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Alcoholic pancreatitis
Gastroenterol Clin N Am 33 (2004) 751–765
Alcoholic pancreatitis Christoph Hanck, MDa, David C. Whitcomb, MD, PhDa,b,* a
Department of Medicine, University of Pittsburgh, UPMC Presbyterian, Mezzanine Level-C Wing, 200 Lothrop Street, Pittsburgh, PA 15213, USA b Departments of Cell Biology and Physiology, and Human Genetics, University of Pittsburgh, UPMC Presbyterian, Mezzanine Level-C Wing, 200 Lothrop Street, Pittsburgh, PA 15213, USA
The relationship between alcohol and pancreatic diseases is difficult to accurately define. Although many individuals with chronic pancreatitis have a history of excessive and sustained alcohol consumption, more that 95% of heavy alcohol users never develop chronic pancreatitis [1,2]. Furthermore, some individuals who do develop chronic pancreatitis have only consumed modest amounts of alcohol for a limited number of years before developing pancreatitis [2]. These observations are consistent with a more general model of recurrent acute and chronic pancreatitis as a complex trait or disorder. In this model, development of recurrent acute pancreatitis requires the coexistence of two or more persistent factors leading to trypsinogen activation, autodigestion, and pancreatitis, either environmental or genetic in nature, before the condition occurs. Chronic pancreatitis requires all factors necessary for recurrent acute pancreatitis plus alterations in the immune response to facilitate chronic inflammation and chronic fibrosis. In the context of a complex disorder model, alcohol becomes especially important, because it can increase the risk of recurrent acute pancreatitis and the risk of chronic pancreatitis through multiple steps and mechanisms [3,4]. What fraction of chronic pancreatitis is caused by alcohol abuse? The etiology of chronic pancreatitis has been ascribed to alcoholism in 70% of all cases United States [5–7]. This often quoted number appears to be supported by three lines of evidence. First, this number parallels estimates from Europe, in which the contribution of alcohol to chronic pancreatitis
* Corresponding author. E-mail address: [email protected] (D.C. Whitcomb). 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2004.07.002 gastro.theclinics.com
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may be inflated because of the higher rate of alcohol consumption among Europeans than Americans. Secondly, the diagnosis of alcoholic chronic pancreatitis may be given to a significant number of subjects who rarely drink alcohol, based on the assumption of some clinicians that calcifying chronic pancreatitis is pathognomonic of alcoholism. The authors base this concern on the testimony of hereditary pancreatitis patients who report that, despite never drinking alcohol in their lives, they were labeled as alcoholics, and some even were referred for alcohol rehabilitation based on the fact that they had otherwise unexplained chronic pancreatitis. Third, the criteria for diagnosing a subject as an alcoholic is inconsistent and may overestimate the true impact of alcohol on a compound, complex disorder. The temptation to label a subject as having alcoholic chronic pancreatitis also may have been driven by the alternate diagnosis of idiopathic chronic pancreatitis, which implies diagnostic failure. Alcohol use in the United States To understand alcoholic pancreatitis within the United States, it is useful to review alcohol use within the general population. This is crucial, because one could argue that if 70% of individuals within the population drink alcohol, and 70% of patients with pancreatitis drink alcohol, then the association could be coincidental. On the other hand, studying adults with chronic pancreatitis but without alcohol use in Europe is challenging, because most Europeans consume alcohol either daily, or weekly. The best epidemiological data on alcohol consumption in the United States comes from the United States Alcohol Epidemiological Data Reference Manual available through the National Institute on Alcohol Abuse and Alcoholism (NIAAA). In 1992, NIAAA conducted the National Longitudinal Alcohol Epidemiologic Survey (NLAES)—at that time, the most ambitious and comprehensive survey of its type ever conducted [8,9]. The NLAES included extensive questions concerning alcohol consumption and items designed to provide psychiatric classification of alcohol use disorders. It also included ethanol conversion factors for comparing alcohol content of different drinks (eg, 0.045 for beer, 0.121 for wine, and 0.409 for liquor). This allowed for estimates of total ethanol consumption during past years. Dividing the annual total by 365 yields an estimate of drinking level, the average daily amount of ethanol consumed [8]. The results of the survey have been published [8,9], and a summary of the primary results is given in Table 1. Among the Caucasian population ages 18 and older, 46.87% were current drinkers; 22.44% were former drinkers, and the remaining 30.69% were lifetime abstainers. Within this group, 12.28% of men and 3.50% of women were considered heavy drinkers (average of 1 or more ounces of ethanol per day). Among the African American population, 32.53% were current drinkers, and 61.72% of females were lifetime abstainers (Table 1), while 6.93% of men, and 2.93% of
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Table 1 Percent distribution of alcohol drinkers in the United States age 18 and over [8] Respondent characteristics Total Current drinker. . . . . . Former drinker. . . . . . Lifetime abstainer. . . . . . Race White Current drinker. . . . . . Former drinker. . . . . . Lifetime abstainer. . . . . . Black Current drinker. . . . . . Former drinker. . . . . . Lifetime abstainer. . . . . .
Both sexes*
Males*
Females*
44.37 0.40 21.63 0.31 34.00 0.42
55.76 0.51 22.53 0.42 21.71 0.43
33.87 0.47 20.80 0.37 45.33 0.57
46.87 0.47 22.44 0.34 30.69 0.47
57.86 0.58 23.11 0.47 19.03 0.45
36.59 0.53 21.81 0.41 41.60 0.61
32.53 0.83 18.82 0.64 48.65 0.90
46.57 1.35 21.01 1.12 32.42 1.35
21.23 0.80 17.05 0.78 61.72 1.07
* Estimated % standard error. The percent distributions were based on the entire population included in the NLAES sample. From Drinking in the United States: main findings from the 1992 National Longitudinal Alcohol Epidemiologic Survey (NLAES). In: US alcohol epidemiologic data reference manual 1998. Bethesda (MD), National Institutes of Health, Publication #99-3519.
women were heavy drinkers. Alcohol drinking was heaviest among younger, never-married adults in urban areas, and lowest in the southern United States [9]. The proportion of individuals drinking alcohol increased with education and income, while the proportion of heavy drinkers also decreased with education and income. On average, the proportion of individuals registered as black or Hispanic consuming alcohol was less than individuals registered as white [9]. This survey provides a foundation for understanding alcohol use in the United States from an epidemiological perspective. Because nearly half of all individuals from the United States never drink alcohol, and less than 10% consume 1 ounce of alcohol or more per day, then the estimate that 70% of subjects with chronic pancreatitis are alcohol drinkers (with at least half being heavy drinkers), provides evidence that there is some type of link between alcohol consumption and pancreatitis. These conclusions are consistent with previous epidemiological studies from around the world [10–12]. Pathophysiology of alcoholi in the pancreas and secretory control mechanisms The reason that alcohol so often is associated with pancreatitis is that it increases risk at multiple steps in the process between normal pancreas and chronic pancreatitis, and it acts through multiple mechanisms. Specifically, alcohol increases the risk of acute pancreatitis, and drives the inflammation leading to fibrosis. The factors surrounding each of these steps will be addressed.
