[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 Role of Phosphate in Alcohol-Induced Experimental Pancreatitis.

BACKGROUND & AIMS: Heavy alcohol consumption is a common cause of acute pancreatitis; however, alcohol abuse does not always result in clinical pancreatitis. As a consequence, the factors responsible for alcohol-induced pancreatitis are not well understood. In experimental animals, it has been difficult to produce pancreatitis with alcohol. Clinically, alcohol use predisposes to hypophosphatemia, and hypophosphatemia has been observed in some patients with acute pancreatitis. Because of abundant protein synthesis, the pancreas has high metabolic demands, and reduced mitochondrial function leads to organelle dysfunction and pancreatitis. We proposed, therefore, that phosphate deficiency might limit adenosine triphosphate synthesis and thereby contribute to alcohol-induced pancreatitis. METHODS: Mice were fed a low-phosphate diet (LPD) before orogastric administration of ethanol. Direct effects of phosphate and ethanol were evaluated in vitro in isolated mouse pancreatic acini. RESULTS: LPD reduced serum phosphate levels. Intragastric administration of ethanol to animals maintained on an LPD caused severe pancreatitis that was ameliorated by phosphate repletion. In pancreatic acinar cells, low-phosphate conditions increased susceptibility to ethanol-induced cellular dysfunction through decreased bioenergetic stores, specifically affecting total cellular adenosine triphosphate and mitochondrial function. Phosphate supplementation prevented ethanol-associated cellular injury. CONCLUSIONS: Phosphate status plays a critical role in predisposition to and protection from alcohol-induced acinar cell dysfunction and the development of acute alcohol-induced pancreatitis. This finding may explain why pancreatitis develops in only some individuals with heavy alcohol use and suggests a potential novel therapeutic approach to pancreatitis. Finally, an LPD plus ethanol provides a new model for studying alcohol-associated pancreatic injury.

Alcohol Reduction to Reduce Relapse in Acute Alcoholic Pancreatitis-Missed Opportunities.

AIM: Resuming drinking is a main contributant to recurrence in alcoholic pancreatitis. We assessed current clinical practice in the Netherlands regarding alcohol in managing patients with a first episode of acute alcoholic pancreatitis. METHODS: A survey was distributed to 35 hospitals affiliated with the Dutch Pancreatitis Study Group. We evaluated current support based on various components of brief interventions, the participation of psychosocial healthcare providers, the cooperation with the primary care physicians and the presence of a protocol and its implementation. RESULTS: The response rate was 100% (n = 35). Psychoeducation is the most frequently performed intervention in current support treatment (97% of hospitals). In 17% of hospitals, healthcare providers with a psychosocial background routinely participate in current support treatment; 37% of hospitals create an individual treatment plan in which goals regarding alcohol cessation are specified and only 46% of hospitals provide the primary care physician with specific discharge information; 31% of hospitals indicate that the treatment is uniformly performed within their division of Gastroenterology. Protocols are available in 3% of the hospitals surveyed. Opportunities to involve the patient's social network were not given sufficient priority. CONCLUSION: Among Dutch hospitals, there is no routine management strategy with regard to enhancing treatment for heavy alcohol use in alcoholic pancreatitis patients. There is a need to test a validated support program in randomized studies. Meanwhile, possible opportunities for effecting change are often missed.

TRO40303 Ameliorates Alcohol-Induced Pancreatitis Through Reduction of Fatty Acid Ethyl Ester-Induced Mitochondrial Injury and Necrotic Cell Death.

OBJECTIVES: Mitochondrial permeability transition pore inhibition is a promising approach to treat acute pancreatitis (AP). We sought to determine (i) the effects of the mitochondrial permeability transition pore inhibitor 3,5-seco-4-nor-cholestan-5-one oxime-3-ol (TRO40303) on murine and human pancreatic acinar cell (PAC) injury induced by fatty acid ethyl esters (FAEEs) or taurolithocholic acid-3-sulfate and (ii) TRO40303 pharmacokinetics and efficacy in experimental alcoholic AP (FAEE-AP). METHODS: Changes in mitochondrial membrane potential (Δψm), cytosolic Ca ([Ca]c), and cell fate were examined in freshly isolated murine or human PACs by confocal microscopy. TRO40303 pharmacokinetics were assessed in cerulein-induced AP and therapeutic efficacy in FAEE-AP induced with palmitoleic acid and ethanol. Severity of AP was assessed by standard biomarkers and blinded histopathology. RESULTS: TRO40303 prevented loss of Δψm and necrosis induced by 100 µM palmitoleic acid ethyl ester or 500 µM taurolithocholic acid-3-sulfate in murine and human PACs. Pharmacokinetic analysis found TRO40303 accumulated in the pancreas. A single dose of 3 mg/kg TRO40303 significantly reduced serum amylase (P = 0.043), pancreatic trypsin (P = 0.018), and histopathology scores (P = 0.0058) in FAEE-AP. CONCLUSIONS: TRO40303 protects mitochondria and prevents necrotic cell death pathway activation in murine and human PACs, ameliorates the severity of FAEE-AP, and is a candidate drug for human AP.

