Structured alcohol cessation support program versus current practice in acute alcoholic pancreatitis (PANDA): Study protocol for a multicentre cluster randomised controlled trial.

BACKGROUND/OBJECTIVES: The most important risk factor for recurrent pancreatitis after an episode of acute alcoholic pancreatitis is continuation of alcohol use. Current guidelines do not recommend any specific treatment strategy regarding alcohol cessation. The PANDA trial investigates whether implementation of a structured alcohol cessation support program prevents pancreatitis recurrence after a first episode of acute alcoholic pancreatitis. METHODS: PANDA is a nationwide cluster randomised superiority trial. Participating hospitals are randomised for the investigational management, consisting of a structured alcohol cessation support program, or current practice. Patients with a first episode of acute pancreatitis caused by harmful drinking (AUDIT score >7 and < 16 for men and >6 and < 14 for women) will be included. The primary endpoint is recurrence of acute pancreatitis. Secondary endpoints include cessation or reduction of alcohol use, other alcohol-related diseases, mortality, quality of life, quality-adjusted life years (QALYs) and costs. The follow-up period comprises one year after inclusion. DISCUSSION: This is the first multicentre trial with a cluster randomised trial design to investigate whether a structured alcohol cessation support program reduces recurrent acute pancreatitis in patients after a first episode of acute alcoholic pancreatitis, as compared with current practice. TRIAL REGISTRATION: Netherlands Trial Registry (NL8852). Prospectively registered.

[Influence of environmental factors and polymorphic loci rs6580502 of the SPINK1 gene, rs10273639 of the PRSS1 gene, rs213950 of the CFTR gene on the risk of developing acute alcoholic-alimentary pancreatitis].

The study of genetic and environmental factors on the risk of acute alcoholic-alimentary pancreatitis (AАAР) is especially relevant to interpret individual links of pathogenesis, to reduce the incidence by eliminating the impact of harmful factors and improve the quality of life of the population through the introduction of optimal nutrition, and a healthy lifestyle, which is especially important for carriers of risk genotypes. The aim of the research was to study the influence of environmental factors and polymorphic loci rs6580502 of the SPINK1 gene, rs10273639 of the PRSS1 gene, rs213950 of the CFTR gene on the risk of АAР. Material and methods. Blood DNA samples obtained from 547 patients with AАAР and 573 healthy individuals were used as the material for the study. The groups were comparable by sex and age. All participants were assessed qualitatively and quantitatively for risk factors, smoking and alcohol consumption, the frequency, quantity and regularity of intake of various types of foods, as well as the size and number of portions eaten. Genomic DNA was isolated by the standard phenol-chloroform extraction method, multiplex genotyping of SNPs was performed on a MALDI-TOF MassARRAY-4 genetic analyzer. Results. It was found that the T/T genotype (p=0.0012) of the rs6580502 SPINK1 was associated with an increased risk of AAAP, and the T allele (p=0.0001) and C/T and T/T genotypes (p=0.0001) of the rs10273639 PRSS1, A allele (p=0.01) and A/G and A/A genotypes (p=0.0006) of the rs213950 CFTR were associated with an decreased risk of the disease. The revealed effects of polymorphic loci of candidate genes were enhanced by the effect of alcohol consumption. The risk of AAAP was reduced by fat intake of less than 89 g per day in carriers of the A/G-A/A CFTR genotypes (rs213950), consumption of fresh vegetables and fruits of more than 27 g per day in carriers of the T/C-T/T PRSS1 genotypes (rs10273639), protein intake of more 84 g per day in carriers of T/C-T/T PRSS1 rs10273639 and A/G-A/A CFTR rs213950. The most significant models of gene-environment interactions included risk factors: deficiency in the diet of protein, fresh vegetables and fruits, smoking, and polymorphic variants of the PRSS1 (rs10273639) and SPINK (rs6580502) genes. Conclusion. In order to prevent the development of AAAP, carriers of risk genotypes of candidate genes need not only to exclude or significantly reduce alcohol consumption (in terms of volume, frequency and duration); but also carriers of the A/G-A/A CFTR genotypes (rs213950) need to balance the diet by reducing fat intake to less than 89 g per day and increasing protein intake to more than 84 g per day; carriers of the T/C-T/T PRSS1 (rs10273639) genotypes should increase their intake of fresh vegetables and fruits over 27 g/day and protein over 84 g/day.