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Alcohol increases the risk of acute pancreatitis It appears that alcohol does not cause acute pancreatitis directly, but rather it lowers the threshold for initiation of acute pancreatitis from other causes. This has been demonstrated most clearly in rat models in which animals or cells are exposed to alcohol and then challenged with various levels of hyperstimulation to initiate pancreatitis. In vitro studies conducted by Katz et al [13] demonstrated that when ethanol (25 nm) was added to pancreatic lobules with low-dose cholecystokinin (0.1 nm) generated zymogen activation was generated at levels that were sixfold higher than cholecystokinin alone, and that was equivalent to levels generated by highdose cholecystokinin (10 lm). This was one of the first clear demonstrations that ethanol selectively sensitizes the pancreatic acinar cell to cholecystokinin-stimulated zymogen proteolysis [13]. Studies in whole animals also demonstrate alcohol sensitization to pancreatitis. Pandol et al [14] fed rats alcohol or control diets intragastrically for 2 or 6 weeks and then infused them with cholecystokinin octapeptide (CCK8) at 3000 pmol/kg per hour. All measures of pancreatitis, NF-kappaB activity, and mRNA expression for tumor necrosis factor alpha (TNF-a), interleukin (IL)-6, monocyte chemotactic protein 1, macrophage inflammatory protein 2, and inducible nitric oxide synthase, were increased significantly only in rats treated with ethanol plus CCK-8 [14]. These studies provide evidence that alcohol does increase sensitivity of the pancreas to hyperstimulation-induced zymogen activation and pancreatitis. The implications are that alcohol increases the risk of acute pancreatitis by lowering the threshold for other factors to trigger an episode of acute pancreatitis. Human alcoholic acute pancreatitis—autopsy studies There is consensus that people develop acute alcoholic pancreatitis [15,16]. The primary evidence has been a series of postmortem studies on patients who either died of acute alcoholic pancreatitis, or who recovered from acute pancreatitis, later died, and had postmortem examinations [17,18]. Regardless of the study method or perspective, all studies report a significant fraction of subjects with severe alcohol-induced acute pancreatitis with no evidence of underlying chronic pancreatitis. Although the mechanism leading to chronic pancreatitis in people is impossible to prove directly, some insights from animal models are instructive. Animal studies on susceptibility to acute pancreatitis after alcohol feeding Animal studies demonstrate that chronic alcohol consumption lowers the threshold for triggering acute pancreatitis, and therefore likely increases risk. Triggering acute pancreatitis means triggering unregulated intrapancreatic trypsinogen activation, leading to pancreatic autodigestion and
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acute pancreatitis. In the absence of specific mutations in trypsin or trypsin regulating genes, sustained intrapancreatic trypsin activation appears to require intra-acinar cell hypercalcemia (which eliminates the trypsinogen autodigestion mechanisms) or failure to clear activated trypsin from the intrapancreatic ducts (which is a high-calcium environment). The pathway connecting the delivery of nutrients into the intestine to release zymogen granules from the acinar cell into the duct contains several steps that are sensitive to alcohol and that increase the risk of intracellular hypercalcemia, potentially leading to unregulated intra-acinar cell trypsin activation and stabilization. The effects of alcohol vary with the timing and amount of alcohol consumed and can be divided into preacinar cell effects and intra-acinar cell effects. Preacinar cell effects lead to neurohormonal hyperstimulation; intra-acinar cell effects lead to organelle injury or fragility, loss of calcium regulation, or zymogen mis-sorting. Route of alcohol administration Several experiments have been done in people and animals to determine the effect of alcohol on pancreatic function. The results of these experiments and interpretation thereof often appear contradictory and confusing. The reason for apparent discrepancies depends on delicacy of the experimental design and the model used, including the presence or type of sedation. Indeed, the authors have shown that the route of alcohol administration (intravenous or intraduodenal) or the duration of exposure makes a significant difference in the response of the pancreas to alcohol [19]. For example, in awake, chronically cannulated rats, the acute effects of alcohol on basal pancreatic secretion depend on the route of administration. Intravenous alcohol inhibits basal pancreatic secretion, whereas duodenal perfusion in fixed or graded doses stimulates basal secretion [19]. Because basal pancreatic secretion is mediated neurally, much of alcohol’s effects may be on the nervous system. Possible mechanisms will be listed. Direct effects of alcohol on the acinar cell Several lines of evidence suggest that chronic alcohol consumption results in significant injury directly at the acinar cells [20,21]. Among the various components of the acinar cell, the mitochondria appear to be especially sensitive [22–24]. Although pancreatic histology appears normal under light microscopy [25,26], electron microscopy reveals severe mitochondrial injury [27,28]. Differential display profiling of mRNA from control and alcoholfed rats also demonstrated upregulation of the cholesterol esterase (CEL) genes [29]. Although these enzymes help metabolize alcohol, they also convert free fatty acids to fatty acid ethyl esters (FAEE), which appear to be a major factor in alcohol-associated acinar cell injury [30,31]. In addition, mRNA profiling identifies up-regulation of multiple stress-related nuclear
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factors, chemokines, and cytokines [32–36]. These observations suggest that alcohol directly and indirectly injures the pancreatic acinar cell, and that with continued alcohol use, the acinar cells are under chronic metabolic stress; thus, some adaptation must occur to overcome these obstacles. Adaptation to alcohol feeding in rats Acute alcohol ingestion appears to have only modest effects on pancreatic secretion through inhibiting the acinar cell function. It appears to enhance neurally mediated pancreatic secretion, however, possibly through vagal–vagal reflexes or acting on the area postrema (AP) in the medulla oblongata [19]. Within a short-term (approximately 2 weeks) alcohol feeding protocol in rats, marked changes in pancreatic responses to CCK and meals were elicited, resulting in pancreatic hyperstimulation and hypersecretion [19]. Alterations in the neurohormonal control mechanisms continue to be seen beyond 3 months of alcohol feeding, with the specific changes being dependent on the dose of alcohol chronically ingested [37]. In rats fed with high-dose alcohol, meal-stimulated pancreatic enzyme secretion is delayed significantly, followed by a late and exaggerated response that may be caused by chronic changes within the acinar cell [37]. The early hypersecretion seen with short-term feeding [19] was lost. Acute withdrawal of ethanol, however, unmasks and exaggerates hyperstimulation of the acinar cell and hypersecretion of pancreatic enzyme release [37]. These rats do not develop acute or chronic pancreatitis, as may occur in people. Under all conditions tested in the rat, however, the acinar cell was subject to greatest neurohormonal hyperstimulation after short-term, high-dose feeding, and also with CCK or meal stimulation after withdrawal of chronic, high-dose alcohol. These may be situations when people are also at highest risk. Direct effects of alcohol in pancreatic pathophysiology Chronic alcohol ingestion affects many different types of cells in the pathway between the duodenum, brain, pancreatic acinar cell, and delivery of digestive enzymes into the duodenum. Some cell types are likely more sensitive than others, and genetic polymorphisms in certain genes are likely to diminish adaptation of protection from the effects of alcohol in some cells more than others. The details of the whole system have not been worked out in detail, but many of the components are understood. Central effects of alcohol on pancreatic function One of the major targets of alcohol appears to be the AP in the dorsal vagal complex of the medulla oblongata. The AP, also known as the chemoreceptor trigger zone or the vomiting center, is situated immediately dorsal the nucleus of the tractus solitarius (NTS), which is dorsal to the
