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References 389

Downloaded from https://onlinelibrary.wiley.com/doi/ by Universität Bern, Wiley Online Library on [22/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

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74 Murugaian EE, Premkumar RM, Radhakrishnan L, Vallath

B. Novel mutations in the calcium sensing receptor gene intropical chronic pancreatitis in India. Scand J Gastroenterol 2008;43:117–121.

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mechanisms underlying the pathogenesis of tropical calcific pancreatitis. World J Gastroenterol 2009;15:264–269.

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tropical chronic pancreatitis is not just a secondary type ofdiabetes. Pancreatology 2004;4:461–467.

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premalignant? Am J Gastroenterol 1992;87:1005–1008.

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390

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CFTR-

Chee Y. Ooi1 and Aliye Uc

Discipline of Paediatrics & Child Health, Randwick Clinical Campus, School of Clinical Medicine, UNSW Medicine & Health, University of New South

Wales and Sydney Children’s Hospital Randwick, Sydney, NSW, Australia

Stead Family Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, Pancreatology and Nutrition, University of Iowa Carver

College of Medicine, Iowa City, IA, USA

Introduction

There is a spectrum of pancreatic diseases associated with CFTR[1,2] mutations, namely classic cystic fibrosis (CF) (pancreatic insufficient or sufficient) and CFTRassociated pancreatitis. The pancreas pathology and damage are dependent on the amount of functional CFTR: the lower the function, the more prominent and earlier the sequelae. In addition, CFTR mutations may contribute to the development of acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP).

Associated Pancreatic Disease

The absence of phenylalanine at position 508 (F508del, a class II mutation) constitutes two-

thirds of CFTR mutations in northern European and North American populations. No other single mutation accounts for more than 5% of CFTR mutations worldwide [4]. Patients with at least one mutation belonging to classes IV or V generally present with milder disease, symptoms in late childhood or adulthood and they are pancreatic sufficient.

CFTR is expressed in epithelial cells of various organs including pancreatic ducts, and it functions as an apical membrane anion channel, involved primarily in anion secretion[7,8]. It is generally agreed that the lack of CFTR leads to acidic, dehydrated, and protein- rich secre-

Pathophysiology— Genotype andPhenotype Correlations

tions [9,10], which then plug the acinar and ductal lumen[11–13] and cause the destruction of the pancreas in CF. Among the various gastrointestinal organs affected

Although more than 2000 CFTR mutations have been identified, the functional importance is known only for a small number of mutations. CFTR mutations can be classified into six types of defects (class I–VI mutations) [3]: absence of protein synthesis (class I); protein misfolding and premature degradation (class II); disordered regulation (class III); defective chloride (Cl

−

) conductance or channel gating (class IV); a reduced number of CFTR transcripts due to a promoter or splicing abnormality (class V); and accelerated turnover from the cell surface (class VI) (Fig. 47.1) [4,5]. CFTR function is virtually absent with class I–III and VI mutations while class IV and V mutations allow some residual CFTR function. Pancreatic involvement correlates well with gene mutations at the CFTR locus and thus residual CFTR function, and less by other genetic modifiers or environmental factors [6]. Exocrine pancreatic insufficiency is seen almost exclusively in association with class I–III and VI mutations[5].

by CF, the exocrine pancreas shows the strongest association between genotype and phenotype. In patients with the lowest CFTR function, considerable destruction of the pancreas starts in utero and functional loss of the exocrine pancreas develops at birth or in early infancy[14]. Agroup of patients with CF who have residual pancreatic exocrine function (pancreatic sufficient) are prone to recurrent attacks of pancreatitis and may become pancreatic insufficient over time[15,16]. The development of symptomatic episodes of CFTR-

associated pancreatitis is dependent on the intricate balance between impaired ductal flow and alkalinization due to reduced CFTR function and the degree of preserved acinar reserve (Fig.47.2).

Early studies suggested that CFTR mutations contributed to the development of CP alone or if additional risk factors were present[17–20]. Many of these studies were limited by relatively small number of patients, lack of control groups, and incomplete CFTR gene sequencing.

