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Alcohol is a major cause of acute and chronic pancreatitis. There have been some recent advances in the understanding of the mechanisms underlying alcoholic pancreatitis, which include perturbation in mitochondrial function and autophagy and ectopic exocytosis, with some of these cellular events involving membrane fusion soluble N-ethylmaleimide-sensitive factor receptor protein receptor proteins. Although new insights have been unraveled recently, the precise mechanisms remain complex, and their finer details have yet to be established. The overall pathophysiology of pancreatitis involves not only the pancreatic acinar cells but also the stellate cells and duct cells. Why only some are more susceptible to pancreatitis and with increased severity, while others are not, would suggest that there may be undefined protective factors or mechanisms that enhance recovery and regeneration after injury. Furthermore, there are confounding influences of lifestyle factors such as smoking and diet, and genetic background. Whereas alcohol and smoking cessation and a generally healthy lifestyle are intuitively the advice given to these patients afflicted with alcoholic pancreatitis in order to reduce disease recurrence and progression, there is as yet no specific treatment. A more complete understanding of the pathogenesis of pancreatitis from which novel therapeutic targets could be identified will have a great impact, particularly with the stubbornly high fatality (>30%) of severe pancreatitis. This review focuses on the susceptibility factors and underlying cellular mechanisms of alcohol injury on the exocrine pancreas.

Pancreatic stellate cells (PSCs) play a critical role in fibrogenesis during alcoholic chronic pancreatitis (ACP). Transforming growth factor‐beta1 (TGF‐β1) is a key regulator of extracellular matrix production and PSC activation. Endotoxin lipopolysaccharide (LPS) has been recognized as a trigger factor in the pathogenesis of ACP. This study aimed to investigate the mechanisms by which LPS modulates TGF‐β1 signalling and pancreatic fibrosis. Sprague‐Dawley rats fed with a Lieber‐DeCarli alcohol (ALC) liquid diet for 10 weeks with or without LPS challenge during the last 3 weeks. In vitro studies were performed using rat macrophages (Mφs) and PSCs (RP‐2 cell line). The results showed that repeated LPS challenge resulted in significantly more collagen production and PSC activation compared to rats fed with ALC alone. LPS administration caused overexpression of pancreatic TLR4 or TGF‐β1 which was paralleled by an increased number of TLR4‐positive or TGF‐β1‐positive Mφs or PSCs in ALC‐fed rats. In vitro, TLR4 or TGF‐β1 production in Mφs or RP‐2 cells was up‐regulated by LPS. LPS alone or in combination with TGF‐β1 significantly increased type I collagen and α‐SMA production and Smad2 and 3 phosphorylation in serum‐starved RP‐2 cells. TGF‐β pseudoreceptor BAMBI production was repressed by LPS, which was antagonized by Si‐TLR4 RNA or by inhibitors of MyD88/NF‐kB. Additionally, knockdown of Bambi with Si‐Bambi RNA significantly increased TGF‐β1 signalling in RP‐2 cells. These findings indicate that LPS increases TGF‐β1 production through paracrine and autocrine mechanisms and that LPS enhances TGF‐β1 signalling in PSCs by repressing BAMBI via TLR4/MyD88/NF‐kB activation.

Background Pancreatic fibrosis is a key pathological feature of alcoholic chronic pancreatitis (ACP). Bacterial endotoxin lipopolysaccharide (LPS) is considered as an important cofactor in the fibrogenesis of ACP. However, there are limitations in the use of exogenous LPS for evaluating the role of endotoxin in ACP pathogenesis. In this study, we determined the relationship between the concentration of LPS in the portal vein and pancreatic type I collagen (Col1) content in chronic alcohol-fed rats. Methods Male Sprague Dawley rats were divided into 2 groups and fed with Lieber–DeCarli isocaloric control (CON) liquid diet or ethanol (EtOH) (15 g/kg/d) liquid diet. Eleven CON or EtOH rats were euthanized at the end of week 8, 9, or 10. The plasma LPS from portal vein was determined. Pancreatic inflammatory injury and fibrosis were assessed. Pancreatic stellate cells (PSCs) and macrophages were identified; pancreatic type I collagen alpha 1 (Col1A1) and Toll-like receptor (TLR4) mRNA and protein were examined; pancreatic chemokines and transforming growth factor-beta1 (TGF-β1) were determined. Results Pancreatic inflammatory scores were increased in 10-week EtOH rats compared with CON rats, but there was no significant difference in collagen deposition between 2 groups. The levels of portal vein LPS and pancreatic TLR4 and Col1A1 mRNA and protein were increased in a time-dependent fashion in EtOH rats, with the highest levels occurring at 10 weeks. Additionally, by 8 weeks, pancreatic TLR4 and Col1A1 mRNA in EtOH rats were statistically increased as compared to CON rats, whereas portal vein LPS remained unchanged. The number of PSCs and macrophages and expression of chemokines (MCP-1, MIP-1α, and RANTES), TGF-β1, or Col1A1 were significantly increased, each of which was positively correlated with the level of portal vein LPS in 10-week EtOH rats. Conclusions These results suggest that LPS is associated with alcohol-induced fibrosis in pancreatitis and targeting of bacterial endotoxin may be a promising therapeutic strategy for ACP.