A Case-CrossovEr study deSign to inform tailored interventions to prevent disease progression in Acute Pancreatitis (ACCESS-AP) - study design and population.

BACKGROUND/OBJECTIVES: Alcohol is the most common etiology of recurrent acute pancreatitis and chronic pancreatitis. The extent and timing of drinking that increases the transient risk of acute pancreatitis is yet unknown. METHODS: We designed a case-crossover study to determine the effective hazard period of drinking in relation to episodes of pancreatitis. We aim to evaluate the dose-response relationship between excess drinking and pancreatitis comparing the extent of drinking during case and control periods from the same individual. We aim to recruit 160 patients hospitalized with acute pancreatitis, whose AUDIT-C score reaches 3 or higher. Interviews of each enrolled patient to define their 15-day history of alcohol consumption employing the timeline follow-back method. Long-term drinking and smoking will be investigated as modifiers of the impact of short-term excess drinking. Patients are followed-up for evaluation of usual alcohol consumption during asymptomatic periods following the index hospitalization. Blood and urine specimens are collected while the patients are hospitalized and during a standard-of-care follow-up visit. RESULTS: We have recruited 31 patients to date, with a median age of 33 years. Females and non-White participants make up 26% and 35% of the enrolled population, respectively. Forty-eight % of patients have had a prior history of acute pancreatitis. CONCLUSIONS: Our study will shed light on the impact of short-term changes in drinking on triggering acute pancreatitis. It will provide data on other covarying factors of drinking and behaviors changes after acute pancreatitis.

The Combination of Alcohol and Cigarette Smoke Induces Endoplasmic Reticulum Stress and Cell Death in Pancreatic Acinar Cells.

BACKGROUND & AIMS: Smoking, an independent risk factor for pancreatitis, accelerates the development of alcoholic pancreatitis. Alcohol feeding of mice induces up-regulation of spliced X-box binding protein 1 (XBP1s), which regulates the endoplasmic reticulum (ER) unfolded protein response and promotes cell survival upon ER stress. We examined whether smoking affects the adaptive mechanisms induced by alcohol and accelerates disorders of the ER in pancreatic acinar cells. METHODS: We studied the combined effects of ethanol (EtOH) and cigarette smoke extract (CSE) on ER stress and cell death responses in mouse and human primary acini and the acinar cell line AR42J. Cells were incubated with EtOH (50 mmol/L), CSE (20-40 µg/mL), or both (CSE+EtOH), and analyzed by immunoblotting, quantitative reverse-transcription polymerase chain reaction, and cell death assays. Some cells were incubated with MKC-3946, an inhibitor of endoplasmic reticulum to nucleus signaling 1 (ERN1, also called IRE1) that blocks XBP1s formation. Male Sprague-Dawley rats were fed isocaloric amounts of an EtOH-containing (Lieber-DeCarli) or control diet for 11 weeks and exposed to cigarette smoke or room air in an exposure chamber for 2 hours each day. During the last 3 weeks, a subset of rats received intravenous injections of lipopolysaccharide (LPS, 3 mg/kg per week) to induce pancreatitis or saline (control). Pancreatic tissues were collected and analyzed by histology and immunostaining techniques. RESULTS: In AR42J and primary acini, CSE+EtOH induced cell death (necrosis and apoptosis), but neither agent alone had this effect. Cell death was associated with a significant decrease in expression of XBP1s. CSE+EtOH, but neither agent alone, slightly decreased adenosine triphosphate levels in AR42J cells, but induced oxidative stress and sustained activation (phosphorylation) of eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3, also called PERK) and increased protein levels of DNA damage inducible transcript 3 (DDIT3, also called CHOP). CHOP regulates transcription to promote apoptosis. Incubation of AR42J or primary mouse or human acinar cells with MKC-3946 reduced expression of XBP1s, increased levels of CHOP, and induced cell death. In rats fed an EtOH diet, exposure to cigarette smoke increased ER stress in acinar cells and sensitized the pancreas to LPS-induced pathology. CONCLUSIONS: Cigarette smoke promotes cell death and features of pancreatitis in EtOH-sensitized acinar cells by suppressing the adaptive unfolded protein response signaling pathway. It also activates ER stress pathways that promote acinar cell death.