The Intensity of Brief Interventions in Patients with Acute Alcoholic Pancreatitis Should be Increased, Especially in Young Patients with Heavy Alcohol Consumption.

AIMS: After the first acute alcoholic pancreatitis (AAP), active repeated brief interventions (BIs) have been shown to protect against recurrent acute pancreatitis (RAP). However, in daily hospital practice the treatment of alcohol problems varies. Our aim was to study BIs performed in the clinic during AAP and whether this prevents from future RAP episodes. METHODS: Data on all patients discharged between 10/2010 and 10/2012 with acute pancreatitis as the primary diagnosis were obtained from the hospital database. Patients with the first attack of AAP were included in the study. Documented BIs during hospitalization for AAP and RAP and the development of RAP and chronic pancreatitis during median (range) follow-up of 4.2 (0.2-6.1) years were analyzed. Patients were also contacted with a mailed questionnaire. RESULTS: A total of 74 patients with first AAP during the study period were included. Of these, 32% developed RAP during follow-up. Of the patients, 72% received a documented BI during initial hospitalization, with no difference between patients who later did or did not develop RAP (71 vs. 72%; ns). Younger age (OR = 0.96, 95% CI = 0.92-1.00) and higher AUDIT points (P = 0.044; OR = 5.6; 95% CI = 1.02-30.9 for ≥20 AUDIT points) were associated with RAP. AUDIT test had 70% sensitivity and 71% specificity at a cut-off value of 20 points for predicting RAP. CONCLUSIONS: Only 72% of the patients received a documented BI during the initial hospitalization for AAP. The in-hospital BI as such did not prevent the development of RAP. Young patients with AUDIT points ≥20 are especially at high risk for developing RAP and should be included in a more intense follow-up care program to maximize prevention. SHORT SUMMARY: During hospitalization for acute alcoholic pancreatitis (AAP), one third of the patients did not receive brief interventions (BIs). The in-hospital BI by itself was not sufficient enough to prevent disease recurrence in follow-up of 4 years. Young age and higher AUDIT-points were significant risk factors for recurrent attacks of AAP.

Lessons from a national audit of acute pancreatitis: A summary of the NCEPOD report 'Treat the Cause'.

The National Confidential Enquiry into Patient Outcome and Death (NCEPOD) is an independent organisation whose remit is to review the quality of medical and surgical care provided in the United Kingdom. We undertook a review into the care provided to patients treated for acute pancreatitis during a 6 month study period between 1st January and 30th June 2014. This included assessment of care at an organisational level, clinical level within hospitals and external peer review. From a random sample, 712 patients underwent hospital clinician review and 418 patients had external peer review. Overall, we found that there was room for improvement in care in over 50% of patients with acute pancreatitis. Case reviewers felt that efforts to prevent recurrent episodes due to gallstones and alcohol were inadequate as 21% of patients in the study had one or more previous episodes of acute pancreatitis. Aspects of general care where improvements could be made include better antibiotic stewardship; as 1/5 of patients were considered to have been given antibiotics unnecessarily. Overall management of the patients' nutrition was considered adequate by the case reviewers in only 85% of cases. The use of an early warning score was omitted in 31% of emergency department admissions. Recommendations include standardised early warning scoring systems to be used throughout the hospital and commenced in the emergency department. The development of better networking arrangements and regional pancreatitis units, with shared management guidelines, is also essential to improve the coordination of care.

The Impact of Social Work Intervention in Alcohol-Induced Pancreatitis in Ireland: a Single-Center Experience.