Diabetes mellitus (DM) is a common disease involving insulin resistance or deficit that, when left unchecked, may cause severe hyperglycemia and subsequent end-organ damage. Acute pancreatitis (AP) is inflammation of the pancreas that can lead to significant morbidity and mortality. AP and DM both account for a significant amount of sudden deaths, and rarely both disease processes may be present in the same decedent, causing some difficulty in wording the cause of death statement. Although much research has been directed at studying the causes and risk factors for AP and DM, there is a complex interplay between these diseases that is not fully understood. This study presents two autopsy cases of sudden, natural deaths that illustrate this interplay, along with a review of the literature. An algorithm for differentiating AP and DM is then discussed in the context of the presented cases as a proposed aid for forensic pathologists in the certification of such deaths.

Pancreatitis is caused by long-term heavy alcohol consumption, which results in injury and death of pancreatic acinar cells (PAC). The PAC play a pivotal role in mediating early inflammatory responses but the underlying mechanisms remain poorly understood. Treatment of C57BL/6 mice with ethanol and cerulein resulted in increased staining for acinar interleukin- 1b (IL-1b), chemokine (C-C motif) ligand 3 (CCL3), or connective tissue growth factor (CTGF/CCN2) by Day 16 and this was associated with increased infiltration of F4/80-positive macrophages and increased expression of pancreatic CTGF/CCN2 mRNA. Compared with wild-type Swiss Webster mice, ethanol treatment of pan-green fluorescent protein (GFP)-CTGF/CCN2 transgenic mice caused enhanced acinar staining for GFP or CTGF/CCN2 and a significant increase in pancreatic infiltration of F4/80-positive macrophages or NIMP-R14-positive neutrophils. Treatment of primary mouse PAC or the rat AR42J PAC line with ethanol or CTGF/CCN2 resulted in enhanced expression of IL-1b or CCL3. Conditioned medium from CTGF/CCN2-treated AR42J cells induced chemotaxis in NR8383 macrophages and this response was abrogated in a dose dependent manner by addition of BX471, an inhibitor of chemokine (C-C motif) receptor 1. These results reveal that acinar CTGF/CCN2 plays a novel role in alcohol-induced inflammatory processes in the pancreas by increasing infiltration of macrophages and neutrophils and increasing acinar production of inflammatory mediators such as IL-1b or CCL3. The early production of CTGF/CCN2 by PAC to drive inflammation is distinct from its previously reported production by pancreatic stellate cells to drive fibrosis at later stages of pancreatic injury.

Background The presence of the less-active form of alcohol dehydrogenase-1B encoded by ADH1B*1/*1 (vs. *2 allele) and active form of aldehyde dehydrogenase-2 (ALDH2) encoded by ALDH2*1/*1 (vs. *2 allele) increases the risk of alcoholism in East Asians. Methods The subjects in this cross-sectional survey were 1,902 Japanese alcoholic men (≥40 years) who underwent ADH1B/ALDH2 genotyping. Results Age-adjusted daily alcohol consumption did not differ according to the ADH1B/ALDH2 genotypes. The age-adjusted odds ratios (AORs; 95% confidence interval) for liver cirrhosis (LC; n = 359, 1.58 [1.19 to 2.09]), chronic calcific pancreatitis (CP; n = 80, 2.24 [1.20 to 4.20]), and diabetes mellitus (DM; n = 383, 1.51 [1.15 to 1.99]) were higher in the ADH1B*2 allele carriers than in the ADH1B*1/*1 carriers. The AORs for LC (1.43 [1.01 to 2.02]), CP (1.68 [0.80 to 3.53]), DM (1.63 [1.15 to 2.30]), and hypertension (HT; n = 495, 1.52 [1.11 to 2.07]) were higher in the ALDH2*1/*1 carriers than in the ALDH2*1/*2 carriers. The ADH1B*2-associated AOR for LC was 2.08 (1.46 to 2.94) among those aged 40 to 59 years, but 0.89 (0.56 to 1.43) among those aged 60 years or over, and the interaction between ADH1B genotype and age on the LC risk was significant (p = 0.009). When the group with non-LC and no/mild fibrosis was used as controls, the ADH1B*2-associated AORs increased according to the severity of their liver disease: 1.67 (1.32 to 2.11) for the group with non-LC and serum type IV collagen values ≥200 ng/ml, 1.81 (1.24 to 2.63) for the group of Child-Pugh class A LC, and 3.17 (1.98 to 5.07) for the group with Child-Pugh class B/C LC. Anti-hepatitis C virus (HCV) antibody was positive in 103 patients, and the groups with a high anti-HCV antibody titer and either the ADH1B*2/*2 genotype or the ALDH2*1/*1 genotype had the highest AORs (8.83 and 4.90, respectively). The population attributable fraction (PAF) due to the ADH1B*2 allele was 29% for LC, 47% for CP, and 27% for DM, and the PAF due to the ALDH2*1/*1 genotype was 26% for LC, 34% for DM, and 30% for HT. Conclusions The ADH1B*2 allele increased the AORs for LC, CP, and DM of the alcoholics, and the ALDH2*1/*1 genotype increased their AORs for LC, DM, and HT. HCV infection and genetic susceptibility had a synergistic effect on the AOR for LC.