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dorsal motor nucleus of the vagus (DMV). The dorsal vagal complex is organized like a visceral homunculus, with the mouth and pharynx represented in the oral end, and the colon and rectum represented in the aboral end. The NTS is the sensory receptive portion of the homunculus, and the DMV is the motor component with the sensory and motor components innervating the same visceral organ to facilitate vagal–vagal reflex arches. The stomach and duodenum represent the disproportionately exaggerated portions of the homunculus, just as the hands are disproportionately large in the somatic sensory–motor homunculus. This is because the activity of the entire digestive system is coordinated based on the size of the meal in the stomach and the osmotic, chemical, and nutritional character as detected by the duodenum. The integration of the digestive processes occurs in the dorsal vagal complex with amplification or diminution of the various reflex signals depending on the progression of various components of the digestion. It was unclear, however, how the response of the efferent vagal stimuli to the various organs, or the progression of digestion in response to various reflex actions was monitored. The answer was the AP, which is a specialized portion of the brain with an incomplete blood–brain barrier that is located over the portions of the dorsal vagal complex representing the stomach, duodenum, pancreas, and liver. The vascular permeability allowed gut hormones to complete a feedback loop from the gut to the brain where they could act directly on neurons in the brainstem [38]. Indeed, a variety of gut hormones including pancreatic polypeptide [39] and peptide YY [40] have specific receptors within the AP that bind circulating hormone. These receptors are functional [41] and act as inhibitory regulators of pancreatic function [42,43] and other digestive organs [44]. The authors recently studied the effects of alcohol on vagal–vagal control of pancreatic secretion in awake (nonanesthetized) rats and found that the AP appears to be impaired specifically by chronic alcohol use [19]. This loss of AP function explains, in part, the functional hyperstimulation of the pancreas that is seen with alcoholics, because it represents loss of feedback regulation of vagal-stimulated pancreatic secretion. The AP is also sensitive to toxic agents that may be absorbed through the digestive tract, and it can trigger vomiting [45], a complex and integrated process involving several central nuclei [46]. Although the effects of alcohol on the AP of people has not been tested formally, it is interesting to observe that college freshmen, recently freed from the previous restrictions of parental supervision, are legendary for weekend episodes of unrestricted alcohol consumption and subsequent vomiting. Alcoholics, on the other hand, appear to suffer no such effects from heavy drinking. Effects of alcohol on the acinar cell The histological appearance of pancreatic acinar cells from alcohol-fed rodents or human samples appears normal under light microscopy [47].
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Electron microscopy evaluation, biochemical and molecular analysis, and physiological studies, however, reveal that the acinar cells in alcoholics is not normal. The results of electron microscopy studies have been variable. The authors’ group and Tandler [48] observed significant changes in mitochondrial ultrastructure in alcohol-fed rats, while Singh [47] did not observe these changes in Sprague-Dawley rats. Additionally, Weesner et al [49] did not observe these changes in hamster. Of note, the Wistar rats used in the authors’ series appeared to have less alcohol aversion and consumed more alcohol than Sprague-Dawley rats consumed in previous studies (unpublished observation). The authors evaluated the pancreas of male Wistar rats fed with diets containing 6.7% (volume/volume) ethanol for 4 weeks by electron microscopy and measurement of mitochondrial ATP synthase subunit 9, isoform 3 (ATP5G3) mRNA levels, which reflect a key component of the mitochondrial electron transport system that is coded by nuclear DNA [50]. Severe mitochondrial damage was seen consistently in this model (increased size, damaged cristae, and fragmentation of the mitochondrial membrane), along with up-regulation of ATP5G3 mRNA which the authors interpret as an adaptive response to mitochondrial injury, repair, and regeneration. Functional impairment of mitochondria also have been demonstrated in alcohol-fed rats [51]. These observations are important for two reasons. First, the mitochondria are essential for generating the large amounts of ATP necessary to synthesize digestive enzymes, and loss of ATP leads to metabolic stress. Secondly, the mitochondria play a critical role in regulating intracellular calcium by absorbing calcium and controlling the spread and duration of calcium waves throughout acinar cells [52]. Control of calcium is critical in preventing acute pancreatitis [53]. As noted previously, chronic alcohol ingestion causes changes in the pancreas that reflect chronic metabolic stress. Some effects are direct and immediate, while others may be related to adaptive changes that have pathological consequences (eg, upregulation of CEL and enhanced FAEEs generation) [29,31]. The stimulation-associated stress of chronic alcohol in the acinar cells has been documented, including increasing NF-kappaB activity and mRNA expression of markers of oxidative and nonoxidative stress such as inducible nitric oxide synthase [14,31,54]. Several other markers also are altered (Whitcomb, unpublished observations, 2001). Physiological effects of alcohol on pancreatic acinar cells also have been observed. A small increase in lipase proteolytic enzyme content typically is seen [47,55]. In awake, chronically cannulated rats fed high-dose alcohol for 3 months, direct stimulation of the acinar cells with bethanechol resulted in pancreatic enzyme secretion after a significant delay compared with control rats, but after the delay there was an exaggerated response to bethanechol in both an early and a late phase of pancreatic secretion [37]. When isolated pancreatic acini cells from rats fed alcohol for a similar time period were tested in vitro, the basal enzyme releases and enzyme dose-response curves