The lifestyle influence on alcoholic pancreatitis versus alcoholic liver disease: a case-control study.

OBJECTIVE: To evaluate the association of lifestyle with the development of alcoholic liver disease (ALD) or alcoholic pancreatitis (AlcP). METHODS: A case-control study was conducted on 80 patients attending a tertiary university hospital, subdivided into three groups: ALD (n = 34), AlcP (n = 21) and a control (CT) group (n = 25) of alcohol abusers without clinical evidence of hepatic or pancreatic disease. Participants were interviewed regarding alcohol consumption, tobacco use and diet. A physical examination was concomitantly performed and we had access to their complementary investigation. RESULTS: We included 10 females and 70 males (mean age 57 ± 10 years). The pure amount of alcohol consumed by the ALD group was significantly higher than the AlcP group, regarding both daily (grams/day) and lifetime (kilograms) consumptions (p = .018 and p = .009, respectively); no statistically significant differences were seen with the CT group. We found no differences regarding the beverage type or drinking outside meals. Smoking was very common in every study group, with higher consumptions and a significantly higher prevalence of ever smokers in the AlcP group, in comparison with ALD and CT patients (p = .033 and p = .036, respectively). There were significant differences in the patients' eating habits before the onset of disease between groups (p < .001), with ALD subjects reporting a less abundant diet and AlcP a more abundant diet in the past; most of the controls had unchanged habits. CONCLUSION: We found differences in lifestyle between ALD and AlcP, not considered sufficient to explain the subjects' susceptibility to one disease or the other.

Pancreatic adaptive responses in alcohol abuse: Role of the unfolded protein response.

The majority of those who drink excessive amounts of alcohol do not develop pancreatic disease. One overarching hypothesis is that alcohol abuse requires additional risk factors, either environmental or genetic, for disease to occur. However, another reason be a result of alcohol-induced activation of adaptive systems that protect the pancreas from the toxic effects of alcohol. We show that mechanisms within the unfolded protein response (UPR) of the endoplasmic reticulum (ER) that can lead to protection of the pancreas from pancreatic diseases with alcohol abuse. The remarkable ability of the pancreas to adapt its machinery to alcohol abuse using UPR systems and continue functioning is the likely reason that pancreatitis from alcohol abuse does not occur in the majority of heavy drinkers. These findings indicate that methods to enhance the protective responses of the UPR can provide opportunities for prevention and treatment of pancreatic diseases.

The role of fat and alcohol in acute pancreatitis: A dangerous liaison.

Excessive alcohol consumption is a major trigger for severe acute pancreatitis which may lead to multi-organ dysfunction and premature death of the individual. Hyperlipidaemia is a risk factor for both acute and chronic pancreatitis and the role of fatty acids in mediating damage has received increasing attention in recent years. In the pancreas ethanol is metabolised by both oxidative and non-oxidative pathways. The latter, predominant route generates fatty acid ethyl esters (FAEEs) from fatty acid substrates via the action of diverse enzymes called FAEE synthases, including carboxylester lipase an enzyme synthesized and secreted by the acinar cells. Inhibition of the oxidative pathway promotes formation of FAEEs which induce sustained elevations of cytosolic calcium leading to inhibition of mitochondrial function, loss of ATP and necrosis of isolated pancreatic acinar cells. Furthermore, FAEEs undergo hydrolysis in the mitochondria releasing free fatty acids that exert toxic effects. Our recent work has shown that pharmacological inhibition of carboxylester lipase ameliorated detrimental effects of non-oxidative ethanol metabolism in isolated pancreatic acinar cells in vitro and in a new in vivo experimental model of alcoholic acute pancreatitis, revealing a specific enzyme target for ethanol-induced injury. Strategies that prevent FAEE synthesis, protect mitochondria, reduce calcium overload or sustain calcium homeostasis by ATP provision may provide promising therapeutic avenues for the treatment of alcoholic acute pancreatitis.

Models of acute and chronic pancreatitis.

