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Inflammatory Response inChronic Pancreatitis 329

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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does not induce pancreatitis [11]. However, animals treated with VPA that are then subjected to an additional injury- provoking stimulus, develop pancreatitis. Thus, VPA predisposes the host to pancreatitis by altering the epigenetic landscape and thereby inhibiting the recovery mechanisms that allow regeneration to occur.

Environmental Exposures asModifying Factors inChronic Pancreatitis

A mechanism thought to initiate pancreatic injury is through environmental exposures. The exposures include alcohol ingestion and byproducts of smoking [12]. The exposures do not by themselves induce pancreatitis, but they pathologically alter acinar cell responses to stressors. The prototypic example is heavy and frequent alcohol ingestion, which has long been known as a major risk factor for both acute and chronic pancreatitis [13,14]. However, only a minority of binge drinkers develop pancreatitis. Ethanol has been shown to affect pancreatic cell types either through its direct effects or through its metabolites. Ethanol or its metabolites can sensitize the acinar cell to pathologic calcium signals[15] mitochondrial dysfunction [16,17], impairment of autophagic or lysosomal responses [18], or the induction of the UPR with increased expression of XBP1 (a key regulator of ER function) [19,20]. Ethanol appears to increase ER stress visualized by ER swelling and UPR induction, and there is an impact on protein trafficking and on some of the structural components of zymogen granules[21]. Ethanol converts a physiological stimulus to the acinar cell into a pathological stimulus, with adverse outcomes, including premature intra- acinar activation of digestive enzymes and acinar injury[22,23]. This effect could be due to the increased expression of digestive enzymes such as trypsinogen, chymotrypsinogen, or lysosomal cathepsin B and to lysosomal fragility[24].

a prime case example of this mechanism. Hereditary pancreatitis is caused by a mutation within the cationic trypsinogen gene (PRSS1), the primary proteolytic enzyme responsible for activating pancreatic digestive enzymes or zymogens[25]. These gain of function mutations lead to premature trypsinogen activation. There are several mutations identified but the most common are R122H and N29I. The penetrance of the disease is about 80%. Although these mutations place an individual at a higher risk of developing CP and there is variable expressivity, the disease course and ultimate outcome are also dependent on additive risk factors, including environmental and metabolic stressors. Environmental exposures or other genetic modifiers are thought to alter the disease course as individuals with the same genetic mutation can have significantly different disease courses, despite having similar histopathology[26]. Monozygotic twin studies attest to this level of discordance, whereby the same genetic mutation in the PRSS1 gene causes profound pancreatic disease in one twin, while the other has no evidence of disease into adulthood [27]. In order to study mechanisms underlying pancreatitis pathogenesis by these genetic mutations, several groups developed hereditary pancreatitis mouse models by manipulating human or mouse trypsinogen genes[28–32]. In addition to the PRSS1 mutations and hereditary pancreatitis, there are other genetic mutations associated with increased risk for CP[33]. They include mutations within the CFTR (cystic fibrosis transmembrane conductance regulator) and SPINK1 (serine protease inhibitor Kazal type 1) genes. As with PRSS1 mutations, identical mutations within these genes do not predict similar disease course for affected individuals. Pathogenic variants in the SPINK1, PRSS1, CTRC, and CFTR genes can lead to earlier disease onset and worsened clinical outcomes in CP patients with varying etiologies such as idiopathic, alcoholic, and smoking- associated CP [34,35]. Overall, these observations suggest a complex disease process that will require careful analysis of multiple factors that impact disease progression.

Genetic Influences inChronic Pancreatitis

A second mechanism shown to mediate the pathologic response in the pancreas is through repeated injury by specific insults in a susceptible patient with genetic risk factors. Genetic or epigenetic alterations may allow the nonclinical or clinical repeated injury to occur which over time results in the destruction of the pancreatic parenchyma and replacement by fibrosis through repeated activation of immune and fibrotic responses. This replacement results in the loss of exocrine and endocrine pancreatic function. Hereditary pancreatitis is

Inflammatory Response inChronic Pancreatitis

The secondary phase of progression to CP involves the inflammatory and fibrotic responses to chronic stress or repeated injury (Fig. 39.3). Recently, progress has been made in understanding this aspect of CP. Injury within the pancreas results in damaged acinar cells that will either repair or undergo cell death through necrosis or apoptosis. The damaged cells promote a sterile inflammatory response to mediate the recovery and regeneration process[36]. The inflammatory response is signaled