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to CCK-8, vasoactive intestinal peptide (VIP), secretin, bombesin, and bethanechol essentially were unchanged in ethanol-fed rats compared with controls [56]. When enzyme secretion was stimulated in isolated cells in the presence of 0.1 molar ethanol in the medium, however, enzyme responses to VIP, secretin, and CCK-8 were inhibited and that to CCK-8 also shifted to the right in ethanol-fed rats compared with controls [56]. Thus, there are significant immediate adaptive changes to the acinar cells chronically exposed to alcohol that factor into pancreatic physiology and may contribute to the susceptibility to acute alcoholic pancreatitis and progression toward chronic pancreatitis. Factors increasing susceptibility to chronic pancreatitis in alcoholics It has been difficult to develop a unified model that considers all of the factors contributing to acute and chronic alcoholic pancreatitis. The authors developed the sentinel acute pancreatitis event (SAPE) model, which recognizes the importance of triggering the immune system to initiate the inflammation and fibrosis that characterize chronic alcoholic pancreatitis [3,57]. The SAPE hypothesis model for chronic pancreatitis suggests that attracts many of the factors associated with chronic pancreatitis only become relevant once an episode of acute pancreatitis occurs and the immunological cells involved in inflammation and attracts into the pancreas. The process is accelerated with recurrent acute pancreatitis and with altered immunological responses that favor fibrosis. Alcohol may be especially important in pancreatic disease, because it can act as a risk factor for acute pancreatitis through multiple mechanisms, and it contributes to chronic pancreatitis through multiple mechanisms. Genetic polymorphisms increase the risk of alcoholic pancreatitis With the discovery that mutations in the cationic trypsinogen gene (PRSS1) cause hereditary pancreatitis, much interest has been focused on determining if genetic cofactors explain the discrepancy between alcohol exposure and susceptibility to pancreatitis. Because alcoholic pancreatitis does not appear to be transmitted as a clear Mendelian trait suitable for genetic linkage studies, most investigators have taken a candidate gene approach to identifying alcoholic pancreatitis-associated genes. The choice of candidate genes generally has fallen into three categories: alcoholmetabolizing genes, acute pancreatitis susceptibility genes, and genes associated with inflammation and fibrosis. Alcohol-metabolizing genes Mutations in the major alcohol-metabolizing genes do not appear to be associated with alcoholic chronic pancreatitis [2,58,59]. Genes that have been
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investigated include alcohol dehydrogenase 2 (ADH 2) and aldehyde dehydrogenase 2 (ALDH 2) [59,60], ADH3, cytochrome P450-2E1 (CYP2E1), glutathione S-transferase-M1 (GSTM1), GSTT1, and others [59–64]. Genes associated with idiopathic recurrent acute and chronic pancreatitis The trypsinogen gene PRSS1, the pancreatic secretory trypsin inhibitor (PSTI) gene (the serine protease inhibitor Kazal type 1, SPINK1), and the cystic fibrosis transmembrane conductance regulator gene (CFTR) have been investigated in the context of alcoholic pancreatitis [58,65]. Numerous investigations have excluded either PRSS1 or SPINK1 gene mutations as a major predisposing cause to alcoholic pancreatitis [66–71]. The role of CFTR mutations is more complex, and further investigations are needed to determine the exact role of CFTR mutations in alcoholic pancreatic disease [65,68,72–76]. Genes associated with inflammation and fibrosis Several HLA antigens had been found to be correlated with alcoholic chronic pancreatitis, but most studies suffered from a poor study design by using nonalcoholic controls and thus could not differentiate between the effects of alcoholism and those of alcoholic pancreatitis [77–79]. The reason for the striking differences in the published HLA patterns are unknown, but they might be explained by ethnic differences between the countries [80]. Wilson et al showed an increased incidence of HLA Bw 39 in pancreatitis that was related to alcoholic pancreatitis rather than to alcoholism itself [80], but this finding fails to explain most cases of alcohol-associated pancreatitis. Several cytokines, including tumor necrosis factor alpha (TNF-a) and interleukin (IL)-1, -6, and -10 appear to be important in modulating the fibrosis of chronic pancreatitis through actions on the pancreatic stellate cells [81,82]. Mutations in the promoter or coding region of TNF-a and the TNF receptor do not appear to act as susceptibility genes for hereditary, familial, idiopathic chronic pancreatitis, or alcoholic chronic pancreatitis [83,84], but the TNF-238A promoter polymorphism may be a modifier gene accelerating chronic pancreatitis in patients with underlying trypsinogen mutations [84]. Many of the IL-10 gene polymorphisms have been excluded as playing the dominant factor leading chronic pancreatitis [84,85], while other cytokines continue to be investigated. Clinical considerations The clinical management of alcohol-related pancreatitis is aimed at reducing alcohol consumption and other risk factors such as tobacco
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smoking [2]. The authors are analyzing the role of alcohol in pancreatitis within the United States to determine risk associated with daily dose, drinking patterns, and clear definitions of alcoholism [82]. Other causes also must be excluded, including genetic factors, possible occult cancers (especially in subjects over age 40 with new onset pancreatitis), and other causes. Finally, various complications and other conditions must be diagnosed and addressed, including the possibility of recurrent acute pancreatitis, splenic vein thrombosis with development of gastric varices, pseudocysts, and pancreatic insufficiency. The role of surgery and other measures to address pain are, in the authors’ minds, unresolved. Genetic variations, however, may explain susceptibility to some complications, including pain, and could serve as a guideline for treatment in the future. Summary Without doubt, alcohol consumption is one of the most important considerations in adults with acute or chronic pancreatitis. Understanding chronic pancreatitis as a complex disorder in which complimentary factors are required for recurrent acute and late chronic pancreatitis to develop in subsets of patients is critical for the early diagnosis and management of these individuals. Recent pathophysiological and genetic findings represent the beginning of major diagnostic and treatment breakthroughs that are likely to continue for the foreseeable future. The information provided in this article should provide the physician with a fresh perspective and remind the clinician of the importance of an accurate and complete history, and the need to document the actual alcohol consumption, pattern of drinking, and raise appropriate concerns if signs of alcoholism are detected. If alcoholassociated pancreatitis is detected, then limitation of pancreatic damage, limitation of progression, or preventative intervention should become the major concern. References [1] Lankisch PG, Lowenfels AB, Maisonneuve P. What is the risk of alcoholic pancreatitis in heavy drinkers? Pancreas 2002;25(4):411–2. [2] Etemad B, Whitcomb DC. Chronic pancreatitis: diagnosis, classification, and new genetic developments. Gastroenterology 2001;120:682–707. [3] Schneider A, Whitcomb DC. Hereditary pancreatitis: a model for inflammatory diseases of the pancreas. Best Pract Res Clin Gastroenterol 2002;16(3):347–63. [4] Whitcomb DC. Value of genetic testing in management of pancreatitis. Gut 2004;53:(in press). [5] Owyang C, Levitt M. Chronic pancreatitis. In: Yamada T, editor. Textbook of gastroenterology. Philadelphia: JB Lippencott Company; 1991. p. 1874–93. [6] Steer ML, Waxman I, Freedman S. Chronic pancreatitis. N Engl J Med 1995;332(22): 1482–90. [7] DiMagno E, Layer P, Clain J. Chronic pancreatitis. In: Go V, editor. The pancreas: biology, pathophysiology and disease. New York: Raven Press; Limited; 1993. p. 665–706.