Background: Excessive consumption of alcohol is involved in the onset of pancreatitis. However, most of heavy drinkers do not always develop chronic pancreatitis. Various genetic factors appear to be involved in these individual differences in onset of chronic alcoholic pancreatitis. Here we investigated a possible association of alcoholic pancreatitis with polymorphisms of the various genes belong to the phase II detoxification enzymes responsible for metabolism of the oxidative compounds, and the several genes that have relevance to inherited pancreatitis. Methods: The subjects consisted of 53 patients with chronic alcoholic pancreatitis, 54 alcoholic patients without pancreatic dysfunction, and 42 healthy individuals. DNA was extracted from the peripheral nucleated blood cells of all subjects and genetic mutations and subtypes were analyzed by the PCR and RFLP methods. We examined the correlation between chronic alcoholic pancreatitis and variants of the phase II detoxification enzymes such as Glutathione S-transferase M1 (GSTM1), glutathione S-transferase theta 1 (GSTTI), NADPH-quinone oxidoreductase 1 (NQO1), and N-acetyl transferase (NAT2). In addition, genes of lipoprotein lipase (LPL), cationic trypsinogen (PRSS1), pancreatic secretory trypsin inhibitor (PSTI), and cystic fibrosis transmembrane conductance regulator (CFTR) were also analyzed. Results: Frequencies of the gene deletion of GSTM1 and GSTT1 in addition to the C-allele frequency of NQO1 tended to be higher in the alcoholic patients with (AlCP) or without pancreatic dysfunction (Alc) than in the healthy controls although the difference was not significant. The NAT2 gene showed no relation with Alc and AICP patients. PSTI, LPL, PRSSI, and CFTR genes presented no association with chronic alcoholic pancreatitis. Conclusions: All genes analyzed in the present study lacked association with chronic alcoholic pancreatitis. However, the gene deletion of GSTM1 and GSTT1, and the C-allele of NQO1 cannot be ruled out for association with alcoholism.

Pancreatitis and pancreatic cancer represent two major diseases of the exocrine pancreas. Pancreatitis exhibits both acute and chronic manifestations. The commonest causes of acute pancreatitis are gallstones and alcohol abuse; the latter is also the predominant cause of chronic pancreatitis. Recent evidence indicates that endotoxinemia, which occurs in alcoholics due to increased gut permeability, may trigger overt necroinflammation of the pancreas in alcoholics and one that may also play a critical role in progression to chronic pancreatitis (acinar atrophy and fibrosis) via activation of pancreatic stellate cells (PSCs). Chronic pancreatitis is a major risk factor for the development of pancreatic cancer, which is the fourth leading cause of cancer-related deaths in humans. Increasing attention has been paid in recent years to the role of the stroma in pancreatic cancer progression. It is now well established that PSCs play a key role in the production of cancer stroma and that they interact closely with cancer cells to create a tumor facilitatory environment that stimulates local tumor growth and distant metastasis. This review summarizes recent advances in our understanding of the pathogenesis of alcoholic pancreatitis and pancreatic cancer, with particular reference to the central role played by PSCs in both diseases. An improved knowledge of PSC biology has the potential to provide an insight into pathways that may be therapeutically targeted to inhibit PSC activation, thereby inhibiting the development of fibrosis in chronic pancreatitis and interrupting stellate cell-cancer cell interactions so as to retard cancer progression.

Pancreatitis (necroinflammation of the pancreas) has both acute and chronic manifestations. Gallstones are the major cause of acute pancreatitis, whereas alcohol is associated with acute as well as chronic forms of the disease. Cases of true idiopathic pancreatitis are steadily diminishing as more genetic causes of the disease are discovered. The pathogenesis of acute pancreatitis has been extensively investigated over the past four decades; the general current consensus is that the injury is initiated within pancreatic acinar cells subsequent to premature intracellular activation of digestive enzymes. Repeated attacks of acute pancreatitis have the potential to evolve into chronic disease characterized by fibrosis and loss of pancreatic function. Our knowledge of the process of scarring has advanced considerably with the isolation and study of pancreatic stellate cells, now established as the key cells in pancreatic fibrogenesis. The present review summarizes recent developments in the field particularly with respect to the progress made in unraveling the molecular mechanisms of acute and chronic pancreatic injury secondary to gallstones, alcohol and genetic factors. It is anticipated that continued research in the area will lead to the identification and characterization of molecular pathways that may be therapeutically targeted to prevent/inhibit the initiation and progression of the disease.

Background: Primary hyperparathyroidism is a rare cause of chronic pancreatitis and there is a paucity of data on this interesting association. There is also no data comparing the clinical profile of chronic pancreatitis secondary to primary hyperparathyroidism with that of alcohol related and idiopathic chronic pancreatitis. Methods: The clinical and biochemical spectrum of chronic pancreatitis secondary to primary hyperparathyroidism was evaluated retrospectively and compared with nine age-matched patients with alcohol related and idiopathic chronic pancreatitis. Results: Renal colic, nephrolithiasis, nephrocalcinosis, bone disease, palpable neck nodule, and psychiatric abnormality were significantly more common in chronic pancre- atitis due to hyperparathyroidism in comparison to alcoholic and idiopathic groups. The corrected calcium (10.8 0.9 vs 9.3 0.6 vs 9.2 0.8 mg/dL; P = 0.001) and intact parathormone (425 130 (SE) vs 22.2 14.3 (SE) vs 30 27.3 (SE) pg/mL; P = 0.009) levels were significantly elevated, while levels of serum phosphate were significantly less (3.1 0.4 vs 3.9 0.5 vs 3.4 0.7 mg/dL, respectively; P = 0.04) in chronic pancreatitis due to hyperparathyroidism in comparison to the alcoholic and idiopathic groups. No significant difference was observed in the frequency of steatorrea, diabetes mellitus, pan- creatic calcification, and pseudocyst between the three groups. Six out of nine patients underwent parathyroidectomy and none had recurrence of pancreatic pain over 14.3 13.8 months. Conclusions: Chronic pancreatitis due to hyperparathyroidism has important characteris- tics in its biochemical and clinical manifestations. Parathyroidectomy relieves pancreatic pain in majority of patients.