AIM: To evaluate the effect on recurrent admission for alcohol-induced pancreatitis (that can be up to 48%) of a brief social work intervention for alcohol dependence in a single center in Ireland METHODS: Retrospective cohort study of patients admitted with acute alcohol-induced pancreatitis to a tertiary hospital in Ireland from January 2009 to December 2012. RESULTS: The relapse rate in the cohort of 160 patients with alcohol-induced pancreatitis was 28.1%. There was no difference in the relapse rate of those patients who received a social work intervention compared with those who did not (ANOVA, P = 0.229). The employment status was a significant risk factor for relapse (ANOVA, P = 0.027), but did not differ between those who did, and did not, receive the intervention. CONCLUSION: Although the cohort size did not allow great statistical power, it appears that our hospital's current social work intervention for alcohol-induced pancreatitis is ineffective in preventing relapse. Long-term prospective studies are required to formulate and better implement more efficacious interventions for such patients.

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.

Abstinence after first acute alcohol-associated pancreatitis protects against recurrent pancreatitis and minimizes the risk of pancreatic dysfunction.

AIMS: To determine the recurrence of pancreatitis and subsequent pancreatic function in patients who stop drinking after the first episode of alcohol-associated pancreatitis. METHODS: Of a total of 118 patients suffering from their first alcohol-associated pancreatitis, 18 (all men, age median 47 (27-71) years) met the inclusion criterion for abstinence during follow-up. The criterion for abstinence was alcohol consumption <24 g per 2 months (self-estimated), which is in line with questionnaires eliciting alcohol consumption and dependency (Alcohol Use Disorders Identification Test < 8 and Short Alcohol Dependence Data < 9). Recurrent attacks of acute pancreatitis were studied. Smoking, body mass index and laboratory tests detecting heavy consumption of alcohol were recorded. Blood and faecal tests were studied to assess endocrine and exocrine pancreatic function. RESULTS: During a mean follow-up time of 5.15 (1.83-9.13) years and a total of 92.7 patient-years, there were no recurrent attacks of acute pancreatitis among the 18 abstainers. Two patients had diabetes prior to and one was diagnosed immediately after the first episode of acute pancreatitis. One patient had impaired glucose metabolism at 2 years. Two patients had low insulin secretion in glucagon-C-peptide test, one at 4 years and the other at 5 years. Only one patient (6%) maintained low elastase-1 activity during the abstinence follow-up. Of the 100 non-abstainers, 34% had at least one recurrence during the follow-up. CONCLUSION: Regardless of the mediator mechanisms of acute alcoholic pancreatitis, abstinence after the first episode protects against recurrent attacks. Pancreatic dysfunction is also rare among abstinent patients.

Alcohol consumption on pancreatic diseases.

Although the association between alcohol and pancreatic diseases has been recognized for a long time, the impact of alcohol consumption on pancreatitis and pancreatic cancer (PC) remains poorly defined. Nowadays there is not consensus about the epidemiology and the beverage type, dose and duration of alcohol consumption causing these diseases. The objective of this study was to review the epidemiology described in the literature for pancreatic diseases as a consequence of alcoholic behavior trying to understand the association between dose, type and frequency of alcohol consumption and risk of pancreatitis and PC. The majority of the studies conclude that high alcohol intake was associated with a higher risk of pancreatitis (around 2.5%-3% between heavy drinkers and 1.3% between non drinkers). About 70% of pancreatitis are due to chronic heavy alcohol consumption. Although this incidence rate differs between countries, it is clear that the risk of developing pancreatitis increases with increasing doses of alcohol and the average of alcohol consumption vary since 80 to 150 g/d for 10-15 years. With regard to PC, the role of alcohol consumption remains less clear, and low to moderate alcohol consumption do not appear to be associated with PC risk, and only chronic heavy drinking increase the risk compared with lightly drinkers. In a population of 10%-15% of heavy drinkers, 2%-5% of all PC cases could be attributed to alcohol consumption. However, as only a minority (less than 10% for pancreatitis and 5% for PC) of heavily drinkers develops these pancreatic diseases, there are other predisposing factors besides alcohol involved. Genetic variability and environmental exposures such as smoking and diet modify the risk and should be considered for further investigations.

Preventive role of gallic acid on alcohol dependent and cysteine protease-mediated pancreas injury.