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Alcoholic pancreatitis Christoph Hanck, MDa, David C. Whitcomb, MD, PhDa,b,* a
Department of Medicine, University of Pittsburgh, UPMC Presbyterian, Mezzanine Level-C Wing, 200 Lothrop Street, Pittsburgh, PA 15213, USA b Departments of Cell Biology and Physiology, and Human Genetics, University of Pittsburgh, UPMC Presbyterian, Mezzanine Level-C Wing, 200 Lothrop Street, Pittsburgh, PA 15213, USA
The relationship between alcohol and pancreatic diseases is difficult to accurately define. Although many individuals with chronic pancreatitis have a history of excessive and sustained alcohol consumption, more that 95% of heavy alcohol users never develop chronic pancreatitis [1,2]. Furthermore, some individuals who do develop chronic pancreatitis have only consumed modest amounts of alcohol for a limited number of years before developing pancreatitis [2]. These observations are consistent with a more general model of recurrent acute and chronic pancreatitis as a complex trait or disorder. In this model, development of recurrent acute pancreatitis requires the coexistence of two or more persistent factors leading to trypsinogen activation, autodigestion, and pancreatitis, either environmental or genetic in nature, before the condition occurs. Chronic pancreatitis requires all factors necessary for recurrent acute pancreatitis plus alterations in the immune response to facilitate chronic inflammation and chronic fibrosis. In the context of a complex disorder model, alcohol becomes especially important, because it can increase the risk of recurrent acute pancreatitis and the risk of chronic pancreatitis through multiple steps and mechanisms [3,4]. What fraction of chronic pancreatitis is caused by alcohol abuse? The etiology of chronic pancreatitis has been ascribed to alcoholism in 70% of all cases United States [5–7]. This often quoted number appears to be supported by three lines of evidence. First, this number parallels estimates from Europe, in which the contribution of alcohol to chronic pancreatitis
* Corresponding author. E-mail address: [email protected] (D.C. Whitcomb). 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2004.07.002 gastro.theclinics.com
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may be inflated because of the higher rate of alcohol consumption among Europeans than Americans. Secondly, the diagnosis of alcoholic chronic pancreatitis may be given to a significant number of subjects who rarely drink alcohol, based on the assumption of some clinicians that calcifying chronic pancreatitis is pathognomonic of alcoholism. The authors base this concern on the testimony of hereditary pancreatitis patients who report that, despite never drinking alcohol in their lives, they were labeled as alcoholics, and some even were referred for alcohol rehabilitation based on the fact that they had otherwise unexplained chronic pancreatitis. Third, the criteria for diagnosing a subject as an alcoholic is inconsistent and may overestimate the true impact of alcohol on a compound, complex disorder. The temptation to label a subject as having alcoholic chronic pancreatitis also may have been driven by the alternate diagnosis of idiopathic chronic pancreatitis, which implies diagnostic failure. Alcohol use in the United States To understand alcoholic pancreatitis within the United States, it is useful to review alcohol use within the general population. This is crucial, because one could argue that if 70% of individuals within the population drink alcohol, and 70% of patients with pancreatitis drink alcohol, then the association could be coincidental. On the other hand, studying adults with chronic pancreatitis but without alcohol use in Europe is challenging, because most Europeans consume alcohol either daily, or weekly. The best epidemiological data on alcohol consumption in the United States comes from the United States Alcohol Epidemiological Data Reference Manual available through the National Institute on Alcohol Abuse and Alcoholism (NIAAA). In 1992, NIAAA conducted the National Longitudinal Alcohol Epidemiologic Survey (NLAES)—at that time, the most ambitious and comprehensive survey of its type ever conducted [8,9]. The NLAES included extensive questions concerning alcohol consumption and items designed to provide psychiatric classification of alcohol use disorders. It also included ethanol conversion factors for comparing alcohol content of different drinks (eg, 0.045 for beer, 0.121 for wine, and 0.409 for liquor). This allowed for estimates of total ethanol consumption during past years. Dividing the annual total by 365 yields an estimate of drinking level, the average daily amount of ethanol consumed [8]. The results of the survey have been published [8,9], and a summary of the primary results is given in Table 1. Among the Caucasian population ages 18 and older, 46.87% were current drinkers; 22.44% were former drinkers, and the remaining 30.69% were lifetime abstainers. Within this group, 12.28% of men and 3.50% of women were considered heavy drinkers (average of 1 or more ounces of ethanol per day). Among the African American population, 32.53% were current drinkers, and 61.72% of females were lifetime abstainers (Table 1), while 6.93% of men, and 2.93% of
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Table 1 Percent distribution of alcohol drinkers in the United States age 18 and over [8] Respondent characteristics Total Current drinker. . . . . . Former drinker. . . . . . Lifetime abstainer. . . . . . Race White Current drinker. . . . . . Former drinker. . . . . . Lifetime abstainer. . . . . . Black Current drinker. . . . . . Former drinker. . . . . . Lifetime abstainer. . . . . .
Both sexes*
Males*
Females*
44.37 0.40 21.63 0.31 34.00 0.42
55.76 0.51 22.53 0.42 21.71 0.43
33.87 0.47 20.80 0.37 45.33 0.57
46.87 0.47 22.44 0.34 30.69 0.47
57.86 0.58 23.11 0.47 19.03 0.45
36.59 0.53 21.81 0.41 41.60 0.61
32.53 0.83 18.82 0.64 48.65 0.90
46.57 1.35 21.01 1.12 32.42 1.35
21.23 0.80 17.05 0.78 61.72 1.07
* Estimated % standard error. The percent distributions were based on the entire population included in the NLAES sample. From Drinking in the United States: main findings from the 1992 National Longitudinal Alcohol Epidemiologic Survey (NLAES). In: US alcohol epidemiologic data reference manual 1998. Bethesda (MD), National Institutes of Health, Publication #99-3519.
women were heavy drinkers. Alcohol drinking was heaviest among younger, never-married adults in urban areas, and lowest in the southern United States [9]. The proportion of individuals drinking alcohol increased with education and income, while the proportion of heavy drinkers also decreased with education and income. On average, the proportion of individuals registered as black or Hispanic consuming alcohol was less than individuals registered as white [9]. This survey provides a foundation for understanding alcohol use in the United States from an epidemiological perspective. Because nearly half of all individuals from the United States never drink alcohol, and less than 10% consume 1 ounce of alcohol or more per day, then the estimate that 70% of subjects with chronic pancreatitis are alcohol drinkers (with at least half being heavy drinkers), provides evidence that there is some type of link between alcohol consumption and pancreatitis. These conclusions are consistent with previous epidemiological studies from around the world [10–12]. Pathophysiology of alcoholi in the pancreas and secretory control mechanisms The reason that alcohol so often is associated with pancreatitis is that it increases risk at multiple steps in the process between normal pancreas and chronic pancreatitis, and it acts through multiple mechanisms. Specifically, alcohol increases the risk of acute pancreatitis, and drives the inflammation leading to fibrosis. The factors surrounding each of these steps will be addressed.
