Alcohol abuse is a common cause of both acute and chronic pancreatitis. There is a wide spectrum of pancreatic manifestations in heavy drinkers from no apparent disease in most individuals to acute inflammatory and necrotizing pancreatitis in a minority of individuals with some progressing to chronic pancreatitis characterized by replacement of the gland by fibrosis and chronic inflammation. Both smoking and African-American ethnicity are associated with increased risk of alcoholic pancreatitis. In this review we describe how our recent studies demonstrate that ethanol feeding in rodents causes oxidative stress in the endoplasmic reticulum (ER) of the digestive enzyme synthesizing acinar cell of the exocrine pancreas. This ER stress is attenuated by a robust unfolded protein response (UPR) involving X-box binding protein-1 (XBP1) in the acinar cell. When the UPR activation is prevented by genetic reduction in XBP1, ethanol feeding causes significant pathological responses in the pancreas. These results suggest that the reason most individuals who drink alcohol heavily do not get significant pancreatic disease is because the pancreas mounts an adaptive UPR to attenuate the ER stress that ethanol causes. We hypothesize that disease in the pancreas results when the UPR is insufficiently robust to alleviate the ER stress caused by alcohol abuse.
Pancreas; Pancreatitis; Unfolded protein response; Alcohol; Smoking
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), an UPR regulator, in prevention of alcohol-induced ER stress in the exocrine pancreas.
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.
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 upregulation of pro-apoptotic 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.
Chronic 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.
alcohol disease; transcription factors; ER protein folding; organelle
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 are revealing that alcohol sensitizes the pancreas to key pathobiologic processes that are involved in pancreatitis. Current studies are focused 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.
Alcohol abuse is a major cause of pancreatitis, a condition that can manifest as both acute necroinflammation and chronic damage (acinar atrophy and fibrosis). Pancreatic acinar cells can metabolize ethanol via the oxidative pathway, which generates acetaldehyde and involves the enzymes alcohol dehydrogenase and possibly cytochrome P4502E1. Additionally, ethanol can be metabolized via a nonoxidative pathway involving fatty acid ethyl ester synthases. Metabolism of ethanol by acinar and other pancreatic cells and the consequent generation of toxic metabolites, are postulated to play an important role in the development of alcohol-related acute and chronic pancreatic injury. This current work will review some recent advances in the knowledge about ethanol actions on the exocrine pancreas and its relationship to inflammatory disease and cancer.
Pancreas; Calcium; Ethanol; Reactive oxygen species; Pancreatitis
Background & Aims
Progression of diseases of the exocrine pancreas, which include pancreatitis and cancer, is associated with increased levels of cell stress. Pancreatic acinar cells are involved in development of these diseases and, because of their high level of protein output, they require an efficient, unfolded protein response (UPR), which mediates recovery from endoplasmic reticulum (ER) stress following the accumulation of misfolded proteins.
To study recovery from ER stress in the exocrine organ, we generated mice with conditional disruption of Xbp1 (a principle component of the UPR) in most adult pancreatic acinar cells (Xbp1fl/fl). We monitored the effects of constitutive ER stress in the exocrine pancreas of these mice.
Xbp1-null acinar cells underwent extensive apoptosis, followed by a rapid phase of recovery in the pancreas that included expansion of the centroacinar cell compartment, formation of tubular complexes that contained Hes1- and Sox9-expressing cells, and regeneration of acinar cells that expressed Mist1 from the residual, surviving Xbp1+ cell population.
XBP1 appears to be required for homeostatisis of acinar cells in mice; ER stress induces a regenerative response in the pancreas that involves acinar and centroacinar cells and promotes organ recovery from exocrine pancreas disease.