The Pancreas: An Integrated Textbook of Basic Science, Medicine, and Surgery, Fourth Edition. Edited by Hans G. Beger, Markus W. Büchler, RalphH. Hruban, Julia Mayerle, John P. Neoptolemos, Tooru Shimosegawa, Andrew L. Warshaw, David C. Whitcomb, and Yupei Zhao. © 2023 John Wiley & Sons Ltd. Published 2023 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/beger/thepancreas4e

CFTR

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Class III

Golgi

Class II

Class I

Figure47.1 Classes of CFTR mutations. CFTR mutations are grouped

into six functional classes. Class I mutations lead to protein synthesis defect, because premature stop codons or frameshifts for deletions or insertions preclude translation of full- length CFTR. Class II mutations lead to impaired protein trafficking, because CFTR is unable to complete its folding and ER machinery eliminates the protein. Class III mutants have defective channel gating, CFTR reaches the cell surface, but it is unable to perform channel gating due to diminished ATP binding and hydrolysis. Class IV mutants produce CFTR with reduced function. Class V mutants have reduced protein maturation caused by amino acid substitution or alternative splicing, the amount and therefore the function of CFTR that reaches the cell surface is reduced. Class VI mutants produce unstable protein, since CFTR at the plasma membrane is removed during the recycling and sent for lysosome degradation. CFTR: cystic fibrosis transmembrane conductance regulator; ER: endoplasmic reticulum.

CFTR

Class IV

Class V

Nucleus

Class VI

CFTR

Proteasome

Recent studies with larger German, French, and North American cohorts confirmed these earlier findings that CFTR variants play a role in idiopathic chronic pancreatitis[21–23], although the frequency of CFTR variants in CP was much lower than previously reported. The recent studies show no increased risk for CP with common polymorphic alleles T5 and TG12; the role of T5- TG12 complex allele remains to be determined[22].

Clinical Manifestations

The clinical manifestations of CFTR- associated pancreatic diseases correlate with the degree of pancreatic injury. Exocrine pancreatic damage in its severe form

Clinical Manifestations 391

manifests as exocrine pancreatic insufficiency (EPI), which is present in 60–75% of infants at time of CF diagnosis[24,25]. Pancreatic lesions begin in utero and continue into early childhood when complete loss of pancreatic acinar tissue occurs [24]. Fat maldigestion with resultant steatorrhea happen only when pancreatic colipase/lipase secretion falls below 1–2% of normal levels[26], with risk of malnutrition and fat-

soluble vitamin deficiencies. A causal relationship between early exocrine pancreatic disease in CF and the development of CF- related diabetes has also been reported[27].

Patients with sufficient pancreatic function who either have CF or CFTR- related disorder, are at risk of developing symptomatic acute and acute recurrent pancreatitis. Recurrent acute and chronic pancreatitis are known complications of CF, and they may occur in ~15–20% of patients with sufficient pancreatic function[28]. It is not known why a subgroup of patients with CF develops pancreatitis, but preservation of acinar cells seems to be a prerequisite for this complication. Recurrent pancreatic inflammation is a risk factor for further loss of residual function and progression to EPI[29].

The clinical landscape in relation to exocrine pancreatic function status and occurrences of symptomatic acute pancreatitis have changed in the era of CFTR modulator therapies. Two open-

label, multicenter studies in young children aged 2–5 years [30] and 1–<2 years [31] have demonstrated, for the first time, the plausibility of a window of opportunity to rescue the exocrine pancreas if modulators are commenced early enough. In addition, there have been accumulating published and anecdotal reports of EPI patients presenting with symptomatic acute pancreatitis associated with a rise in fecal elastase levels[32,33]. Consequently, clinicians need to be vigilant of this potential effect. In contrast, among pancreatic sufficient patients with recurrent pancreatitis, there have been reports of resolution or reduction of subsequent attacks following the use of modulators[34,35].

With increasing survival of patients with CF, an increased risk of malignancy in the gastrointestinal and biliary tracts has been observed[36]. The risk of malignancy in the pancreas was reported, in a subanalysis, to be greater than the overall risk of cancer in the digestive tract (odds ratio [95% CI] of 31.5 [4.8–205] vs. 6.4 [2.9–14], respectively).