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Alcohol increases the risk of acute pancreatitis It appears that alcohol does not cause acute pancreatitis directly, but rather it lowers the threshold for initiation of acute pancreatitis from other causes. This has been demonstrated most clearly in rat models in which animals or cells are exposed to alcohol and then challenged with various levels of hyperstimulation to initiate pancreatitis. In vitro studies conducted by Katz et al [13] demonstrated that when ethanol (25 nm) was added to pancreatic lobules with low-dose cholecystokinin (0.1 nm) generated zymogen activation was generated at levels that were sixfold higher than cholecystokinin alone, and that was equivalent to levels generated by highdose cholecystokinin (10 lm). This was one of the first clear demonstrations that ethanol selectively sensitizes the pancreatic acinar cell to cholecystokinin-stimulated zymogen proteolysis [13]. Studies in whole animals also demonstrate alcohol sensitization to pancreatitis. Pandol et al [14] fed rats alcohol or control diets intragastrically for 2 or 6 weeks and then infused them with cholecystokinin octapeptide (CCK8) at 3000 pmol/kg per hour. All measures of pancreatitis, NF-kappaB activity, and mRNA expression for tumor necrosis factor alpha (TNF-a), interleukin (IL)-6, monocyte chemotactic protein 1, macrophage inflammatory protein 2, and inducible nitric oxide synthase, were increased significantly only in rats treated with ethanol plus CCK-8 [14]. These studies provide evidence that alcohol does increase sensitivity of the pancreas to hyperstimulation-induced zymogen activation and pancreatitis. The implications are that alcohol increases the risk of acute pancreatitis by lowering the threshold for other factors to trigger an episode of acute pancreatitis. Human alcoholic acute pancreatitis—autopsy studies There is consensus that people develop acute alcoholic pancreatitis [15,16]. The primary evidence has been a series of postmortem studies on patients who either died of acute alcoholic pancreatitis, or who recovered from acute pancreatitis, later died, and had postmortem examinations [17,18]. Regardless of the study method or perspective, all studies report a significant fraction of subjects with severe alcohol-induced acute pancreatitis with no evidence of underlying chronic pancreatitis. Although the mechanism leading to chronic pancreatitis in people is impossible to prove directly, some insights from animal models are instructive. Animal studies on susceptibility to acute pancreatitis after alcohol feeding Animal studies demonstrate that chronic alcohol consumption lowers the threshold for triggering acute pancreatitis, and therefore likely increases risk. Triggering acute pancreatitis means triggering unregulated intrapancreatic trypsinogen activation, leading to pancreatic autodigestion and
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acute pancreatitis. In the absence of specific mutations in trypsin or trypsin regulating genes, sustained intrapancreatic trypsin activation appears to require intra-acinar cell hypercalcemia (which eliminates the trypsinogen autodigestion mechanisms) or failure to clear activated trypsin from the intrapancreatic ducts (which is a high-calcium environment). The pathway connecting the delivery of nutrients into the intestine to release zymogen granules from the acinar cell into the duct contains several steps that are sensitive to alcohol and that increase the risk of intracellular hypercalcemia, potentially leading to unregulated intra-acinar cell trypsin activation and stabilization. The effects of alcohol vary with the timing and amount of alcohol consumed and can be divided into preacinar cell effects and intra-acinar cell effects. Preacinar cell effects lead to neurohormonal hyperstimulation; intra-acinar cell effects lead to organelle injury or fragility, loss of calcium regulation, or zymogen mis-sorting. Route of alcohol administration Several experiments have been done in people and animals to determine the effect of alcohol on pancreatic function. The results of these experiments and interpretation thereof often appear contradictory and confusing. The reason for apparent discrepancies depends on delicacy of the experimental design and the model used, including the presence or type of sedation. Indeed, the authors have shown that the route of alcohol administration (intravenous or intraduodenal) or the duration of exposure makes a significant difference in the response of the pancreas to alcohol [19]. For example, in awake, chronically cannulated rats, the acute effects of alcohol on basal pancreatic secretion depend on the route of administration. Intravenous alcohol inhibits basal pancreatic secretion, whereas duodenal perfusion in fixed or graded doses stimulates basal secretion [19]. Because basal pancreatic secretion is mediated neurally, much of alcohol’s effects may be on the nervous system. Possible mechanisms will be listed. Direct effects of alcohol on the acinar cell Several lines of evidence suggest that chronic alcohol consumption results in significant injury directly at the acinar cells [20,21]. Among the various components of the acinar cell, the mitochondria appear to be especially sensitive [22–24]. Although pancreatic histology appears normal under light microscopy [25,26], electron microscopy reveals severe mitochondrial injury [27,28]. Differential display profiling of mRNA from control and alcoholfed rats also demonstrated upregulation of the cholesterol esterase (CEL) genes [29]. Although these enzymes help metabolize alcohol, they also convert free fatty acids to fatty acid ethyl esters (FAEE), which appear to be a major factor in alcohol-associated acinar cell injury [30,31]. In addition, mRNA profiling identifies up-regulation of multiple stress-related nuclear
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factors, chemokines, and cytokines [32–36]. These observations suggest that alcohol directly and indirectly injures the pancreatic acinar cell, and that with continued alcohol use, the acinar cells are under chronic metabolic stress; thus, some adaptation must occur to overcome these obstacles. Adaptation to alcohol feeding in rats Acute alcohol ingestion appears to have only modest effects on pancreatic secretion through inhibiting the acinar cell function. It appears to enhance neurally mediated pancreatic secretion, however, possibly through vagal–vagal reflexes or acting on the area postrema (AP) in the medulla oblongata [19]. Within a short-term (approximately 2 weeks) alcohol feeding protocol in rats, marked changes in pancreatic responses to CCK and meals were elicited, resulting in pancreatic hyperstimulation and hypersecretion [19]. Alterations in the neurohormonal control mechanisms continue to be seen beyond 3 months of alcohol feeding, with the specific changes being dependent on the dose of alcohol chronically ingested [37]. In rats fed with high-dose alcohol, meal-stimulated pancreatic enzyme secretion is delayed significantly, followed by a late and exaggerated response that may be caused by chronic changes within the acinar cell [37]. The early hypersecretion seen with short-term feeding [19] was lost. Acute withdrawal of ethanol, however, unmasks and exaggerates hyperstimulation of the acinar cell and hypersecretion of pancreatic enzyme release [37]. These rats do not develop acute or chronic pancreatitis, as may occur in people. Under all conditions tested in the rat, however, the acinar cell was subject to greatest neurohormonal hyperstimulation after short-term, high-dose feeding, and also with CCK or meal stimulation after withdrawal of chronic, high-dose alcohol. These may be situations when people are also at highest risk. Direct effects of alcohol in pancreatic pathophysiology Chronic alcohol ingestion affects many different types of cells in the pathway between the duodenum, brain, pancreatic acinar cell, and delivery of digestive enzymes into the duodenum. Some cell types are likely more sensitive than others, and genetic polymorphisms in certain genes are likely to diminish adaptation of protection from the effects of alcohol in some cells more than others. The details of the whole system have not been worked out in detail, but many of the components are understood. Central effects of alcohol on pancreatic function One of the major targets of alcohol appears to be the AP in the dorsal vagal complex of the medulla oblongata. The AP, also known as the chemoreceptor trigger zone or the vomiting center, is situated immediately dorsal the nucleus of the tractus solitarius (NTS), which is dorsal to the