endoplasmic reticulum stress; pancreatic progenitor cells; protein folding; tissue regeneration
Hypothesis: Bile and pancreatic juice exclusion from gut activates acinar stress kinases and exacerbates gallstone pancreatitis as evidenced by ameliorating effects of replacement therapy in an experimental model of duct ligation-induced acute pancreatitis. In early stages of gallstone pancreatitis, bile-pancreatic juice cannot enter the gut. Enteral exclusion worsens pancreatitis by causing feedback hyperstimulation of the exocrine pancreas that activates acinar cell stress kinases. Investigations using a unique surgical model, the Donor Rat Model, showed that duodenal replacement of bile-pancreatic juice in rats with duct ligation attenuates pancreatic stress kinase activation, reduces pancreatic cytokine production, and ameliorates pancreatic morphologic changes. These findings suggest that exclusion-induced acinar hyperstimulation, in the presence of duct obstruction, exacerbates acute pancreatitis via stress kinase activation. Although acinar hyperstimulation has often been implicated in acute pancreatitis pathogenesis, the lack of supporting evidence remains a conspicuous lacuna. The proposed hypothesis draws on fresh evidence to present a new paradigm that re-examines the role of exocrine pancreatic hyperstimulation in gallstone pancreatitis pathogenesis.
Alcohol abuse is the major cause of chronic inflammation of the pancreas (i.e., chronic pancreatitis). Although it has long been thought that alcoholic pancreatitis is a chronic disease from the outset, evidence is accumulating to indicate that chronic damage in the pancreas may result from repeated attacks of acute tissue inflammation and death (i.e., necroinflammation). Initially, research into the pathogenesis of alcoholic pancreatitis was related to ductular and sphincteric abnormalities. In recent years, the focus has shifted to the type of pancreas cell that produces digestive juices (i.e., acinar cell). Alcohol now is known to exert a number of toxic effects on acinar cells. Notably, acinar cells have been shown to metabolize alcohol (i.e., ethanol) via both oxidative (i.e., involving oxygen) and nonoxidative pathways. The isolation and study of pancreatic stellate cells (PSCs)—the key effectors in the development of connective tissue fibers (i.e., fibrogenesis) in the pancreas—has greatly enhanced our understanding of the pathogenesis of chronic pancreatitis. Pancreatic stellate cells become activated in response to ethanol and acetaldehyde, a toxic byproduct of alcohol metabolism. In addition, PSCs have the capacity to metabolize alcohol via alcohol dehydrogenase (the major oxidizing enzyme for ethanol). The fact that only a small percentage of heavy alcoholics develop chronic pancreatitis has led to the search for precipitating factors of the disease. Several studies have investigated whether variations in ethanol-metabolizing enzymes may be a trigger factor for chronic pancreatitis, but no definite relationship has been established so far.
Alcohol abuse; ethanol metabolism; ethanol-to-acetaldehyde metabolism; alcohol dehydrogenase (ADH); acetaldehyde; cytochrome P4502E1 (CYP2E1); reactive oxygen species (ROS); oxidation; pancreas; chronic pancreatitis; acute pancreatitis; alcoholic pancreatitis; acinar cell; pancreatic stellate cells (PSCs); fatty acid ethyl esters (FAEEs); genetic factors; genetic polymorphisms
It has been shown recently that longterm but not short term heavy drinking of alcohol frequently results in increased serum activities of pancreatic enzymes suggesting subclinical pancreatic injury. Serum pancreatitis associated protein (PAP) is a novel protein, whose synthesis in the acinar cells and release into serum is specifically induced by acute pancreatic damage. This study was performed to further characterise the alcohol induced subclinical pancreatic injury by using serum PAP measurements. Three groups were studied: (1) control group (n = 25), (2) short term drinking group (n = 20), who consumed 2.0 g of ethanol per kg body weight during four hours, and (3) longterm drinking group (n = 32), who were admitted to withdrawal clinic after a median 30 months heavy drinking period. Serum PAP concentration was low in the control group (8 (5 to 12) micrograms/l, geometric mean (95% confidence intervals)). In the short term drinking group serum PAP was in the range of the control group values during 56 hours after drinking. Longterm drinking induced at least a 10-fold increase in serum PAP, the highest concentrations being seen on day 2 after drinking had ended (106 (61 to 184) micrograms/l). The patients did not develop abdominal symptoms, increased blood white cell count, or increased serum C reactive protein concentration. These results further support the suggestion that heavy longterm drinking often induces subclinical pancreatic damage, but not clinical pancreatitis.