Despite treatment with pancreatic enzymes that prevent severe malnutrition, exocrine pancreatic involvement impairs growth and accelerates the progression of lung disease[37,38], the major cause of mortality in CF[39]. CF patients develop diabetes mellitus as they age: ~10% of patients have cystic fibrosis- related diabetes mellitus (CFRD) by 10 years of age, and ~50% of CF patients over 30 years of age have CFRD [40,41]. CFRD is associated with a rapid decline in pulmonary

CFTR- Associated Pancreatic Disease

Degree of pancreatic ductal obstruction (dotted

CFTR function (%)

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392

Ductal obstruction

100

Ductal obstruction

100

Pancreatic acinar reserve

Pancreatitis

050

line) and pancreatic acinar reserve (solid line) (%)

CFTR function (%)

100

High

None

Risk of pancreatitis

Decreased risk of developing

symptomatic pancreatitis

CFTR Modulation

(shaded area)

Increased risk of developing

symptomatic pancreatitis

050

Ductal obstruction

100

050

Pancreatic acinar reserve

Pancreatitis

100

CFTR function (%)

Pancreatic acinar reserve

Pancreatitis

100

Figure47.2 Proposed pathogenesis model explaining the effects of CFTR modulation on either reducing or increasing risk of development

of symptomatic pancreatitis. The development of symptomatic episodes of CFTR- associated pancreatitis is associated with the opposing factors of severity of ductal obstruction and degree of preserved pancreatic acinar reserve. With CFTR modulation, there is a shift to the right along the x- axis toward greater CFTR function. In pancreatic sufficient individuals who are already experiencing symptomatic pancreatitis, there is reduction in risk of pancreatitis due to improved ductal flow. Among people with pancreatic insufficiency, there is no/ minimal risk of pancreatitis despite severe ductal obstruction present due to lack of sufficient acinar tissue. However, with improved CFTR function, there is risk of developing pancreatitis if there is sufficient ductal obstruction in the presence of residual acinar tissue.

function, higher morbidity, and greater mortality [14,42]. The diagnosis of CFRD is preceded by a decline in body weight and lung function, along with insulin deficiency[41,43].

Diagnosis

The rationale for testing for CF is the risk of multiorgan involvement in CF- affected organs and available effective therapies. Several studies have shown that a large proportion of pediatric and adult patients with idiopathic acute recurrent and chronic pancreatitis carry mutations in the CFTR gene. In a study of children affected by pancreatitis, CFTR mutations were identified in 30 out of 89 (34%) and 24 out of 104 (23%) children with acute recurrent and chronic pancreatitis, respectively[44]. In a separate study of 42 children and adults with idiopathic acute recurrent and chronic pancreatitis, extensive CFTR genotyping identified 50% of patients with either one or two CFTR variants[45].

Currently, the diagnostic criteria for CF require the

presence of characteristic symptom(s) of CF disease or a

positive family history, plus an abnormal sweat chloride value (≥60 mmol/L) and/or two CF disease- causing mutations [46]. Consensus guidelines [46,47] recommend the diagnostic terminologies of: (i) “CF disease,” to describe patients who fulfill the currently accepted diagnostic criteria; or (ii) “CFTR- related disorder” to describe individuals with the CF phenotype (e.g., pancreatitis), who have evidence of CFTR dysfunction but insufficient to fulfill the diagnostic criteria for CF disease (e.g., borderline sweat test [30–59 mmol/L] and/or one or two non- CF causing mutations).

As the majority of CFTR variants have unclear clinical significance, genotyping is the least sensitive diagnostic test for CF, compared to sweat testing and nasal potential difference (NPD)[20,45]. If performed, genotyping results should be interpreted with experts in CF genetics since nondiagnostic mutations for CF may be identified[48]. In a study comparing the yield of various diagnostic tests for CF, genotyping identified one or two CFTR mutations in 21 of 42 (50%) patients with idiopathic acute recurrent or chronic pancreatitis but was unable to establish or exclude the diagnosis of CF in any of them[45]. In contrast, sweat chloride and transepithelial NPD were able to diagnose

References 393

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CF in 5% and 29% of patients respectively [45]. While NPD is a sensitive and reproducible determinant of CFTR function[49], it has limitations. It is complex to perform, time- and labor- intensive, and operator- dependent. Access to NPD is also limited to specialized centers with NPD expertise. False positive results can occur with minor perturbations of the nasal epithelium, allergies, respiratory infections, and smoking.