Animal models of acute and chronic pancreatitis have been created to examine mechanisms of pathogenesis, test therapeutic interventions, and study the influence of inflammation on the development of pancreatic cancer. In vitro models can be used to study early stage, short-term processes that involve acinar cell responses. Rodent models reproducibly develop mild or severe disease. One of the most commonly used pancreatitis models is created by administration of supraphysiologic concentrations of caerulein, an ortholog of cholecystokinin. Induction of chronic pancreatitis with factors thought to have a role in human disease, such as combinations of lipopolysaccharide and chronic ethanol feeding, might be relevant to human disease. Models of autoimmune chronic pancreatitis have also been developed. Most models, particularly of chronic pancreatitis, require further characterization to determine which features of human disease they include.

Alcohol-induced severe acute pancreatitis followed by hemolytic uremic syndrome managed with continuous renal replacement therapy.

BACKGROUND: Acute kidney injury in patients with acute pancreatitis carries a poor prognosis. Hemolytic uremic syndrome (HUS) is characterized by non-immune hemolytic anemia, thrombocytopenia, and renal failure caused by platelet thrombi in the microcirculation of the kidney, and though rare in adults it is associated with high mortality and a high rate of chronic renal failure. CASE PRESENTATION: Herein, we report a case of alcohol-induced acute pancreatitis in a 38-year-old Chinese female complicated by HUS. Her renal function progressively deteriorated in 2 days, and daily continuous renal replacement therapy (CRRT) was thus performed for a total of 13 treatments. She also received intermittent transfusions of fresh frozen plasma. Her renal failure was successfully managed, with subsequent return of normal renal function. She was discharged 1 month after admission and follow-up at 3 months revealed normal urea and creatinine. CONCLUSION: CRRT was shown to be useful for the treatment of HUS following acute pancreatitis. Prior case reports and our case should remind clinicians that HUS is a possible complication of acute pancreatitis. This study highlights the importance of early diagnosis and prompt initiation of CRRT to prevent mortality and improve outcomes.

Time trends in the etiology of chronic pancreatitis in South India.

BACKGROUND: Recent reports indicate a decline in prevalence of classical tropical chronic pancreatitis (TCP). We studied the etiologies and risk factors over a 14-year period at a tertiary care university hospital. METHODS: We compared the etiology in chronic pancreatitis (CP) patients presenting and followed-up in our Pancreas Clinic over two time periods (2000-06 and 2007-13). RESULTS: Idiopathic chronic pancreatitis (ICP) was the predominant etiology seen over the two time periods. However an increase in prevalence of alcoholic chronic pancreatitis (ACP) during the latter time period suggests that it may be emerging as a dominant etiology over recent years. Hypertriglyceridemia and hyperparathyroidism were uncommon causes of non-alcoholic CP. Autoimmune pancreatitis was noted only during 2007-13, but remains a rare cause of CP. There are multiple risk factors for CP in our population. CONCLUSIONS: The high prevalence of ICP indicates need closer examination of risk factors and ICP pathogenesis. ACP appears to be emerging as a dominant cause of CP which suggests a need to reorient preventive strategies.

[The association study of the promoter polymorphism -308G>A of tumor necrosis factor gene with the development and severity of acute pancreatitis in Russian population of Kursk region].

The aim of this study was to investigate the relationship between the polymorphism -308G>A of tumor necrosis factor (TNF) gene and the risk and severity of acute pancreatitis (AP) in unrelated Russians from Kursk region. DNA samples were obtained from 190 AP patients and 217 healthy controls for genotyping the polymorphism through a TaqMan allelic discrimination assay. Although -308G>A genotypes did not show a significant association with disease risk, the genotype -308GA was found to be associated only with non-severe type of acute alcohol-related pancreatitis (odds ratio 1.81 (95% CI 1.02-3.23 p=0.04).

Alcohol and plasma triglycerides.