In order to investigate an association between alcohol consumption and lysosomal cysteine protease induced pancreatic injury and preventive effect of gallic acid as dose-dependent, we determined myeloperoxidase and malondialdehyde levels, serum amylase activities and cathepsin B and L activities in the cytosolic and lysosomal fractions of pancreatic tissue in the ethanol (8 g/kg) and ethanol plus gallic acid (at different doses 50, 100 and 200 mg/kg) given rats. Absolute ethanol (8 g/kg) was given by oral gavage. Gallic acid was dissolved in the saline (2 ml/kg) and administered before 30 min the oral administration of ethanol. Pancreatic myeloperoxidase and also malondialdehyde levels and serum amylase activities were measured. Besides, histological investigations were made. Cathepsin B activities in the cytosolic fraction were decreased by gallic acid (200 mg/kg) and increased in ethanol given rats. Cytosolic/lysosomal ratio of cathepsin B and L were found to be low in the all doses of gallic acid as compared to ethanol group. Serum amylase, pancreatic myeloperoxidase activities and malondialdehyde levels in the ethanol group were higher than in the control group. These were not statistically significant for myeloperoxidase and malondialdehyde. Also, our histopathologic results indicated that ethanol administration increased pancreatic tissue injury. Gallic acid especially at 200 mg/kg improved ethanol-mediated pancreatic tissue damage.In conclusion, gallic acid treatments were decreased release of lysosomal cathepsin B and L enzymes into cytoplasmic fraction and prevented alcohol mediated pancreatic tissue injury. Preventive effect of gallic acid might be dose-dependent.

Recent advances in the epidemiology of alcoholic pancreatitis.

Clinical observation has defined the medical profile of alcoholic pancreatitis, but its low incidence and prevalence has limited characterizing the disease at a population level, the contribution of environmental exposures, and a clear picture of its natural history. Recent studies have defined the impact of alcohol use and smoking on disease risk, and a threshold for alcohol consumption has been identified. Recurrent attacks of acute pancreatitis have been linked with continued alcohol consumption, and aggressive alcohol intervention has been shown to decrease recurrence. Progression from alcoholic acute pancreatitis to chronic pancreatitis is now believed to occur infrequently, and factors associated with progression have been identified. Alcoholic pancreatitis reduces lifespan in these patients, and the economic impact of pancreatitis is substantial. Efforts are needed to increase awareness of the impact of alcohol consumption and smoking on risk for pancreatitis and the benefits of cessation for primary and secondary prevention.

Adaptive unfolded protein response attenuates alcohol-induced pancreatic damage.

BACKGROUND & AIMS: Endoplasmic reticulum (ER) stress responses (collectively known the unfolded protein response [UPR]) have important roles in several human disorders, but their contribution to alcoholic pancreatitis is not known. We investigated the role of X-box binding protein 1 (XBP1), a UPR regulator, in prevention of alcohol-induced ER stress in the exocrine pancreas. METHODS: Wild-type and Xbp1(+/-) mice were fed control or ethanol diets for 4 weeks. Pancreatic tissue samples were then examined by light and electron microscopy to determine pancreatic alterations; UPR regulators were analyzed biochemically. RESULTS: In wild-type mice, ethanol activated a UPR, increasing pancreatic levels of XBP1 and XBP1 targets such as protein disulfide isomerase (PDI). In these mice, pancreatic damage was minor. In ethanol-fed Xbp1(+/-) mice, XBP1 and PDI levels were significantly lower than in ethanol-fed wild-type mice. The combination of XBP1 deficiency and ethanol feeding reduced expression of regulators of ER function and the up-regulation of proapoptotic signals. Moreover, ethanol feeding induced oxidation of PDI, which might compromise PDI-mediated disulfide bond formation during ER protein folding. In ethanol-fed Xbp1(+/-) mice, ER stress was associated with disorganized and dilated ER, loss of zymogen granules, accumulation of autophagic vacuoles, and increased acinar cell death. CONCLUSIONS: Long-term ethanol feeding causes oxidative ER stress, which activates a UPR and increases XBP1 levels and activity. A defective UPR due to XBP1 deficiency results in ER dysfunction and acinar cell pathology.

[Can the recurrence of alcohol-induced pancreatitis be prevented?]. / Voidaanko alkoholihaimatulehduksen uusiutumista ehkäistä?

70% of pancreatitis cases are considered to be induced by alcohol. Half of those fallen ill with alcohol-induced acute pancreatitis will have relapses. A prospective follow-up study showed that the level of dependence on alcohol constitutes the most important risk factor. Continued drinking was shown to be a dose-responsive risk factor for relapse; abstinence provided for a complete protection against renewed pancreatitis. In a randomized study, a semi-annual meeting with a healthcare professional specialized in substance abuse problems significantly reduced new episodes of acute pancreatitis. It is thus possible to at least reduce relapses by intervening in the risk factors.

The recurrence of acute alcohol-associated pancreatitis can be reduced: a randomized controlled trial.