The observation that only a minority of heavy drinkers develop pancreatitis has prompted an intensive search for a trigger factor/cofactor/susceptibility factor that may precipitate a clinical attack. Putative susceptibility factors examined so far include diet, smoking, amount and type of alcohol consumed, the pattern of drinking and lipid intolerance. In addition, a range of inherited factors have been assessed including blood group antigens, human leukocyte antigen serotypes, alpha-1-antitrypsin phenotypes and several genotypes. The latter group comprises mutations/polymorphisms in genes related to alcohol-metabolizing enzymes, detoxifying enzymes, pancreatic digestive enzymes, pancreatic enzyme inhibitors, cystic fibrosis and cytokines. Disappointingly, despite this concerted research effort, no clear association has been established between the above factors and alcoholic pancreatitis. Experimentally, the secretagogue cholecystokinin (CCK) has been investigated as a candidate 'trigger' for alcoholic pancreatitis. However, the clinical relevance of CCK as a trigger factor has to be questioned, as it is difficult to envisage a situation in humans where abnormally high levels of CCK would be released into the circulation to trigger pancreatitis in alcoholics. In contrast, bacterial endotoxemia is a candidate cofactor that does have relevance to the clinical situation. Plasma lipopolysaccharide (LPS, an endotoxin) levels are significantly higher in drinkers (either after chronic alcohol intake or a single binge) compared to non-drinkers. We have recently shown that alcohol-fed animals challenged with otherwise innocuous doses of LPS exhibit significant pancreatic injury. Moreover, repeated LPS exposure in alcohol-fed rats leads to progressive injury to the gland characterized by significant pancreatic fibrosis. These studies support the concept that endotoxin may be an important factor in the initiation and progression of alcoholic pancreatitis. Scope remains for further studies examining proteins related to cellular anti-oxidant defenses, minor cystic fibrosis (CF) mutations and trans-heterozygosity involving a combination of mutations of different genes (such as CFTR alterations combined with SPINK1 or PRSS1 variants), as potential triggers of alcoholic pancreatitis.

The molecular mechanism of clinical alcohol-induced pancreatitis remains vague. We had reported that experimental high-dose cholecystokinin (CCK)-induced pancreatitis is in part because of excessive aberrant basolateral exocytosis. High-dose CCK caused Munc18c on basolateral plasma membrane (BPM) to dissociate from syntaxin (Syn)-4, activating Syn-4 to complex with plasma membrane (PM)-SNAP-23 and granule-VAMP to mediate basolateral exocytosis. We now hypothesize that alcohol could render the acinar cell BPM conducive to exocytosis by a similar mechanism. Weakly stimulating postprandial doses of alcohol (20-50 mM) inhibited postprandial low-dose CCK-stimulated secretion by blocking physiologic apical exocytosis and redirecting exocytosis to less-efficient basal PM (visualized by FM1-43 fluorescence imaging) and lateral PM sites (electron microscopy). Alcohol or low-dose CCK had no effect on PM-Munc18c, but alcohol preincubation enabled low-dose CCK to displace Munc18c from BPM, leading to SNARE complex assembly in the BPM. Similarly, alcohol diet-fed rats did not exhibit morphologic defects in the pancreas nor affected PM-Munc18c behavior, but subsequent intraperitoneal injections of low-dose CCK analog cerulein caused Munc18c displacement from BPM and cytosolic degradation, which contributed to pancreatitis. We conclude that alcohol induces BPM-Munc18c to become receptive to postprandial CCK-induced displacement into the cytosol, a process which facilitates SNARE complex assembly that in turn activates restricted BPM sites to become available for aberrant exocytosis into the interstitial space, where zymogen activation would take place and cause pancreatitis.

Background: Alcohol misuse is a common cause of liver disease, upper gastrointestinal (GI) bleeding, and pancreatitis, but it is not known whether alcohol screening questionnaires can identify patients at increased risk for hospitalizations due to these conditions. Objective: To evaluate the association of alcohol screening scores with the risk of subsequent hospitalization for alcohol-related GI conditions. Design: Retrospective cohort study. Participants: Male general medicine outpatients from 7 Veterans Affairs (VA) medical centers who returned mailed questionnaires. Measurements: The CAGE questionnaire (0–4 points) and the Alcohol Use Disorders Identification Test-Consumption questions (AUDIT-C; 0–12 points) were included on mailed surveys. The main outcome, “GI hospitalization,” was a primary VA or Medicare discharge diagnosis indicating liver disease, upper GI bleeding, or pancreatitis. Results: Among 31,311 patients followed, a median of 3.75 years, patients with CAGE scores ≥2 points or AUDIT-C scores ≥6 points were at a significantly increased risk for GI hospitalizations. Adjusted hazard ratios (HRadj) ranged from 1.6 (95% CI 1.2–2.0) for CAGE score 2, to 1.7 (1.4–2.2) for CAGE 4, and from 1.4 (1.01–2.0) for AUDIT-C scores from 6 to 7, to 2.7 (1.9–3.8) for AUDIT-C scores from 10 to 12. Secondary analyses demonstrated that the association was the strongest among patients less than 50 years of age who reported drinking in the past year. Conclusions: Brief alcohol screening questionnaires predict subsequent hospitalizations for alcohol-related GI conditions.