The epidemiologic evidence for the role of alcohol use in pancreatic cancer development is equivocal. The authors prospectively examined the relation between alcohol use and risk of pancreatic cancer among 470,681 participants who were aged 50–71 years in 1995–1996 in the US National Institutes of Health-AARP Diet and Health Study. The authors identified 1,149 eligible exocrine pancreatic cancer cases through December 2003. Multivariate Cox proportional hazards regression models were used to calculate relative risks and 95% confidence intervals with the referent group being light drinkers (<1 drink/day). The relative risks of developing pancreatic cancer were 1.45 (95% confidence interval (CI): 1.17, 1.80; Ptrend = 0.002) for heavy total alcohol use (≥3 drinks/day, ∼40 g of alcohol/day) and 1.62 (95% CI: 1.24, 2.10; Ptrend = 0.001) for heavy liquor use, compared with the respective referent group. The increased risk with heavy total alcohol use was seen in never smokers (relative risk = 1.35, 95% CI: 0.79, 2.30) and participants who quit smoking 10 or more years ago before baseline (relative risk = 1.41, 95% CI: 1.01, 2.00). These findings suggest a moderately increased pancreatic cancer risk with heavy alcohol use, particularly liquor; however, residual confounding by cigarette smoking cannot be completely excluded.
alcohol drinking; cohort studies; pancreatic neoplasms; risk; smoking
Alcohol abuse is one of the most common factors associated with acute and chronic pancreatitis. Although it is evident that alcohol abuse can have an important role in the development of pancreatitis, it does not appear that alcohol abuse alone is responsible for this disease. We investigated the involvement of ethanol in impairment of pancreatic repair after induction of pancreatitis.
A biologically relevant mouse model of alcoholic pancreatitis, combining chronic ethanol consumption and coxsackievirus infection, was used to investigate the effects of ethanol on pancreatic regeneration. Tissues were harvested and analyzed by RT-PCR and immunoblot.
These studies demonstrate that chronic ethanol consumption impairs the structural repair of the exocrine pancreas. This is accompanied by a delay in the restitution of lipase expression. Additionally, impaired expression of the critical pancreatic transcription factors, PDX1 and PTF1, and the mediator of Notch signaling, HES1, were observed.
Chronic ethanol consumption impairs the structural repair and functional restitution of the pancreas after severe injury. These impairments may, in part, be explained by impaired expression of factors important in the development and maintenance of the exocrine pancreas. Impaired pancreatic regeneration may have a role in the pathogenesis of alcoholic pancreatitis.
Acute Pancreatitis; Coxsackievirus; Ethanol; Tissue Repair; Alcoholic Pancreatitis; Developmental Factors
Previous studies have shown increased secretion of total calcium in the duodenal juice of patients with chronic alcoholic pancreatitis compared with healthy subjects. In order to get more detailed information on calcium secretion and pancreatic stone formation in chronic alcoholic pancreatitis, ionised and total calcium concentrations were determined in the duodenal juice of normal subjects, chronic alcoholics, and patients with various stages of chronic alcoholic pancreatitis. Total calcium secretion was in agreement with previously published data. Chronic alcoholics presented a significant increase of ionised calcium. In the course of pancreatitis all calcium fractions increased progressively revealing highest concentrations in patients with severe exocrine insufficiency. In non-calcified and calcified pancreatitis all calcium fractions were identical. It is suggested that the increase of ionised calcium originates from serum ionised calcium passing by diffusion into the damaged pancreatic duct system.
BACKGROUND & AIMS
Opening of the mitochondrial permeability transition pore (MPTP) causes loss of the mitochondrial membrane potential (ΔΨm) and, ultimately, adenosine triphosphate depletion and necrosis. Cells deficient in cyclophilin D (CypD), a component of the MPTP, are resistant to MPTP opening, loss of ΔΨm, and necrosis. Alcohol abuse is a major risk factor for pancreatitis and is believed to sensitize the pancreas to stressors, by poorly understood mechanisms. We investigated the effects of ethanol on the pancreatic MPTP, the mechanisms of these effects, and their role in pancreatitis.