BACKGROUND & AIMS: In the long term, half of patients with their first alcohol-associated acute pancreatitis (AP) develop acute recurrence, alcohol consumption being the main risk factor. None of the recent national or international guidelines for treatment include recommendations aimed to decrease recurrences, possibly because of a lack of studies. This study investigated whether AP recurrences can be reduced. METHODS: One hundred and twenty patients admitted to a university hospital for their first alcohol-associated AP were randomized either to repeated intervention (n = 59) or initial intervention only (n = 61). The patients in the 2 groups did not differ. A registered nurse performed an intervention in both groups before discharge, after which it was repeated in the study group at 6-month intervals at the gastrointestinal outpatient clinic. Acute recurrences during the next 2 years were monitored. RESULTS: There were 9 recurrent AP episodes in 5 patients in the repeated-intervention group compared with 20 episodes (P = .02) in 13 patients (P = .04) in the control group. The recurrence rates were similar during the first 6 months (4 vs 5 episodes), after which the repeated-intervention group had fewer recurrences than the control group (5 vs 15 episodes; P = .02). CONCLUSIONS: The repeated visits at 6-month intervals at the gastrointestinal outpatient clinic, consisting of an intervention against alcohol consumption, appear to be better than the single standardized intervention alone during hospitalization in reducing the development of recurrent AP during a 2-year period.

Fatty acid ethyl esters cause pancreatic calcium toxicity via inositol trisphosphate receptors and loss of ATP synthesis.

BACKGROUND & AIMS: Fatty acid ethyl esters are ethanol metabolites inducing sustained, toxic elevations of the acinar cytosolic free calcium ion concentration ([Ca(2+)](C)) implicated in pancreatitis. We sought to define the mechanisms of this elevation. METHODS: Isolated mouse pancreatic acinar cells were loaded with fluorescent dyes for confocal microscopy to measure [Ca(2+)](C) (Fluo 4, Fura Red), endoplasmic reticulum calcium ion concentration ([Ca(2+)](ER), Mg Fluo 4), mitochondrial membrane potential (TMRM), ADP:ATP ratio (Mg Green), and NADH autofluorescence in response to palmitoleic acid ethyl ester and palmitoleic acid (10-100 micromol/L). Whole-cell patch clamp was used to measure the calcium-activated chloride current and apply ethanol metabolites and/or ATP intracellularly. RESULTS: Intracellular delivery of ester induced oscillatory increases of [Ca(2+)](C) and calcium-activated currents, inhibited acutely by caffeine (20 mmol/L), but not atropine, indicating involvement of inositol trisphosphate receptor channels. The stronger effect of extracellular ester or acid caused depletion of [Ca(2+)](ER), not prevented by caffeine, but associated with depleted ATP, depleted NADH autofluorescence, and depolarized mitochondria, suggesting calcium-ATPase pump failure because of lack of ATP. Intracellular ATP abolished the sustained rise in [Ca(2+)](C), although oscillatory signals persisted that were prevented by caffeine. Inhibition of ester hydrolysis markedly reduced its calcium-releasing effect and consequent toxicity. CONCLUSIONS: Fatty acid ethyl ester increases [Ca(2+)](C) through inositol trisphosphate receptors and, following hydrolysis, through calcium-ATPase pump failure from impaired mitochondrial ATP production. Lowering cellular fatty acid substrate concentrations may reduce cell injury in pancreatitis.

First-time admissions with alcohol-related medical problems: a 10-year follow-up of a national sample of alcoholic patients.

OBJECTIVE: We estimated the rate of first-time hospital admission over 10 years with alcohol-related medical problems among a large national sample of patients with diagnosed alcohol abuse disorders. METHOD: We identified a nationwide cohort of all patients (N = 46,680) discharged in 1980 from all Department of Veterans Affairs (VA) medical centers with alcohol-related diagnoses. Two comparison cohorts also were identified: patients with musculoskeletal disorders (N = 18,231) and a random sample of nonalcoholic patients (N = 45,204). Using secondary databases, ICD-9-CM coded diagnostic information was collected for all VA inpatient admissions these patients experienced over the decade following their index hospitalizations. Admission rates within age strata and age/race standardized rates were computed. Adjusted rate ratios were estimated using Poisson regression. RESULTS: Alcoholic patients were at substantial risk of admission for multiple medical disorders. Admission rates varied for patients of different ages. Those who were between 50 and 59 years of age during their index hospital stay were at the highest risk of admission with an alcohol-related medical disease over the subsequent decade. CONCLUSIONS: The admission rates for these medical disorders among alcoholic patients provide an important baseline estimate of individual patients' risk profiles and may help providers set priorities among diagnostic tests.