Alcohol exposure is known to sensitize acinar cells to various insults but the pathophysiological mechanisms of alcoholic pancreatitis remain unknown. Alcohol abuse has been shown to mediate an anti-inflammatory response and periods of immune suppression seem to be associated with organ injury and mortality. The purpose of this study was to determine the mechanisms by which alcohol exerts transcriptional activities in the rat pancreas and how alcohol alters the inflammatory response. Using the Lieber-DeCarli alcohol/control diet, rats that were fed with alcohol over 14 weeks demonstrated a decrease of inflammatory cells in pancreatic tissue compared to controls. The anti-inflammatory effects of alcohol were confirmed by decreased expression of pro-inflammatory cytokines including TNFalpha, IL-1beta, IL-18, TGFbeta, and MCP-1. In addition, alcohol significantly increased the activity of PPARgamma, which is a known anti-inflammatory transcription factor, while pro-inflammatory factors including AP-2 and EGR-1 were significantly suppressed. NFkappaB binding showed a tendency towards a reduction. Electron microscopy studies revealed enlarged and injured mitochondria and lysosomes, accompanied by peri-cellular fibrosis. Furthermore, alcohol exposure increased the activities of trypsin and cathepsin B, both known to be critical in initiating acinar cell injury and pancreatitis. Despite the known alcohol-mediated acinar cell and mitochondrial injury, the mitochondrial-mediated apoptotic pathway was attenuated. These data demonstrate that the pancreas exposed to alcohol maintains an anti-inflammatory state by activating PPARgamma. Intracellular mitochondrial and lysosomal damage after chronic alcohol exposure induces premature activation of digestive enzymes and establishment of peri-cellular fibrosis in the absence of inflammation.

Alcohol-associated acute and chronic pancreatitis occur in a minority of alcohol users, suggesting that most drinkers are protected from pancreatic diseases while a subset is susceptible. Ongoing studies suggest that the pathophysiology is complex and can involve multiple genetic and environmental pathways and stochastic events. Both rat models and human genetic epidemiology studies have been used to understand susceptibility and modifying factors in humans. Rat studies suggest that different types of altered pancreatic physiology occur depending on dose, they occur rapidly and that alcohol changes the immune response to recurrent pancreatic injury. Human studies suggest that PRSS1 and SPINK1 mutation increase the pancreas' susceptibility to alcohol-associated pancreatitis, and that tobacco smoking, and some factors, affect disease progression.

Background: Genetic polymorphism of enzymes involved in alcohol metabolism plays a relevant role in etiopathogenesis of alcohol disease. The aim of the present study was to find in the Polish population the CYP2E1 genotypes that are likely to be responsible for higher susceptibility to alcohol disease of the liver and chronic alcohol pancreatitis. Methods: The CYP2E1 genotype and c1 and c2 alleles frequency were examined in 198 patients. Genotyping of the CYP2E1 was performed using polymerase chain reaction–restriction fragment length polymorphism methods on white cell DNA. Results: In the examined population encompassing 198 subjects, the c2 allele was present only in 1.5% of patients. It was found only in patients abusing alcohol. In the group of patients with alcoholic cirrhosis, it was present in 3.5% of cases, whereas in patients with chronic alcoholic pancreatitis, in 2.3%. The genotype c1/c2 was present in 3% of subjects. The genotype c2/c2 was not found in any patient. Heterozygotes c1/c2 were present only in patients consuming excessive amounts of ethanol; in 7% of patients with alcoholic cirrhosis and in 4.5% of those with chronic alcoholic pancreatitis. The c2 allele occurred only in men. None of the examined women had the genotype c1/c2. Conclusions: Our studies suggest that the frequency of the c2 alleles in Polish population is low. Because of their rare frequency, it is difficult to conclude explicitly that the presence of the c2 allele promotes alcoholic damage to alimentary organs among Poles. It seems, however, that they pose the risk of alcoholic cirrhosis; their role in chronic alcoholic pancreatitis is difficult to assess.

Background: Fatty acid ethyl esters (FAEE) are nonoxidative ethanol metabolites shown to produce toxic effects in the liver and pancreas in vivo and in vitro. Because alcohol-induced chronic pancreatitis is associated with mutations in the gene responsible for cystic fibrosis (CFTR), we hypothesized that CFTR dysfunction leads to increased levels of these toxic nonoxidative ethanol metabolites following alcohol administration. Methods: Cystic fibrosis (CF) and wild-type (WT) mice were injected intraperitoneally with 1, 2, or 3 g/kg of 50% ethanol. Mice were sacrificed and the liver and pancreas removed for FAEE analysis. Results: The mean FAEE concentration (pmol/g) detected in the liver of cftr−/− mice following injection with 2 g/kg of ethanol was significantly greater than the amount detected in WT (p < 0.005). A similar trend in FAEE concentration was seen in the pancreas, but the difference was not statistically different. In both the liver and pancreas, analysis of individual FAEE species demonstrated a selective increase in ethyl oleate. Conclusion: These data show an association between CFTR dysfunction and qualitative and quantitative changes in FAEE in liver and pancreas upon ethanol exposure.