As such, the sweat test remains the primary diagnostic test for CF[46,48]. Borderline (40–59 mmol/L) or abnormal (≥60 mmol/L) sweat chloride concentrations should lead to a referral to a CF clinic for further diagnostic evaluation, including for CFTR genotyping and alternative ion channel measurements (e.g., NPD or intestinal ion channel measurement), and various endorgan testing (e.g., lung function). Disease- specific counseling (e.g., fertility and smoking cessation) and genetic counseling are also important management considerations. Once the diagnosis of CF is made, the next step is to establish the exocrine pancreatic function and determine whether the patient requires pancreatic enzyme replacement therapy (PERT).

Because CF and CP share many pathological characteristics including pancreatic fibrosis, atrophy, and fatty infiltration[50], imaging studies proposed for the assessment of pancreatic involvement in CP may be applicable to CF pancreas. Magnetic resonance imaging/magnetic resonance cholangiopancreatography (MRI/MRCP) can assess fibrosis (T1mapping)[51], pancreas size[52], and ductal fluid secretion in response to secretin [53]. However, there are variations between studies and the ability of imaging studies to differentiate between pancreatic sufficient vs. pancreatic insufficient status in CF remains limited[54]. More data are needed before imaging studies can be used as diagnostic studies of CF pancreatic diseases to assess pancreatic structure and function.

Therapy

For patients with advanced pancreatic damage and EPI, the only treatment available currently is PERT[8]. Children <4 years of age require 1000 lipase units/kg per meal;

500lipase units/kg per meal are used for those >4 years of age and 25,000–40,000 units/meal are used for adults[55]. For snacks half the dose is recommended. Infants may be given 2000–4000 units per 120

mL of infant formula or per breast feeding. The daily dose for most patients is less than 10,000 units of lipase/kg per day or 6000 units of lipase/kg per meal to prevent fibrosing colonopathy[56]. Aggressive nutritional management, fat- soluble vitamin supplementation is mandatory for all patients with EPI. Insulin is the treatment of choice for CFRD[57].

The ideal therapeutic strategy in CF should be repairing the underlying CFTR defect. Recent studies using CFTR modulators suggest that early initiation of ivacaftor may improve pancreatic function in infants and young children with gating mutations. In the ARRIVAL study, improvement in exocrine pancreatic function was observed in 4–24- month- old subjects after 24- week use of ivacaftor[31,58]. Similar improvements were observed in older children 2–5 years old by the use of ivacaftor for 24weeks (KIWI study)[30] and results were sustained at week 84 (KLIMB study)[59]. These results were similar to the work done in the G551D CF ferret model, which showed protection from pancreatic disease if treated with ivacaftor in utero, but pancreatic destruction if withdrawn postnatally[60].

People with CF experiencing recurrent pancreatitis have observed a significant reduction in the number of attacks while on ivacaftor [34,35,61], suggesting that improving CFTR function can ameliorate pancreatitis. There are rare reports of pancreas transplantation reported in people with CFRD, which not only corrects the diabetes, but also eliminates the need for pancreatic enzyme use. Pancreas transplants are typically coordinated with other organ transplants (mostly liver), but combined liver, lung, and pancreas transplants have also been reported[62,63].

Future studies will examine the effects of highly effective CFTR modulators on the pancreas at various ages. Gene therapy remains an area of active research, targeting primarily lungs, as challenges exist to access the pancreas [64,65]. A minimally invasive method was successfully used to deliver gene therapy vectors to the newborn porcine pancreatic ducts[66], but there are no similar studies yet in humans.