We measured ΔΨm in mouse pancreatic acinar cells incubated with ethanol alone and in combination with physiologic and pathologic concentrations of cholecystokinin-8 (CCK). To examine the role of MPTP, we used ex vivo and in vivo models of pancreatitis, induced in wild-type and CypD−/− mice by a combination of ethanol and CCK.
Ethanol reduced basal ΔΨm and converted a transient depolarization, induced by physiologic concentrations of CCK, into a sustained decrease in ΔΨm, resulting in reduced cellular adenosine triphosphate and increased necrosis. The effects of ethanol and CCK were mediated by MPTP because they were not observed in CypD−/− acinar cells. Ethanol and CCK activated MPTP through different mechanisms— ethanol by reducing the ratio of oxidized nicotinamide adenine dinucleotide to reduced nicotinamide adenine dinucleotide, as a result of oxidative metabolism, and CCK by increasing cytosolic Ca2+. CypD−/− mice developed a less-severe form of pancreatitis after administration of ethanol and CCK.
Oxidative metabolism of ethanol sensitizes pancreatic mitochondria to activate MPTP, leading to mitochondrial failure; this makes the pancreas susceptible to necrotizing pancreatitis.
Tissue Damage; Ethanol Toxicity; Cell Death; Exocrine Pancreas
Alcohol abuse is associated with the development of both acute and chronic pancreatitis. The majority of patients who abuse alcohol will not develop pancreatitis; the reasons for different susceptibilities to alcohol are unknown. Most patients who present with acute alcoholic pancreatitits will have underlying chronic disease, but up to a third will have no evidence of chronic pancreatitis. Alcohol has a number of acute effects on the pancreas that are potentially toxic. These include increasing pancreatic duct pressure, decreasing pancreatic blood flow, generating free radicals, and stimulating pathologic zymogen activation within the pancreatic acinar cell.
The association between alcohol consumption and pancreatitis has been recognized for over 100 years. Despite the fact that this association is well recognized, the mechanisms by which alcohol abuse leads to pancreatic tissue damage are not entirely clear. Alcohol abuse is the major factor associated with pancreatitis in the Western world. Interestingly, although most cases of chronic pancreatitis and many cases of acute pancreatitis are associated with alcohol abuse, only a small percentage of individuals who abuse alcohol develop this disease. This situation is reminiscent of the association between alcohol abuse and the incidence of alcoholic liver disease. The liver and the pancreas are developmentally very closely related. Even though these two organs are quite different, they exhibit a number of general structural and functional similarities. Furthermore, the diseases mediated by alcohol abuse in these organs exhibit some striking similarities. The diseases in both organs are characterized by parenchymal cell damage, activation of stellate cells, aberrant wound healing, and fibrosis. Because of the similarities between the liver and the pancreas, and the alcohol-associated diseases of these organs, we may be able to apply much of the knowledge that we have gained regarding the effects of alcohol on the liver to the pancreas.
Alcoholic pancreatitis; Alcohol metabolism; Stellate cells; Fibrosis
The five major diseases of the pancreas together make a significant contribution to morbidity and mortality among the people of the United States. These diseases are diabetes, cystic fibrosis, acute and chronic pancreatitis, and carcinoma of the exocrine pancreas. Four of these diseases can be modeled in laboratory animals by acute or chronic administration of chemical poisons or carcinogens. Human pancreatic diseases attributed to the effect of chemical agents including alcohol and drugs include many cases of chronic pancreatitis and some cases of acute pancreatitis. The cause is not known in many cases of human pancreatitis, including interstitial, acute, and chronic clinical forms. Epidemiologic studies suggest that the increasing incidence of carcinoma of the exocrine pancreas in the United States may reflect chemical carcinogenesis. On the basis of experimental observations, we know that pancreatic islet cells can be damaged directly by toxic chemicals, and that islet cell tumors can be chemically induced. Thus, there is adequate background data to conclude that several pancreatic diseases of obscure etiology may be due in part to hitherto unidentified toxic effects of chemical agents encountered in personal or general environments.