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dorsal motor nucleus of the vagus (DMV). The dorsal vagal complex is organized like a visceral homunculus, with the mouth and pharynx represented in the oral end, and the colon and rectum represented in the aboral end. The NTS is the sensory receptive portion of the homunculus, and the DMV is the motor component with the sensory and motor components innervating the same visceral organ to facilitate vagal–vagal reflex arches. The stomach and duodenum represent the disproportionately exaggerated portions of the homunculus, just as the hands are disproportionately large in the somatic sensory–motor homunculus. This is because the activity of the entire digestive system is coordinated based on the size of the meal in the stomach and the osmotic, chemical, and nutritional character as detected by the duodenum. The integration of the digestive processes occurs in the dorsal vagal complex with amplification or diminution of the various reflex signals depending on the progression of various components of the digestion. It was unclear, however, how the response of the efferent vagal stimuli to the various organs, or the progression of digestion in response to various reflex actions was monitored. The answer was the AP, which is a specialized portion of the brain with an incomplete blood–brain barrier that is located over the portions of the dorsal vagal complex representing the stomach, duodenum, pancreas, and liver. The vascular permeability allowed gut hormones to complete a feedback loop from the gut to the brain where they could act directly on neurons in the brainstem [38]. Indeed, a variety of gut hormones including pancreatic polypeptide [39] and peptide YY [40] have specific receptors within the AP that bind circulating hormone. These receptors are functional [41] and act as inhibitory regulators of pancreatic function [42,43] and other digestive organs [44]. The authors recently studied the effects of alcohol on vagal–vagal control of pancreatic secretion in awake (nonanesthetized) rats and found that the AP appears to be impaired specifically by chronic alcohol use [19]. This loss of AP function explains, in part, the functional hyperstimulation of the pancreas that is seen with alcoholics, because it represents loss of feedback regulation of vagal-stimulated pancreatic secretion. The AP is also sensitive to toxic agents that may be absorbed through the digestive tract, and it can trigger vomiting [45], a complex and integrated process involving several central nuclei [46]. Although the effects of alcohol on the AP of people has not been tested formally, it is interesting to observe that college freshmen, recently freed from the previous restrictions of parental supervision, are legendary for weekend episodes of unrestricted alcohol consumption and subsequent vomiting. Alcoholics, on the other hand, appear to suffer no such effects from heavy drinking. Effects of alcohol on the acinar cell The histological appearance of pancreatic acinar cells from alcohol-fed rodents or human samples appears normal under light microscopy [47].
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Electron microscopy evaluation, biochemical and molecular analysis, and physiological studies, however, reveal that the acinar cells in alcoholics is not normal. The results of electron microscopy studies have been variable. The authors’ group and Tandler [48] observed significant changes in mitochondrial ultrastructure in alcohol-fed rats, while Singh [47] did not observe these changes in Sprague-Dawley rats. Additionally, Weesner et al [49] did not observe these changes in hamster. Of note, the Wistar rats used in the authors’ series appeared to have less alcohol aversion and consumed more alcohol than Sprague-Dawley rats consumed in previous studies (unpublished observation). The authors evaluated the pancreas of male Wistar rats fed with diets containing 6.7% (volume/volume) ethanol for 4 weeks by electron microscopy and measurement of mitochondrial ATP synthase subunit 9, isoform 3 (ATP5G3) mRNA levels, which reflect a key component of the mitochondrial electron transport system that is coded by nuclear DNA [50]. Severe mitochondrial damage was seen consistently in this model (increased size, damaged cristae, and fragmentation of the mitochondrial membrane), along with up-regulation of ATP5G3 mRNA which the authors interpret as an adaptive response to mitochondrial injury, repair, and regeneration. Functional impairment of mitochondria also have been demonstrated in alcohol-fed rats [51]. These observations are important for two reasons. First, the mitochondria are essential for generating the large amounts of ATP necessary to synthesize digestive enzymes, and loss of ATP leads to metabolic stress. Secondly, the mitochondria play a critical role in regulating intracellular calcium by absorbing calcium and controlling the spread and duration of calcium waves throughout acinar cells [52]. Control of calcium is critical in preventing acute pancreatitis [53]. As noted previously, chronic alcohol ingestion causes changes in the pancreas that reflect chronic metabolic stress. Some effects are direct and immediate, while others may be related to adaptive changes that have pathological consequences (eg, upregulation of CEL and enhanced FAEEs generation) [29,31]. The stimulation-associated stress of chronic alcohol in the acinar cells has been documented, including increasing NF-kappaB activity and mRNA expression of markers of oxidative and nonoxidative stress such as inducible nitric oxide synthase [14,31,54]. Several other markers also are altered (Whitcomb, unpublished observations, 2001). Physiological effects of alcohol on pancreatic acinar cells also have been observed. A small increase in lipase proteolytic enzyme content typically is seen [47,55]. In awake, chronically cannulated rats fed high-dose alcohol for 3 months, direct stimulation of the acinar cells with bethanechol resulted in pancreatic enzyme secretion after a significant delay compared with control rats, but after the delay there was an exaggerated response to bethanechol in both an early and a late phase of pancreatic secretion [37]. When isolated pancreatic acini cells from rats fed alcohol for a similar time period were tested in vitro, the basal enzyme releases and enzyme dose-response curves