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396

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Alcohol andSmoking inChronic Pancreatitis

Atsushi Masamune, Kazuhiro Kikuta, and Kiyoshi Kume

Division of Gastroenterology, Tohoku University Graduate School of Medicine, Miyagi, Japan

Introduction

Chronic pancreatitis (CP) develops resulting from interactions of multiple environmental, metabolic, and genetic risk factors[1]. Alcohol is the leading cause for CP in many Western countries, and the association between alcohol misuse and CP has been recognized for a long time. As early as 1878, Friedreich [2] described “drunkard’s pancreas”: chronic interstitial inflammation in the pancreas which might result from alcohol misuse. In 1946, Comfort etal.[3] described the clinical presentation of chronic relapsing pancreatitis in subjects with alcohol misuse. Thereafter, it has been established that alcohol misuse is an important risk factor for CP. Of note, unlike the alcohol- induced liver injury, only 1–5 % of heavy drinkers develop pancreatitis[4], indicating that alcohol- related pancreatitis is not caused by alcohol misuse alone. Some individuals may develop alcohol- related pancreatitis with alcohol intake as low as 20 g/day, whereas most individuals do not develop pancreatitis no matter how much they drink or how long. In animals, ethanol feeding alone does not cause a pronounced pancreatic injury. Therefore, additional genetic and/or environmental predisposing factors are required for the development of clinical CP.

Conversely, the independent effects and risks associated with smoking have not been well recognized until recently. Because smoking is strongly associated with drinking alcohol[5,6], the independent effect of smoking can be difficult to assess. Smoking is now recognized to confer a strong, independent and doseCP[5–7]. Importantly, smoking and alcohol interact and worsen acinar cell injury and pancreatitis synergistically[5,6]. In this chapter, we review the clinical observations and pathophysiology of alcohol- related and smoking- related CP.

dependent risk of

Alcohol andChronic Pancreatitis

Clinical Observations

Historically, alcohol misuse is the leading cause of CP and accounts for approximately 60–90% of CP cases in industrialized nations worldwide [6]. However, in recent years, the proportion of alcohol- related CP (ACP) cases might be smaller than expected. The North American Pancreatitis Study 2 (NAPS2) showed that the frequency of ACP at tertiary referral centers in the United States was 44.5%[6]. A report from Italy showed a shift in the etiologic profile of CP[8]. Alcohol misuse was the leading cause of CP (74%) between 1971 and 1995, but the proportion was decreased to 43% in patients evaluated between 2000 and 2006. These findings suggest that the contribution of alcohol misuse to the pathogenesis of CP might have been overestimated[6]. Referral bias might exist in tertiary referral centers and accurate assessment of alcohol exposure to determine the association with CP is challenging because self- reports about alcohol consumption are usually unreliable. Conversely, in Asia, ACP accounted for 72% of all CP cases in Japan in 2016[9]. In India and China, the proportion of ACP was lower and idiopathic pancreatitis was the most common type, accounting for approximately 70% of the CP cases[10]. Importantly, alcohol consumption has been stable or decreasing in many North American and European countries as well as in Japan, whereas it has been increasing in India and China[10]. It would be of interest to see whether the trends in alcohol consumption affect the burden of ACP in India and China in the future.

There have been many studies that aimed to clarify the dose–response relationship between alcohol consumption and CP. The association between alcohol

Pathophysiology 397

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consumption and pancreatitis was evaluated in 540 cases and 695 controls in the NAPS2 [5]. Logistic regression analyses revealed a significant association between alcohol and CP only in very heavy drinkers who consumed ≥5 alcoholic drinks per day (odds ratio [OR] = 3.1). In another case- control study[11], among patients with onset of CP after the age of 35, alcohol intake, even less than 50 g/day, induced earlier disease characterized by more frequent severe pain, calcification, and complications such as pseudocysts. In a Japanese case- control study[12], compared with nondrinkers, the OR (95% confidence interval [CI]) for alcohol consumption of 20≤~<40 g/day, 40≤~<60 g/ day, 60≤~<80 g/day, 80≤~<100 g/day, and ≥100 g/day were

2.6 (1.2–5.5), 3.2 (1.5–7.1), 9.2 (4.1–20.3), 13.0 (5.3–31.6), and 19.6 (8.2–46.8), respectively. A systematic review and meta- analysis of four studies (three case- control and one cohort studies) showed that the risk of CP increased monotonically according to the average alcohol consumption with no identifiable threshold in men[13]. The relative risks (RR) (95% CI) were 1.58 (1.32–1.90) at 25 g/day;

2.51 (1.74–3.61) at 50 g/day; 3.97 (2.30–6.85) at 75 g/day; and 6.29 (3.04–13.02) at 100 g/day.

It is well known that ACP is predominantly a disease of men [5,9]. However, alcohol misuse is an important health problem in women, too. It has been shown that susceptible women might develop ACP with shorter duration and lower cumulative amounts of alcohol consumption than men[14].

