatic ducts. József Maléth et al noticed that these are similar to alterations of the exocrine pancreas in patients with cystic fibrosis.

They therefore investigated whether changes in the function or expression of the CFTR (a chloride channel) in pancreatic ductal epithelial cells were involved in development of alcohol-induced pancreatitis.

They measured CFTR activity, based on chloride concentrations, in sweat from patients with cystic fibrosis, patients admitted to the emergency department because of excessive alcohol consumption, and healthy volunteers (controls).

Maléth et al found that chloride concentrations were higher in sweat samples from patients who were acute abusers of alcohol than in controls, providing evidence that alcohol affects CFTR function.

When the authors measured levels of CFTR and localization in pancreatic tissues from patients with acute or chronic pancreatitis induced by alcohol, they found that alcohol consumption reduced activity and expression of the CFTR chloride channel.

Although a single binge of alcohol consumption by controls did not impair CFTR function (based on sweat chloride absorption), excessive alcohol consumption by habitual drinkers greatly reduced the function of CFTR.

Pancreatic tissues metabolize ethanol mainly via a nonoxidative pathway that results in production of fatty acid ethyl esters, which damage cells.

Maléth et al showed that adding alcohol and the nonoxidative ethanol metabolite palmitoleic acid to pancreatic ductal epithelial cells inhibited secretion of fluid and HCO3, as well as the CFTR chloride current. These effects were mediated by sustained increases in concentrations of intracellular calcium and adenosine 3′,5′-cyclic monophosphate, depletion of adenosine triphosphate, and depolarization of mitochondrial membranes.

Ethanol and nonoxidative ethanol metabolites induce sustained intracellular calcium overload, cellular cAMP and ATP depletion, and mitochondrial membrane depolarization in pancreatic ductal epithelial cells. These events inhibit CFTR activity and decrease pancreatic HCO3− secretion. Ethanol and nonoxidative ethanol metabolites also reduce CFTR mRNA, cell surface stability, and protein folding. Reductions in pancreatic fluid and HCO3− secretion increase the severity of alcohol-induced acute pancreatitis.

Ethanol and nonoxidative ethanol metabolites induce sustained intracellular calcium overload, cellular cAMP and ATP depletion, and mitochondrial membrane depolarization in pancreatic ductal epithelial cells. These events inhibit CFTR activity and decrease pancreatic HCO3− secretion. Ethanol and nonoxidative ethanol metabolites also reduce CFTR mRNA, cell surface stability, and protein folding. Reductions in pancreatic fluid and HCO3− secretion increase the severity of alcohol-induced acute pancreatitis.

Administration of ethanol to mice or guinea pigs reduced expression of CFTR mRNA in pancreatic tissues, reduced the stability of CFTR at the cell surface, and disrupted folding of CFTR at the endoplasmic reticulum. Similar observations were made in pancreatic cell lines.

In mice, intraperitoneal administration of ethanol and the fatty acid palmitic acid induced many features of pancreatitis (pancreatic water content, serum amylase activity, edema score, leukocyte score, and necrosis)—these alterations increased significantly CFTR-knockout mice. So, when the expression and activity of CFTR are impaired by alcohol, pancreatitis becomes more severe.

Maléth et al conclude that loss of CFTR function is not only associated with pancreatitis in patients with cystic fibrosis, but also in chronic abusers of alcohol. Strategies to restore CFTR function might be developed to treat both types of pancreatitis.

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