Table of Contents  

Wilson, Pirola, and Apte: Alcoholic pancreatitis in the modern era


The association of the overuse of alcohol with pancreatitis was first reported in the medical literature in 1815,1,2 with further systematic analyses being carried out by Freidreich in 18783 and Fitz in 1889.4

Over the past 100 years or so, considerable effort has been expended in exploring the clinical and epidemiological features of alcoholic pancreatitis and possible cofactors of the disease, as well as mechanisms whereby alcohol may be directly injurious to the pancreas.

Alcoholic pancreatitis represents a clinical paradox: the risk of developing the disease increases with the amount of alcohol consumed, suggesting direct toxic effects of alcohol on the gland; however, only a minority (≤ 5%) of heavy drinkers develop the disease, suggesting a role for individual susceptibility factors.


In Western society, alcohol ranks with gallstone disease as a major cause of acute pancreatitis and as the major cause of chronic pancreatitis. There has been variation in attribution rates among different studies;58 this variation most likely relates to the background alcohol consumption of the population under study, the types of institutions surveyed (e.g. private facilities vs. county or Veterans Affairs facilities in the USA), the difficulties associated with eliciting an accurate alcohol consumption history and the growing awareness of possible cofactors in the disease (e.g. smoking).

For a long time, acute alcoholic pancreatitis and chronic alcoholic pancreatitis were considered separate diseases,9 but it is now generally recognized that they are part of the same continuum. There is good clinical10,11 and experimental evidence12,13 that repeated attacks of pancreatic necroinflammation lead to chronic pancreatitis (the necrosis–fibrosis sequence).

There has been some debate regarding the amount of alcohol consumption required to produce pancreatitis. Episodic binge drinking or the isolated alcoholic debauch rarely, if ever, causes pancreatitis.14 In the case of chronic alcohol intake, which is common, an early study suggested that the risk of developing pancreatitis was linear, even at relatively low (social) levels of consumption.15 Later studies have suggested that there is a threshold above which pancreatitis is more likely to occur.6,16,17 Most clinicians, basing their views on clinical experience, would agree that the diagnosis is not made in the absence of chronic heavy alcohol consumption (80–100 g of alcohol per day for at least 5 years). However, alcoholic pancreatitis is now emerging as a polyfactorial/polygenic disease (see below), so that smaller amounts of alcohol consumed may be responsible for the phenotype. Obviously, more work needs to be undertaken on this concept.

Direct toxicity of alcohol on the pancreas

Alcohol is thought to damage the pancreas directly via its metabolism by intrapancreatic enzyme systems, generating metabolites that are toxic to intracellular organelles and membranes. The cellular targets are acinar, stellate and duct cells.

Alcohol is metabolized by pancreatic acinar cells via oxidative and non-oxidative pathways.1820 The oxidative pathway results in the production of acetaldehyde18,19 and reactive oxygen species,21,22 both of which can result in oxidative stress. The non-oxidative pathway results in fatty acid ethyl esters capable of disrupting membrane function23 and altering intracellular calcium homeostasis with resultant calcium overload, leading to mitochondrial dysfunction and cell death.24

Alcohol intake increases the digestive and lysosomal enzyme content of acinar cells2528 and destabilizes intracellular membranes,23,2931 predisposing to autodigestion. Alcohol is also responsible for increased inflammatory cytokine production by acinar cells.16

Alcohol causes an adaptive increase in the unfolded protein response and may impair autophagy in acinar cells.32,33

Alcohol metabolism activates stellate cells, causing increased production of extracellular matrix proteins and inflammatory cytokines.34,35 Alcohol also impairs CFTR (cystic fibrosis transmembrane conductance regulator) gene expression and function in duct cells, affecting the composition and viscosity of pancreatic juice.36

Individual susceptibility to alcoholic pancreatitis

The fact that only a small minority of heavy drinkers develop alcoholic pancreatitis has led to the search for additional susceptibility factors. Candidate environmental and genetic factors have been investigated (Table 1).