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to CCK-8, vasoactive intestinal peptide (VIP), secretin, bombesin, and bethanechol essentially were unchanged in ethanol-fed rats compared with controls [56]. When enzyme secretion was stimulated in isolated cells in the presence of 0.1 molar ethanol in the medium, however, enzyme responses to VIP, secretin, and CCK-8 were inhibited and that to CCK-8 also shifted to the right in ethanol-fed rats compared with controls [56]. Thus, there are significant immediate adaptive changes to the acinar cells chronically exposed to alcohol that factor into pancreatic physiology and may contribute to the susceptibility to acute alcoholic pancreatitis and progression toward chronic pancreatitis. Factors increasing susceptibility to chronic pancreatitis in alcoholics It has been difficult to develop a unified model that considers all of the factors contributing to acute and chronic alcoholic pancreatitis. The authors developed the sentinel acute pancreatitis event (SAPE) model, which recognizes the importance of triggering the immune system to initiate the inflammation and fibrosis that characterize chronic alcoholic pancreatitis [3,57]. The SAPE hypothesis model for chronic pancreatitis suggests that attracts many of the factors associated with chronic pancreatitis only become relevant once an episode of acute pancreatitis occurs and the immunological cells involved in inflammation and attracts into the pancreas. The process is accelerated with recurrent acute pancreatitis and with altered immunological responses that favor fibrosis. Alcohol may be especially important in pancreatic disease, because it can act as a risk factor for acute pancreatitis through multiple mechanisms, and it contributes to chronic pancreatitis through multiple mechanisms. Genetic polymorphisms increase the risk of alcoholic pancreatitis With the discovery that mutations in the cationic trypsinogen gene (PRSS1) cause hereditary pancreatitis, much interest has been focused on determining if genetic cofactors explain the discrepancy between alcohol exposure and susceptibility to pancreatitis. Because alcoholic pancreatitis does not appear to be transmitted as a clear Mendelian trait suitable for genetic linkage studies, most investigators have taken a candidate gene approach to identifying alcoholic pancreatitis-associated genes. The choice of candidate genes generally has fallen into three categories: alcoholmetabolizing genes, acute pancreatitis susceptibility genes, and genes associated with inflammation and fibrosis. Alcohol-metabolizing genes Mutations in the major alcohol-metabolizing genes do not appear to be associated with alcoholic chronic pancreatitis [2,58,59]. Genes that have been
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investigated include alcohol dehydrogenase 2 (ADH 2) and aldehyde dehydrogenase 2 (ALDH 2) [59,60], ADH3, cytochrome P450-2E1 (CYP2E1), glutathione S-transferase-M1 (GSTM1), GSTT1, and others [59–64]. Genes associated with idiopathic recurrent acute and chronic pancreatitis The trypsinogen gene PRSS1, the pancreatic secretory trypsin inhibitor (PSTI) gene (the serine protease inhibitor Kazal type 1, SPINK1), and the cystic fibrosis transmembrane conductance regulator gene (CFTR) have been investigated in the context of alcoholic pancreatitis [58,65]. Numerous investigations have excluded either PRSS1 or SPINK1 gene mutations as a major predisposing cause to alcoholic pancreatitis [66–71]. The role of CFTR mutations is more complex, and further investigations are needed to determine the exact role of CFTR mutations in alcoholic pancreatic disease [65,68,72–76]. Genes associated with inflammation and fibrosis Several HLA antigens had been found to be correlated with alcoholic chronic pancreatitis, but most studies suffered from a poor study design by using nonalcoholic controls and thus could not differentiate between the effects of alcoholism and those of alcoholic pancreatitis [77–79]. The reason for the striking differences in the published HLA patterns are unknown, but they might be explained by ethnic differences between the countries [80]. Wilson et al showed an increased incidence of HLA Bw 39 in pancreatitis that was related to alcoholic pancreatitis rather than to alcoholism itself [80], but this finding fails to explain most cases of alcohol-associated pancreatitis. Several cytokines, including tumor necrosis factor alpha (TNF-a) and interleukin (IL)-1, -6, and -10 appear to be important in modulating the fibrosis of chronic pancreatitis through actions on the pancreatic stellate cells [81,82]. Mutations in the promoter or coding region of TNF-a and the TNF receptor do not appear to act as susceptibility genes for hereditary, familial, idiopathic chronic pancreatitis, or alcoholic chronic pancreatitis [83,84], but the TNF-238A promoter polymorphism may be a modifier gene accelerating chronic pancreatitis in patients with underlying trypsinogen mutations [84]. Many of the IL-10 gene polymorphisms have been excluded as playing the dominant factor leading chronic pancreatitis [84,85], while other cytokines continue to be investigated. Clinical considerations The clinical management of alcohol-related pancreatitis is aimed at reducing alcohol consumption and other risk factors such as tobacco
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smoking [2]. The authors are analyzing the role of alcohol in pancreatitis within the United States to determine risk associated with daily dose, drinking patterns, and clear definitions of alcoholism [82]. Other causes also must be excluded, including genetic factors, possible occult cancers (especially in subjects over age 40 with new onset pancreatitis), and other causes. Finally, various complications and other conditions must be diagnosed and addressed, including the possibility of recurrent acute pancreatitis, splenic vein thrombosis with development of gastric varices, pseudocysts, and pancreatic insufficiency. The role of surgery and other measures to address pain are, in the authors’ minds, unresolved. Genetic variations, however, may explain susceptibility to some complications, including pain, and could serve as a guideline for treatment in the future. Summary Without doubt, alcohol consumption is one of the most important considerations in adults with acute or chronic pancreatitis. Understanding chronic pancreatitis as a complex disorder in which complimentary factors are required for recurrent acute and late chronic pancreatitis to develop in subsets of patients is critical for the early diagnosis and management of these individuals. Recent pathophysiological and genetic findings represent the beginning of major diagnostic and treatment breakthroughs that are likely to continue for the foreseeable future. The information provided in this article should provide the physician with a fresh perspective and remind the clinician of the importance of an accurate and complete history, and the need to document the actual alcohol consumption, pattern of drinking, and raise appropriate concerns if signs of alcoholism are detected. If alcoholassociated pancreatitis is detected, then limitation of pancreatic damage, limitation of progression, or preventative intervention should become the major concern. References [1] Lankisch PG, Lowenfels AB, Maisonneuve P. What is the risk of alcoholic pancreatitis in heavy drinkers? Pancreas 2002;25(4):411–2. [2] Etemad B, Whitcomb DC. Chronic pancreatitis: diagnosis, classification, and new genetic developments. Gastroenterology 2001;120:682–707. [3] Schneider A, Whitcomb DC. Hereditary pancreatitis: a model for inflammatory diseases of the pancreas. Best Pract Res Clin Gastroenterol 2002;16(3):347–63. [4] Whitcomb DC. Value of genetic testing in management of pancreatitis. Gut 2004;53:(in press). [5] Owyang C, Levitt M. Chronic pancreatitis. In: Yamada T, editor. Textbook of gastroenterology. Philadelphia: JB Lippencott Company; 1991. p. 1874–93. [6] Steer ML, Waxman I, Freedman S. Chronic pancreatitis. N Engl J Med 1995;332(22): 1482–90. [7] DiMagno E, Layer P, Clain J. Chronic pancreatitis. In: Go V, editor. The pancreas: biology, pathophysiology and disease. New York: Raven Press; Limited; 1993. p. 665–706.
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