Ethanol Metabolism inthe Pancreas

Ethanol can be metabolized in the pancreas, mainly in pancreatic acinar cells. Two pathways of ethanol metabolism have been described in pancreatic acinar cells: oxidative and nonoxidative pathways[15]. Ethanol oxidation involves the conversion of ethanol to acetaldehyde and acetate, a reaction catalyzed by ADH and cytochrome P450 2E1. The nonoxidative pathway of ethanol metabolism involves the esterification of ethanol with fatty acids to form fatty acid ethyl esters (FAEE) such as palmitic acid ethyl ester. This reaction is catalyzed by FAEE synthases. FAEE synthase activity in the pancreas is much greater than that in the liver, whereas pancreatic ADH and cytochrome P450 2E1 activities are low [15]. Therefore, the dominant nonoxidative metabolism is a characteristic feature of ethanol metabolism in the pancreas.

Pathophysiology

Several pathophysiological mechanisms linking alcohol consumption and pancreatitis have been suggested. At the cellular level, ethanol and its metabolites affect the

Table48.1 Effects of ethanol on pancreatic cells[16,17].

1. induces mitochondrial damage

2. elevates intracellular calcium levels

3. disrupts expression and function of the CFTR

4. decreases bicarbonate secretion

5. increases pancreatic digestive enzyme content

6. redirects exocytosis to the basolateral surface

7. enhances pancreatitis responses elicited by hyperstimulation

8. induces endoplasmic reticulum stress

9. promotes oxidative stress

10. increases the fragility of lysosomes and zymogen granules

11. regulates transcription factors NF-

12. activates stellate cells to promote fibrosis

CFTR: cystic fibrosis transmembrane conductance regulator; NF- κB: nuclear factor- κB; AP- 1: activator protein- 1.

κB and AP- 1

cell functions and homeostasis of pancreatic cells including acinar cells, ductal cells, and stellate cells (Table48.1) [16,17 and references therein]. Importantly, animal studies have suggested that ethanol alone does not induce pancreatitis unless additional pathogenic insults are present. One explanation would be that the pancreas can compensate harmful effects of alcohol through an adaptive stress response. Pancreatitis develops only when the compensatory mechanisms are disrupted/exhausted or if increased vulnerability due to other genetic and environmental cofactors are present. Findings in animal studies support the concept that alcohol misuse alone does not cause CP and additional cofactors are required for the development of CP in susceptible humans.

Pancreatic Acinar Cells

Ethanol induces a sustained elevation of the intracellular calcium levels, which is central in promoting pathological events of pancreatitis. FAEE cause pancreatic calcium toxicity via inositol trisphosphate receptors and loss of adenosine triphosphate production [18]. Calcium overload reduces adenosine triphosphate production and subsequently causes dysfunction of endoplasmic reticulum (ER). Ethanol increases the fragility of zymogen granules and lysosomes, which sequester lysosomal enzymes such as cathepsin B within the cells. Oxidative alcohol metabolism induces mitochondrial dysfunction, which might play a role in ethanol- induced necrosis of the pancreatic acinar cells[19]. Mitochondrial dysfunction occurs due to membrane permeabilization mediated by persistent opening of the mitochondrial permeability transition pore, leading to loss of mitochondrial membrane potential and mitochondrial fragmentation.

Alcohol andSmoking inChronic Pancreatitis

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398

These changes might make the pancreas susceptible to necrotizing pancreatitis.

Chronic ethanol feeding in mice perturbs protein folding and induces ER stress, which in turn induces an unfolded protein response (UPR) involving the upregulation of spliced X box- binding protein 1 (sXBP1) in pancreatic acinar cells[20]. Ethanol administration to mice heterozygous for XBp1 (XBP1

+/-

) resulted in dilated ER, loss of zymogen granules, accumulation of autophagic vacuoles, and acinar cells death, suggesting that these responses serve as a protective adaptive mechanism that prevents ethanol- induced damage.