This article represents the proceedings of a symposium presented at the 12th Congress of the International Society for Biomedical Research on Alcoholism held in Heidelberg/Mannheim, Germany, on October 1, 2004. The organizers and cochairs were Nassima Ait-Daoud, MD, and Gerhard A. Wiesbeck, MD. The presentations included the following:L (1) The Role of Nicotinic Acetylcholine Receptors in Alcohol-Seeking Behavior, by Przemyslaw Bienkowski, MD, PhD; (2) Utilization of Linkage Analysis Combined with Microarray Technology to Identify Genes and Mechanisms Underlying Nicotine and Alcohol Use and Abuse in Humans and Rodents, by Ming D. Li, PhD; (3) Smoking and Alcoholic Chronic Pancreatitis: The Underestimated Risk?, by Roland H. Pfützer, MD; (4) Anticraving Medication in Alcohol and Nicotine Dependence, by Otto M. Lesch, MD, PhD; and (5) Pharmacotherapy for Promotion of Abstinence from Nicotine Among Alcohol-Dependent Individuals, by Bankole A. Johnson, DSc, MD, PhD.

Background: Alcohol abuse is associated with several gastrointestinal diseases, such as esophageal carcinoma, chronic alcoholic pancreatitis, and liver cirrhosis. Increased mean corpuscular volume (MCV) has been recognized as a biomarker for alcohol abuse and heavy drinkers. Recent studies from Japan revealed that macrocytosis is related to ALDH-2/2 genotype, leading to increased acetaldehyde accumulation. It has also demonstrated that increased MCV values could also be an independent biomarker for esophageal cancer in Asians. Therefore, the aim of the current study was to investigate possible associations of MCV value with polymorphisms of ADH1C in white patients with alcohol-associated esophageal carcinoma, chronic alcoholic pancreatitis, and alcoholic cirrhosis as well as in heavy drinkers without organ damage. Methods: In this study, a total of 510 alcoholic patients were enrolled with esophageal cancer (n= 98), chronic pancreatitis (n= 98), alcoholic liver cirrhosis (n= 151), and alcohol abuse without gastrointestinal disease (n= 163). ADH1C genotyping was performed by PCR-based restriction fragment length polymorphism (PCR-RFLP) analysis from whole blood. The relation between MCV and ADH1C gene polymorphisms (ADH1C*1 and 1C*2) controlled for the amount of drinking, smoking, and age were investigated using both univariate and multivariate analysis. Results: In univariate analysis, higher alcohol consumption was associated with increased MCV. Other variables were not associated with macrocytosis. In multiple linear regression analysis, after adjustment for age and smoking, higher alcohol consumption and female sex were independently associated with higher MCV values. No other variables, including which alcohol-associated disease the patient had, had an independent effect. Adding ADH genotype rendered no independent significant effect on MCV value. Conclusions: In a white population, MCV values were not associated with genotype polymorphisms of ADH1C. In contrast to findings in Asians, macrocytosis does not seem to be an independent biomarker for esophageal cancer. The role of ADH1C polymorphism in increasing MCV and the potential use of MCV as a marker for esophageal carcinoma are still pending.

Background: This study sought to identify demographic characteristics of hospitalized patients with alcoholic liver disease (ALD) in Los Angeles County for the purpose of implementing new preventive and educational programs. Another specific aim of the study was to characterize demographic and comorbid differences between patients with ALD and patients with pancreatitis, another alcohol-related disease. Methods: Analyses were performed on discharge data from all nonfederal short-stay hospitals within Los Angeles County, released for the year 1999 by the Office of Statewide Health Planning and Development. Repeated hospital stays for ALD by the same patients were deleted from the data analysis based on individual identification numbers. For the analysis of medical costs of ALD, repeated hospital stays were included. Results: Primary diagnosis of ALD accounted for 1.2% of total deaths among hospitalized patients and was the eighth most common cause of death among diseases examined. Moreover, the fatality rate of primary ALD among ALD hospital visits was the second highest, behind septicemia. ALD was most prevalent in the middle-aged (45–65 years old) and low- to middle-income men. The age-standardized hospitalization rate of ALD was highest in Hispanic men (61.1 per 100,000 per year), whereas that of chronic pancreatitis, another common complication of alcohol abuse, was most prevalent in African American men. Conclusions: Middle-aged Hispanic men with low- to middle-income status were identified as a high-risk group for ALD in Los Angeles County. These data will guide us to develop a new strategy for future preventative and educational programs for ALD.

Background: We have reported that the serum level of amylase, different from other pancreatic enzymes, increases temporarily after abstinence in alcoholics. To elucidate the mechanism of this phenomenon, pancreatic isoamylase, salivary isoamylase, and amylase in urine were measured together with total serum amylase. Methods: Total serum amylase, pancreatic isoamylase, and salivary isoamylase values were measured in 38 male patients admitted to the National Alcoholism Center, Kurihama Hospital, for alcoholism after abstinence. In an investigation of amylase secretion, amylase in urine was measured in some patients after abstinence. Results: In the group with abnormally high total serum amylase on admission, levels were found to decrease after abstinence. In patients with pancreatic disorders in this group, abstinence leads to a decrease in total serum amylase, but in patients with no such disorders, total serum amylase increases temporarily due to increases in salivary isoamylase. In the group with normal total serum amylase on admission, levels increased sharply after abstinence, and both pancreatic isoamylase and salivary isoamylase contributed to the gains. In the group with low total serum amylase, a sharp increase of 2-fold or more was noted after abstinence, and a major contributor was pancreatic isoamylase. The ratio of urine amylase to total serum amylase gradually declined, indicating clearly that abstinence led to a decrease in the excretion of amylase in urine. Conclusions: In cases of heavy alcohol consumption, a decrease in the production or secretion of pancreatic isoamylase and salivary isoamylase while drinking could happen. It was thus suggested that the increase in serum amylase might be due to the fact that this situation is improved by abstinence, plus the fact that excretion of amylase in urine increases during alcohol consumption, and abstinence brings about a decline in such excretion. Measurement of total serum amylase is not appropriate for diagnosing pancreatitis in alcoholic patients or those who consume large quantities of alcohol.