Acute pancreatitis is an inflammatory disease of exocrine pancreas that carries considerable morbidity and mortality; its pathophysiology remains poorly understood. During the past decade, new insights have been gained into signaling pathways and molecules that mediate the inflammatory response of pancreatitis and death of acinar cells (the main exocrine pancreas cell type). By contrast, much less is known about the acinar cell organellar damage in pancreatitis and how it contributes to the disease pathogenesis.
This review summarizes recent findings from our group, obtained on experimental in vivo and ex vivo models, which reveal disordering of key cellular organelles, namely, mitochondria, autophagosomes, and lysosomes, in pancreatitis. Our results indicate a critical role for mitochondrial permeabilization in determining the balance between apoptosis and necrosis in pancreatitis, and thus the disease severity. We further investigate how the mitochondrial dysfunction (and hence acinar cell death) is regulated by Ca2+, reactive oxygen species, and Bcl-xL, in relation to specific properties of pancreatic mitochondria. Our results also reveal that autophagy, the principal cellular degradative, lysosome-driven pathway, is impaired in pancreatitis due to inefficient lysosomal function, and that impaired autophagy mediates two key pathological responses of pancreatitis—accumulation of vacuoles in acinar cells and the abnormal, intra-acinar activation of digestive enzymes such as trypsinogen.
Critical Issues and Future Directions
The findings discussed in this review indicate critical roles for mitochondrial and autophagic/lysosomal dysfunctions in the pathogenesis of pancreatitis and delineate directions for detailed investigations into the molecular events that underlie acinar cell organellar damage. Antioxid. Redox Signal. 15, 2699–2710.
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.
Acute pancreatitis; Chronic pancreatitis; Alcohol consumption; Alcohol metabolism; Genetic variability; Pancreatic cancer; Risk
Pancreatic exocrine insufficiency is an important cause of maldigestion and a major complication in chronic pancreatitis. Normal digestion requires adequate stimulation of pancreatic secretion, sufficient production of digestive enzymes by pancreatic acinar cells, a pancreatic duct system without significant outflow obstruction and adequate mixing of the pancreatic juice with ingested food. Failure in any of these steps may result in pancreatic exocrine insufficiency, which leads to steatorrhea, weight loss and malnutrition-related complications, such as osteoporosis. Methods evaluating digestion, such as fecal fat quantification and the 13C-mixed triglycerides test, are the most accurate tests for pancreatic exocrine insufficiency, but the probability of the diagnosis can also be estimated based on symptoms, signs of malnutrition in blood tests, fecal elastase 1 levels and signs of morphologically severe chronic pancreatitis on imaging. Treatment for pancreatic exocrine insufficiency includes support to stop smoking and alcohol consumption, dietary consultation, enzyme replacement therapy and a structured follow-up of nutritional status and the effect of treatment. Pancreatic enzyme replacement therapy is administered in the form of enteric-coated minimicrospheres during meals. The dose should be in proportion to the fat content of the meal, usually 40-50000 lipase units per main meal, and half the dose is required for a snack. In cases that do not respond to initial treatment, the doses can be doubled, and proton inhibitors can be added to the treatment. This review focuses on current concepts of the diagnosis and treatment of pancreatic exocrine insufficiency.
Chronic pancreatitis; Pancreatic exocrine insufficiency; Pancreatic enzyme replacement therapy
Alcohol abuse is a leading cause of pancreatitis in humans. However, rodent models suggest that alcohol only sensitizes the pancreas to subsequent insult, indicating that additional factors play a role in alcohol-induced pancreatic injury. The goal of this study was to determine if an absence of MIST1, a transcription factor required for complete differentiation of pancreatic acinar cells in mice, increased the sensitivity to alcohol.
Two to four month-old mice lacking MIST1 (Mist1−/−) or congenic C57 Bl6 mice were placed on a Lieber-DeCarli diet (36% of total kcal from ethanol and fat), a control liquid diet (36% kcal from fat) or a regular breeding chow diet (22% kcal from fat). After six weeks, pancreatic morphology was assessed. Biochemical and immunofluorescent analysis was used to assess mediators of the unfolded protein response (UPR).