PURPOSE OF REVIEW: This study reviews recent developments concerning the effects of alcohol on plasma triglycerides. The focus will be on population, intervention and metabolic studies with respect to alcohol and plasma triglycerides. RECENT FINDINGS: Alcohol consumption and fat ingestion are closely associated and stimulated by each other via hypothalamic signals and by an elevated cephalic response. A J-shaped relationship between alcohol intake and plasma triglycerides has been described. A normal body weight, polyphenols in red wine and specific polymorphisms of the apolipoprotein A-V and apolipoprotein C-III genes may protect against alcohol-associated hypertriglyceridemia. In contrast, obesity exaggerates alcohol-associated hypertriglyceridemia and therefore the risk of pancreatitis. SUMMARY: High alcohol intake remains harmful since it is associated with elevated plasma triglycerides, but also with cardiovascular disease, alcoholic fatty liver disease and the development of pancreatitis. Alcohol-induced hypertriglyceridemia is due to increased very-low-density lipoprotein secretion, impaired lipolysis and increased free fatty acid fluxes from adipose tissue to the liver. However, light to moderate alcohol consumption may be associated with decreased plasma triglycerides, probably determined by the type of alcoholic beverage consumed, genetic polymorphisms and lifestyle factors. Nevertheless, patients should be advised to reduce or stop alcohol consumption in case of hypertriglyceridemia.

Effects of ethanol metabolites on exocytosis of pancreatic acinar cells in rats.

BACKGROUND & AIMS: During development of alcoholic pancreatitis, oxidative (acetaldehyde) and nonoxidative metabolites (ethyl palmitate, ethyl oleate), rather than ethanol itself, mediate toxic injury. Exposure of pancreatic acini to ethanol blocks cholecystokinin (CCK)-8-stimulated apical exocytosis and redirects exocytosis to the basolateral plasma membrane, causing interstitial pancreatitis. We examined how each ethanol metabolite contributes to these changes in exocytosis. METHODS: Rat pancreatic acini were incubated with concentrations of ethanol associated with alcoholic pancreatitis (20-50 mmol/L) or ethanol metabolites (1-3 mmol/L) and then stimulated with CCK-8. We performed single zymogen granule (ZG) exocytosis assays, Ca(2+) imaging studies, ultrastructural analyses (with electron microscopy), and confocal microscopy to assess the actin cytoskeleton and track the movement of vesicle-associated membrane protein (VAMP)-8-containing ZGs. Coimmunoprecipitation assays were used to identify complexes that contain the distinct combinations of Munc18 and the soluble N-ethylmaleimide sensitive factor attachment protein receptor proteins, which mediate apical (ZG-apical plasma membrane) and basolateral exocytosis and fusion between ZGs (ZG-ZG). RESULTS: The ethanol metabolites acetaldehyde, ethyl palmitate, and ethyl oleate reduced CCK-8-stimulated apical exocytosis and formation of apical exocytotic complexes (between Munc18b and Syntaxin-2, synaptosomal-associated protein of 23 kilodaltons [SNAP23], and VAMP2) in rat pancreatic acini. Acetaldehyde and ethyl oleate redirected CCK-8-stimulated exocytosis to the basal and lateral plasma membranes and translocation of VAMP8-containing ZGs toward the basolateral plasma membrane. This process was mediated primarily via formation of basolateral exocytotic complexes (between Munc18c and Syntaxin-4, SNAP23, and VAMP8). Exposure of the acini to acetaldehyde and ethyl oleate followed by CCK-8 stimulation mildly perturbed the actin cytoskeleton and Ca(2+) signaling; exposure to ethyl palmitate severely affected Ca(2+) signaling. Acetaldehyde, like ethanol, promoted fusion between ZGs by the formation of ZG-ZG exocytotic complexes (between Munc18b and Syntaxin-3, SNAP23, and VAMP8), whereas ethyl palmitate and ethyl oleate reduced ZG-ZG fusion and formation of these complexes. CONCLUSIONS: The ethanol metabolites acetaldehyde, ethyl palmitate, and ethyl oleate perturb exocytosis processes in cultured rat pancreatic acini (apical blockade, basolateral exocytosis, and fusion between ZGs). Acetaldehyde and, to a lesser degree, ethyl oleate produce many of the same pathologic effects of ethanol on CCK-8-stimulated exocytosis in pancreatic acini.

Alcoholic liver disease and pancreatitis: global health problems being addressed by the US National Institute on Alcohol Abuse and Alcoholism.

The review article summarizes the mission of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) with focus on the NIAAA's current and future research version for alcoholic liver disease and alcoholic pancreatitis.

Effect of type of alcoholic beverage in causing acute pancreatitis.