Acute pancreatitis (AP) is a common disease with wide variation of severity. The diagnosis of AP is usually based on high serum amylase or lipase values but the accuracy of these methods is considered unsatisfactory. One in five of the patients develops a severe disease and carries a considerable risk of development of organ failure and high mortality. Early detection of patients with severe AP and especially those with increased risk of organ failure is importance since such patients seem to benefit from treatment in an intensive care unit started as soon as possible after presentation. In addition to enzymological methods, increasing interest has been focused on laboratory markers reflecting the level of inflammatory response in AP. At present, in routine clinical work the most commonly used severity marker is serum C-reactive protein, the concentration of which rises too slowly to be used for early prediction of severity. New therapies aiming at modifying the course of systemic inflammation in AP are being developed and therefore monitoring the patient's immune inflammatory status is needed. In this review article we present the current knowledge of laboratory tests, which has been evaluated for diagnostic and prognostic purposes in AP.

Background and Aim: Susceptibility to organ damage induced by alcohol may be due to inherited variation (polymorphism) in ethanol-metabolizing enzymes, or to polymorphisms affecting free radical or lipid metabolism mediated by enzymes such as glutathione S-transferases and apolipoprotein E. The aim was to compare the genotype frequencies of alcohol dehydrogenase-2 (ADH2), ADH3, aldehyde dehydrogenase-2 (ALDH2), cytochrome P450-2E1 (CYP2E1), glutathione S-transferase-M1 (GSTM1), GSTT1, and apolipoprotein E in patients with alcoholic cirrhosis and alcoholic chronic pancreatitis to those in control groups. Patients and Methods: The case‐control study was restricted to Caucasian adults: 57 with alcoholic cirrhosis, 71 with alcoholic chronic pancreatitis, 57 alcoholics without apparent organ damage and 200 healthy blood donors. Genotypes were determined by restriction fragment length polymorphism after amplification of genomic DNA by polymerase chain reaction. Results: The genotype ADH3*2/*2 was more frequent in patients with cirrhosis (40%) than blood donors (12%; OR 4.92, 95% CI 2.36‐10.31) and patients with chronic pancreatitis (8%; OR 7.33, 95% CI 2.54‐23.78) but was not significantly different from alcoholic controls (23%; OR 2.27, 95% CI 0.95‐5.66). Patients with cirrhosis also had a higher frequency (P < 0.05) of ADH2*1/*1 (100%) than blood donors (92%) and those with chronic pancreatitis (93%). The frequencies of genotypes of ALDH2, CYP2E1, GSTM1, GSTT1 and apolipoprotein E were similar in all groups. Conclusion: Alcoholic cirrhosis but not alcoholic chronic pancreatitis is associated with ADH3*2/*2 and perhaps with ADH2*1/*1. Both genes encode less active alcohol-metabolizing enzymes that may be associated with cirrhosis because of delayed formation of acetaldehyde (with higher intakes of alcohol), or diversion of alcohol metabolism through pathways other than ADH. © 2002 Blackwell Science Asia Pty Ltd

Fifteen cases of tumor-forming pancreatitis, detected as tumors by diagnostic imaging or by physical examination were histologically examined. Eleven of the 15 patients were heavy drinkers. Tumorous lesions were located in the head of the pancreas in 11 cases and in the body or tail of the pancreas in four cases. Macroscopic examination revealed tumorous swelling or sclerotic appearance in the pancreatic tissue. Histologically, these lesions showed tumorous swelling with (n = 12) or without (n = 3) a background of chronic pancreatitis. In the former, the tumorous lesions consisted of extensive fibrosis, including necrosis or abscesses, stones and reparative granulation tissue, and there was a successive transition to the surrounding chronic pancreatitis pattern. The latter three tumorous lesions presented with inter- and intralobular fibrosis with lymphoid hyperplasia or lymphoplasmacytic infiltration and were adjacent to normal pancreatic tissue. Therefore, tumor-forming pancreatitis shows at least two distinct types: a reparative tumorous swelling with a background of chronic pancreatitis, which is considered to have given rise to the tumor at some stage; and a lymphoid and fibrous proliferation in normal pancreatic tissue, which is considered to represent an autoimmune-related disease process.

Background: A rational algorithm for the management of symptomatic pancreatic pseudocysts is necessary with the increasing availability of radiological, surgical and endoscopic methods of treatment. Methods: A retrospective audit of the management and outcome of all patients who presented with symptomatic pancreatic pseudocysts to the Auckland Hospital over a 9-year period (1988–96) was made. Results: There were 44 patients (28 men, 16 women; median age 50; range 18–81) in this series. Initial management was not based on pseudocyst size, duration, location, wall thickness, the patients' symptoms and comorbidity, or the aetiology of pancreatitis. Of the 27 patients who had initial conservative management, 15 pseudocysts (56%) completely resolved. Of the 17 patients who were initially or subsequently treated with percutaneous catheter drainage (PCD), 10 pseudocysts (59%) completely resolved without additional treatment. Of the 13 patients initially or subsequently treated by surgery, all but one completely resolved after the first procedure. Two patients were successfully treated with endoscopic pancreatic stent placement. Complications arose in eight patients treated with PCD (47%) and four patients treated with surgery (31%). There was no mortality. The decision for active treatment was not preceded by delineation of the pancreatic duct by ERCP (endoscopic retrograde cholangiopancreatography) in 60% of patients. Conclusions: More than one-third of all patients with symptomatic pancreatic pseudocysts can be managed conservatively. Surgery yields excellent results but PCD has a high failure rate in patients with an underlying pancreatic duct stricture. A rational management algorithm is presented, based on pre-intervention ERCP, which should improve patient selection and outcome.