Ethanol-fed Mist1−/− mice developed periductal accumulations of inflammatory cells that did not appear in wild type or control-fed Mist1−/− mice. Wild type mice fed diets high in ethanol or fat showed enhancement of the UPR based on increased accumulation of peIF2α and spliced XBP1. These increases were not observed in Mist1−/− pancreatic tissue, which had elevated levels of UPR activity prior to diet exposure. Indeed, exposure to ethanol resulted in a reduction of UPR activity in Mist1−/− mice.
Our findings suggest that an absence of MIST1 increases the sensitivity to ethanol that correlated with decreased activity of the UPR. Therefore, events that affect the expression and/or function of MIST1 may be confounding factors in pancreatitis.
Heavy alcohol drinking has been related to pancreatic cancer, but the issue is still unsolved.
To evaluate the role of alcohol consumption in relation to pancreatic cancer, we conducted a pooled analysis of 10 case–control studies (5585 cases and 11 827 controls) participating in the International Pancreatic Cancer Case–Control Consortium. We computed pooled odds ratios (ORs) by estimating study-specific ORs adjusted for selected covariates and pooling them using random effects models.
Compared with abstainers and occasional drinkers (<1 drink per day), we observed no association for light-to-moderate alcohol consumption (≤4 drinks per day) and pancreatic cancer risk; however, associations were above unity for higher consumption levels (OR = 1.6, 95% confidence interval 1.2–2.2 for subjects drinking ≥9 drinks per day). Results did not change substantially when we evaluated associations by tobacco smoking status, or when we excluded participants who reported a history of pancreatitis, or participants whose data were based upon proxy responses. Further, no notable differences in pooled risk estimates emerged across strata of sex, age, race, study type, and study area.
This collaborative-pooled analysis provides additional evidence for a positive association between heavy alcohol consumption and the risk of pancreatic cancer.
alcohol drinking; case–control studies; ethanol; pancreatic cancer; pooled analysis; risk factors
The exocrine pancreas has the greatest protein synthetic capacity of any mammalian organ and is challenged with the synthesis, processing and transporting a large load of digestive enzymes. Based on recent findings we present a hypothesis proposing that mutations in the digestive enzymes and environmental risks impacting the pancreas (i.e., alcohol abuse, smoking, metabolic disorders, and drugs) cause endoplasmic reticulum (ER) stress. We review recent findings showing that in normal pancreas the ER stress resulting from alcohol abuse leads to an adaptive unfolded protein response (UPR) allowing for maintenance of protein synthesis, processing, and transport. However, when key pathways necessary for the adaptive UPR are altered, the exocrine cell of the pancreas is unable to maintain these processes and cellular pathology results. These findings may explain why some individuals with alcohol abuse disorders develop organ injury and disease while most do not. Further, the findings allow us to hypothesize that the UPR in the exocrine pancreas adapts the protein synthetic machinery of the ER stress resulting from mutational and environmental stressors. When the ability of the UPR to adapt to the stressors is exceeded, pathologic pathways and disease develop.
UPR; pancreas; gastrointestinal; research; exocrine; pancreatic function
Background and aims
Epidemiological data clearly indicate that cigarette smoking is associated with an increased risk for developing chronic pancreatitis and pancreatic cancer. Despite of this clear epidemiological correlation, cigarette smoke-induced pancreatic damage has only been investigated in a small number of experimental studies.
Experimental studies examining the effect of cigarette smoke or cigarette smoke constituents on the pancreas were reviewed.
Recent data indicate that smoking also induces chronic pancreatic inflammation in rodents within a period of 12 weeks upon exposure with environmental cigarette smoke. Supported by the finding that morphologic pancreatic damage is also induced by nicotine treatment, cigarette smoke-induced pancreatic damage is likely to be caused by a disturbance of regulation of exocrine pancreas. The morphological alterations, however, induced by nicotine, are less pronounced and therefore, other substances and pathophysiologic mechanisms, such as carcinogen action or cigarette smoke-induced reduction of anti-protease activity, are likely to aggravate pancreatic damage upon cigarette smoke inhalation.
These data indicate that several constituents of cigarette smoke induce a disturbance of pancreatic function. This multifactorial event induces morphologic pancreatic damage upon cigarette smoke exposure in rodents.