BACKGROUND: The effect of different alcoholic beverages and drinking behaviour on the risk of acute pancreatitis has rarely been studied. The aim of this study was to investigate the effect of different types of alcoholic beverage in causing acute pancreatitis. METHODS: A follow-up study was conducted, using the Swedish Mammography Cohort and Cohort of Swedish Men, to study the association between consumption of spirits, wine and beer and the risk of acute pancreatitis. No patient with a history of chronic pancreatitis was included and those who developed pancreatic cancer during follow-up were excluded. Multivariable Cox proportional hazards models were used to estimate rate ratios. RESULTS: In total, 84,601 individuals, aged 46-84 years, were followed for a median of 10 years, of whom 513 developed acute pancreatitis. There was a dose-response association between the amount of spirits consumed on a single occasion and the risk of acute pancreatitis. After multivariable adjustments, there was a 52 per cent (risk ratio 1·52, 95 per cent confidence interval 1·12 to 2·06) increased risk of acute pancreatitis for every increment of five standard drinks of spirits consumed on a single occasion. The association weakened slightly when those with gallstone-related pancreatitis were excluded. There was no association between consumption of wine or beer, frequency of alcoholic beverage consumption including spirits, or average total monthly consumption of alcohol (ethanol) and the risk of acute pancreatitis. CONCLUSION: The risk of acute pancreatitis was associated with the amount of spirits consumed on a single occasion but not with wine or beer consumption.

Alcohol screening scores and the risk of new-onset gastrointestinal illness or related hospitalization.

BACKGROUND: Excessive alcohol use is associated with a variety of negative health outcomes, including liver disease, upper gastrointestinal bleeding, and pancreatitis. OBJECTIVE: To determine the 2-year risk of gastrointestinal-related hospitalization and new-onset gastrointestinal illness based on alcohol screening scores. DESIGN: Retrospective cohort study. PARTICIPANTS: Male (N = 215, 924) and female (N = 9,168) outpatients who returned mailed questionnaires and were followed for 24 months. MEASUREMENTS: Alcohol Use Disorder Identification Test-Consumption Questionnaire (AUDIT-C), a validated three-item alcohol screening questionnaire (0-12 points). RESULTS: Two-year risk of hospitalization with a gastrointestinal disorder was increased in men with AUDIT-C scores of 5-8 and 9-12 (OR 1.54, 95% CI = 1.27-1.86; and OR 3.27; 95% CI = 2.62-4.09 respectively), and women with AUDIT-C scores of 9-12 (OR 6.84, 95% CI = 1.85 - 25.37). Men with AUDIT-C scores of 5-8 and 9-12 had increased risk of new-onset liver disease (OR 1.49, 95% CI = 1.30-1.71; and OR 2.82, 95% CI = 2.38-3.34 respectively), and new-onset of upper gastrointestinal bleeding (OR 1.28, 95% CI = 1.05-1.57; and OR 2.14, 95% CI = 1.54-2.97 respectively). Two-year risk of new-onset pancreatitis in men with AUDIT -C scores 9-12 was also increased (OR 2.14; 95% CI = 1.54-2.97). CONCLUSIONS: Excessive alcohol use as determined by AUDIT-C is associated with 2-year increased risk of gastrointestinal-related hospitalization in men and women and new-onset liver disease, upper gastrointestinal bleeding, and pancreatitis in men. These results provide risk information that clinicians can use in evidence-based conversations with patients about their alcohol consumption.

Genetics and alcohol: a lethal combination in pancreatic disease?

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.

Investigating the pathobiology of alcoholic pancreatitis.

Alcohol abuse is one of the most common causes of pancreatitis. The risk of developing alcohol-induced pancreatitis is related to the amount and duration of drinking. However, only a small portion of heavy drinkers develop disease, indicating that other factors (genetic, environmental, or dietary) contribute to disease initiation. Epidemiologic studies suggest roles for cigarette smoking and dietary factors in the development of alcoholic pancreatitis. The mechanisms underlying alcoholic pancreatitis are starting to be understood. Studies from animal models reveal that alcohol sensitizes the pancreas to key pathobiologic processes that are involved in pancreatitis. Current studies are focussed on the mechanisms responsible for the sensitizing effect of alcohol; recent findings reveal disordering of key cellular organelles including endoplasmic reticulum, mitochondria, and lysosomes. As our understanding of alcohol's effects continue to advance to the level of molecular mechanisms, insights into potential therapeutic strategies will emerge providing opportunities for clinical benefit.