Individual susceptibility to alcoholic pancreatitis

Factor Association
Drinking pattern No (Wilson et al. 198537)
Beverage type No (Wilson et al. 198537)
Yes (Nakamura et al. 200338)a
Diet No (Wilson et al. 198537)
Smoking Yes (Lowenfels et al. 198739)
No (Haber et al. 199340)
Yes (Maisonneuve et al. 200541)
Obesity Yes (Ammann et al. 201042)a
Inherited factors
 HLA No (Wilson et al. 198443)
 α1-Antitrypsin deficiency No (Haber et al. 199144)
 Cystic fibrosis genotype No (Norton et al. 199845)
 Cytochrome P4502E1 polymorphism No (Frenzer et al. 200246)
 ADH genotype No (Frenzer et al. 200246)
Yes (Shimosegawa et al. 200847)
Yes (Maruyama et al. 199948)
Yes (Matsumoto et al. 199649)
Yes (Maruyama et al. 200850)
Yes (Zhong et al. 201551)a
 Anionic trypsinogen gene mutation Yes (Witt et al. 200652)a
Yes (Whitcomb et al. 201253)a
Yes (Derikx et al. 201554)
 PSTI/SPINK1 mutations Yes (Witt et al. 200155)
 Claudin-2 Yes (Whitcomb et al. 201253)a
Yes (Derikx et al. 201554)
 TNF-α, TGF-β, IL-10, IFN-ϒ polymorphisms No (Schneider et al. 200456)a
 Detoxifying enzymes
  Glutathione S-transferase No (Frenzer et al. 200246)
  UDP-glucuronosyl transferase Yes (Ockenga et al. 200357)a
 CEL polymorphism Yes (Miyasaka et al. 200558)
No (Ragvin et al. 201359)a
 Hybrid allele of CEL (CEL-HYB) Yes (Fjeld et al. 201560)a

ADH, alcohol dehydrogenase; CEL, carboxyl ester lipase; HLA, human leucocyte antigen.

a Studies that did not include alcoholics without pancreatitis as controls.

In studying susceptibility to alcoholic pancreatitis, ideally comparisons should be made between alcoholics with pancreatitis and alcoholics without pancreatitis so that the index and control groups differ in only one variable (i.e. the presence or absence of pancreatitis).

Among environmental influences, concomitant smoking has emerged as a significant factor. Smoking appears to accelerate disease progression.41 It remains unclear whether or not smoking is an initiating factor for alcoholic pancreatitis.

A number of genetic factors (variants involving alcohol-metabolizing enzymes or protease–antiprotease systems) have been discovered in a small minority of patients (see Table 1).

There is increasing interest in the role of increased intestinal permeability resulting in endotoxaemia and pancreatic damage in alcoholics:

  • Alcoholics manifest increased intestinal permeability and endotoxaemia in both the acute and chronic settings.61,62

  • Coadministration of alcohol and endotoxin to rodents results in pancreatic injury phenotypically similar to human alcoholic pancreatitis.63

  • Alcohol in vitro increases intestinal permeability via cytochrome P450 2E1 (CYP 2E1, the major microsomal alcohol-metabolizing enzyme) and the circadian proteins CLOCK and PER2.64

  • Most recently, a polymorphism in the gene encoding for claudin 2 (a tight junction protein) has been associated with alcoholic pancreatitis in two genome-wide association studies.53,54


  • Alcohol is a major association of both acute and chronic pancreatitis.

  • There is evidence that chronic alcoholic pancreatitis develops as a result of repeated episodes of pancreatic necroinflammation.

  • There is a threshold of alcohol consumption above which alcoholic pancreatitis becomes more likely.

  • The pancreatic toxicity of alcohol appears to be related to pancreatic metabolism of alcohol with the generation of toxic metabolites injurious to acinar, pancreatic stellate and duct cells.

  • Research into the pathogenesis of alcoholic pancreatitis has been hampered by the lack of a suitable animal model. The most plausible model to date involves coadministration of alcohol and endotoxin to rodents. In humans and rodents, alcohol is known to increase intestinal permeability and to cause endotoxaemia. Administration of alcohol plus endotoxin to rodents results in pancreatic necroinflammation and fibrosis.

  • Only a small minority of alcoholics (≥ 5%) develop clinically evident pancreatitis, suggesting the presence of one or more susceptibility factors. Smoking appears to play a role in disease development in humans and animals. In addition, a number of inherited factors have been identified. These include polymorphisms in genes for alcohol-metabolizing enzymes, for the protease/protease inhibitor system and for claudin 2, a tight junction protein.

  • There is an emerging concept that the pathogenesis of alcoholic pancreatitis is multifactorial with alcohol playing an essential role, but other factors, both environmental and hereditary, may be significant and require further investigation (e.g. claudin 2 mutations and endotoxaemia).


This is an edited version of the upcoming chapter: Wilson JS, Pirola RC, Apte MV. Epidemiology and aetiology of alcohol-induced pancreatitis. In: Beger H, Hruban R, Warshaw A, et al. (eds.) The Pancreas, 3rd edn – An Integrated Textbook of Basic Science, Medicine and Surgery. Oxford: John Wiley; in press (2017).



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