Pancreatitis and pancreatic insufficiency are associated with both cystic fibrosis and alcoholism. The pathogenesis of alcoholic pancreatitis is unknown, but only a minority of alcoholics develop pancreatitis, and it has been suggested that a genetic predisposition may play a role in this disease. Two observations led to the hypothesis that this genetic predisposition could result from mutations in the cystic fibrosis gene. First, the prevalence of cystic fibrosis mutations in the Caucasian population (approximately 5%) is similar to the prevalence of pancreatitis among heavy drinkers. Second, in both diseases, pancreatic duct damage is a prominent feature and has been postulated to be the initial site of injury. Therefore, the aim of this study was to determine whether an increased frequency of mutations in the cystic fibrosis gene occurs in alcoholic pancreatitis. The 15 most common cystic fibrosis mutations in a Caucasian community were sought in 24 subjects with alcoholic pancreatitis. None were homozygous or heterozygous for these mutations. These findings suggest that cystic fibrosis mutations are not a major genetic factor predisposing to pancreatic injury in alcoholics.

Background The incidence of acute pancreatitis has increased sharply in many European countries and the USA in recent years. Aim To establish trends in incidence and mortality for acute pancreatitis in Wales, UK, and to assess how incidence may be linked to factors including social deprivation, seasonal effects and alcohol consumption. Methods Use of record linked inpatient, mortality and primary care data for 10 589 hospitalised cases of acute pancreatitis between 1999 and 2010. Results The incidence of acute pancreatitis was 30.0 per 100 000 population overall, mortality was 6.4% at 60 days. Incidence increased significantly from 27.6 per 100 000 in 1999 to 36.4 in 2010 (average annual increase = 2.7% per year), there was little trend in mortality (0.2% average annual reduction). The largest increases in incidence were among women aged

The present study shows that scanty hair distribution over the trunk is a specific finding in patients with alcoholic liver disease (ALD), and is not seen in alcoholic pancreatitis. This observation not only provides a useful clinical marker of individuals at increased risk of developing alcohol-related liver disease, but from the pathogenetic viewpoint, it suggests that at the tissue level, the male sex hormones protect the liver against ethanol-related damage.

Whereas oral or intraduodenal ethanol causes a moderate stimulation of pancreatic bicarbonate and enzyme output, intravenous ethanol inhibits basal and hormonally stimulated pancreatic exocrine secretion in humans, dogs, cats, pigs, rabbits, and rats. This inhibition could be mediated by inhibitory cholinergic mechanisms or be the result of a direct cellular effect of ethanol. In vitro investigations have specified several signaling molecules that may be involved in the action of ethanol on stimulus-secretion coupling in the exocrine pancreas, including cyclic adenosine monophosphate, intracellular calcium, and cholecystokinin and somatostatin receptors. In difference to pure ethanol solutions and distilled spirits, beer strongly stimulates pancreatic enzyme output, probably by nonalcoholic fermentation products. During chronic alcoholism, the ethanol-induced inhibition is replaced by an enhanced enzyme output that causes intraductal protein precipitation. In vitro investigations suggest that this increase is reversible after alcohol withdrawal. The occurrence of protein precipitates is considered to be a crucial step in the development of chronic alcoholic pancreatitis in humans. Other ethanol-induced secretory alterations that may contribute to the development of alcoholic pancreatitis are a decreased secretion of trypsin inhibitor, an increased cholinergic tone, and changes in the concentration of lithostathine.

An acetaldehyde (AcH) adduct was prepared using rabbit low-density lipoprotein as carrier proteins. An antibody against this adduct was raised in Watanabe heritable hyperlipidemic rabbits and cross-reacted with human low-density lipoprotein and bovine serum albumin adducts. Using this antibody, serum anti-AcH-adduct antibody levels were measured by a direct ELISA method in 56 Japanese adults (healthy adults and patients with nonalcoholic gastrointestinal diseases, alcoholic liver injury, or alcoholic pancreatitis). The antibody level (mean +/- SD) was 22 +/- 10 microg/ml in healthy adults, 22 +/- 11 microg/ml in nonalcoholic gastrointestinal diseases, and 16 +/- 13 microg/ml in alcoholic pancreatitis. These antibody levels tended to increase with the progression of alcoholic liver injury, starting from fatty liver via hepatitis to cirrhosis, 29 +/- 24 microg/ml in fatty liver, 35 +/- 29 microg/ml in alcoholic hepatitis, and 46 +/- 54 microg/ml in alcoholic cirrhosis. The antibody level in patients taking 100 g or more of ethanol per day tended to be higher, compared with those in people taking less ethanol. A follow-up observation revealed that alcohol abstinence after hospitalization raised serum anti-AcH-adduct antibody level in some patients and kept it constantly low in other patients. The immunohistochemical study using the anti-AcH-adduct antibody revealed the presence of adduct-like substance in hepatocytes of liver biopsy specimens obtained from patients with alcoholic liver disease. The results indicate that the anti-AcH-adduct antibody may be associated with the progress of alcoholic liver diseases.