Cigarette smoking; Nicotine; Carcinogen; Pancreatic cancer; Chronic pancreatitis
Background & Aims
Bmi1 is a member of the Polycomb protein family and represses transcription by modifying chromatin organization at specific promoters. Bmi1 is implicated in the control of stem cell self-renewal and has been shown to regulate cell proliferation, tissue homeostasis, and differentiation. Bmi1 is present in a subpopulation of self-renewing pancreatic acinar cells and is expressed in response to pancreatic damage. We investigated the role of Bmi1 in exocrine pancreas regeneration.
Acute pancreatitis was induced in Bmi1−/− mice with caerulein; pancreatic cell regeneration, differentiation, and apoptosis were assessed. Cultured Bmi1−/− and wild-type primary acini were analyzed in vitro, to determine acinar-specific consequences of Bmi1 deletion. To investigate cell-autonomous vs non–cell-autonomous roles for Bmi1 in vivo, pancreatitis was induced in Bmi1−/− mice reconstituted with a wild-type hematopoietic system.
Bmi1 expression was upregulated in the exocrine pancreas during regeneration after caerulein-induced pancreatitis. Exocrine regeneration was impaired following caerulein administration to Bmi1−/− mice. Pancreata of Bmi1−/− mice were hypoplastic, and the exocrine pancreas was replaced with ductal metaplasia that had increased apoptosis and decreased cell proliferation, compared to that of wild-type mice. Expression of Cdkn2a and p53-dependent apoptotic genes were markedly upregulated in Bmi1−/− pancreas, compared to wild-type mice, after injury. Furthermore, after transplantation of bone marrow from wild-type to Bmi1−/− mice, the chimeric mice had intermediate levels of pancreatic hypoplasia and significant, but incomplete, rescue of impaired exocrine regeneration after caerulein injury.
Bmi1 contributes to regeneration of the exocrine pancreas after caerulein-induced injury through cell-autonomous mechanisms—in part by regulating Cdkn2a expression—and non-cell-autonomous mechanisms.
pancreatitis; polycomb proteins; tissue regeneration; mouse model
Purpose of review
We review important new clinical observations in chronic pancreatitis (CP) reported in 2011.
Smoking increases the risk of non-gallstone acute pancreatitis (AP) and the progression of AP to CP. Binge drinking during Oktoberfest did not associate with increased hospital admissions for AP. The unfolded protein response is an adaptive mechanism to maintain pancreatic health in response to noxious stimuli such as alcohol. Onset of diabetes mellitus in CP is likely due to progressive disease rather than individual variables. Insufficient pancreatic enzyme dosing is common for treatment of pancreatic steatorrhea; 90,000 USP U of lipase should be given with meals. Surgical drainage provides sustained, superior pain relief compared to endoscopic treatment in patients advanced CP with a dilated main duct +/− pancreatic stones. The central acting gabapentoid pregabalin affords a modest 12% pain reduction in patients with CP but ~30% of patients have significant side effects.
Patients with non-gallstone related AP or CP of any etiology should cease smoking. Results of this year’s investigations further elucidated the pancreatic pathobiology due to alcohol, onset of diabetes mellitus in CP, and the mechanisms and treatment of neuropathic pain in CP.
chronic pancreatitis; exocrine pancreatic insufficiency; diabetes mellitus; pain
The case history of a 34-year-old patient with precirrhotic idiopathic haemochromatosis and severe chronic steatorrhoea is presented. The pancreas had a normal appearance on ultrasonography and endoscopic retrograde pancreaticography. However, pancreatic function tests revealed significant abnormalities. The pancreatic output of trypsin, amylase, lipase and bicarbonate was deficient and basal and stimulated serum pancreatic polypeptide levels were subnormal. In contrast, the oral glucose tolerance test was unimpaired. The pancreatic insufficiency had started suddenly during a summer vacation and may have had a viral aetiology. The hypothesis is advanced that in haemochromatosis the iron-laden pancreatic acinar and PP-producing cells are more susceptible to damage by viruses than normal pancreatic cells.