Autophagy is impaired in pancreatitis and lysosome dysfunction might be involved. Autophagy comprises several intracellular pathways of lysosome- mediated degradation and recycling of organelles, long- lived proteins and lipids[21]. Fortunato etal. [22] reported that the combination of ethanol exposure and endotoxemia resulted in the depletion of several lysosomal proteins including lysosomal-

associated membrane protein- 2 (LAMP- 2), a protein required for the proper fusion of autophagosomes with lysosomes. Cathepsin B- induced LAMP degradation and genetic LAMP- 2 deletion caused pancreatitis through impaired autophagy in mice [23]. Human patients with alcoholic pancreatitis also exhibited local LAMP- 2 depletion, indicating the crucial roles of LAMP- 2 and autophagy in acinar cell death in humans.

Although numerous invitro and ex vivo studies have shown the actions of ethanol and its metabolites on pancreatic cells, invivo studies have shown that feeding ethanol to rats and mice even for a long time, with either liquid diet or continuous intragastric infusion, did not cause a prominent injury to the pancreas. Chronic ethanol feeding by the Lieber- DeCarli pair- feeding model[24] induces a number of metabolic changes in the acinar cells including an increase in the content of digestive enzymes and lysosomal enzyme and fragility of the zymogen granules and lysosomes. However, chronic pathological changes resembling CP will not develop. Conversely, chronic ethanol exposure sensitizes the pancreas to other insults. Pancreatitis developed in rats that had received an ethanol- containing diet in response to low doses of cholecystokinin octapeptide or its analogue caerulein, which do not cause pancreatitis by themselves [25]. The sensitization was accompanied by increased activation of nuclear factor- κB (NF- κB) and the upregulation of proinflammatory cytokines and chemokines in the pancreas[26]. Ethanol might regulate NF- κB and activator protein (AP)- 1: the key transcrip- tion factors regulating the gene expression of inflammatory responses and cell survival. FAEE activate NF- κB and AP- 1, whereas ethanol and acetaldehyde inhibit NF- κB activation [26]. Thus, ethanol may regulate the activation of NF- κB and AP- 1 positively or negatively,

depending on the predominance of which metabolic pathway’s effects. These effects may play a role in the ethanol-

induced toxicity in the pancreas. Of note, ethanol and its metabolites altered the cholecystokinin 8- induced activation of these transcription factors, which might be a mechanism by which ethanol sensitizes pancreatic acinar cells to pancreatitis.

Gukovsky etal. [27] reported that ethanol dramatically aggravated the pathological effects of the combination of cyclosporine A and caerulein. In ethanol- fed, but not control diet- fed, animals, the combined treatment of cyclosporine A and caerulein resulted in severe pancreatic injury that displayed three key responses of human ACP: loss of parenchyma, sustained inflammation, and fibrosis. Conversely, for the repair of the exocrine pancreas, acinar cells could act as progenitor cells; mature acinar cells undergo dedifferentiation and redifferentiation back to the differentiated phenotype [28]. Clemens et al. [29] reported that chronic ethanol administration delayed the structural and functional regeneration of the pancreas in mice. The delayed regeneration was associated with the decreased expression of pancreatic developmental factors including

1. These findings suggest that ethanol might

PDXimpair the recovery from acute pancreatic injury, thus facilitating the progression from acute pancreatic injury to CP.

Pancreatic Ductal Cells

Alcohol increases viscosity and precipitation of pancreatic juice and formation of protein plugs inside pancreatic ducts. Protein plugs lead to formation of calculi which damage ductal epithelium and cause obstruction of pancreatic ducts[30]. Several studies have highlighted the role of the pancreatic duct in the pathogenesis of alcohol- induced pancreatitis. Ethanol reduced the expression of cystic fibrosis transmembrane conductance regulator (CFTR), disrupted the folding of CFTR at the ER, and inhibited CFTR function in pancreatic ductal cells, all contributing to the increased viscosity of the pancreatic juice and small duct obstruction[31]. CFTR knockout mice given ethanol or fatty acids developed more severe pancreatitis than mice not given ethanol or fatty acids.

Pancreatic Stellate Cells

PSC play a pivotal role in pancreatic fibrosis in CP. Ethanol and its metabolites induced the activation, extracellular matrix production, and chemokine expression in PSC, leading to the perpetuated activation of PSC and pancreatic fibrosis [32]. A combination of short- term administration of caerulein and long- term intraperito-

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