Molecular Understanding ofChronic Pancreatitis

M1 M2

IL-13

PDGF

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330

IL-4 IL-13

Activation

Pancreatic injury

TGF-β PDGF

Activation

Figure39.3 Pancreatic injury activates resident immune cells as well as pancreatic stellate cells to promote pancreatic recovery. However,

persistent injury or pathologic signaling between macrophages and stellate cells leads to persistent activation and fibrogenic replacement of the pancreatic parenchyma.

by cytokines released from injured acinar cells and mediated by neutrophils, monocytes, lymphocytes, and macrophages which mediate the resolution of the damaged cells and promote the regeneration of the pancreas[37]. During progression of CP, inflammation appears to be mediated by different immune cells depending on the experimental model used [38–40]. Those immune cells including neutrophils, macrophages, and T- cell subsets play multiple roles depending upon disease progression in acute, severe acute, or chronic pancreatitis[38,39,41,42]. These cells will produce additional inflammatory mediators such as TNFα, IL-

1β, Il- 6, IL10, and MCP1. Initially these signals are produced by damaged acinar cells but with repeated injury and activation of other resident pancreatic cells such as macrophages and stellate cells, there appears to be a shift towards cytokine production from activated immune and stellate cells that promotes and allows progression towards CP. Neutrophils are thought to activate trypsinogen and allow progression towards severe injury in acute pancreatitis; however, in CP, T cells and macrophages are the predominant immune cell infiltrates[43,44]. Neutrophils and macrophages can play a dual role during inflammation, either releasing cytokines such as IFN- g leading to a proinflammatory phenotype repressing regeneration but are also responsible for repair signals necessary for regeneration to occur [45]. T cells

TGF-β PDGF

ActivatedQuiescent

are thought to help control the immunedestruction initiated in CP demonstrated by the secretion of IL- 10 by these T cells [46]. However, IL- 17 or IL- 22secreting T- cell subset (Th17 or Th22) promotes fibrogenesis by activating pancreatic stellate cells (PSC) and contributes to the progression of CP[39,47]. Macrophages can promote healing and regeneration, depending upon macrophage polarity [48]. However, alternatively activated M2macrophages can play a pathogenic role in CP in both rodents and humans[38]. Furthermore, pancreatic immune cell analyses using unbiased singleimmune analysis technologies reveal novel diseaserelevant immune subpopulations. Single-cell RNA/T-cell receptor sequencing analysis of pancreatic immune cells isolated from pancreatic tissues of CP patients who underwent total pancreatectomy identified hereditary versus idiopathic CP-specific novel T cell and myeloid immune subsets and T cell receptor repertoire changes. This study provides insights into human CP-specific immunopathogenic mechanisms and etiology subtypespecific immunotherapeutic targets in CP [49]. Determining unique immune subsets and their signals to neighbor cells during the disease course that can either promote or suspend disease progression is critical to a better understanding of immunopathogenic mechanisms and identifying novel therapeutic targets for healing.

IL-4

TGF-β

mediated

cell

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Fibrogenesis inChronic Pancreatitis

The fibrogenic response during CP is influenced by mesenchymal cells known as the pancreatic stellate cells (PSC), along with immune cell interactions. PSC have emerged as a critical player in mediating pancreatic recovery after injury[50]. PSC are localized to the periacinar region and, at baseline (i.e., the quiescent state), they are characterized by vitamin A droplets [51]. In response to injury, PSC undergo transient activation and take on a fibroblast- like role to secrete extracellular matrix (ECM), particularly collagen [52,53], which is a necessary substrate scaffold for proper regeneration and recovery. The hallmarks of pancreatic injury and recovery are regenerative structures called acinar to ductal metaplasia (ADM) [54,55]. The stroma surrounding ADM is composed of activated PSC (aPSC) that function to remodel ECM and are thought to coax ADM to redifferentiate into new acinar cells. Aberrant regulation of PSC has been implicated in the pathogenesis of CP and pancreatic cancer[52,56–58]. PSC are not only activated by acinar cell injury but can be activated by cellular stress and ethanol byproducts. TGFβ appears to be a major contributor to fibrotic properties of PSC by increasing collagen and fibronectin expression but also by inhibiting metalloproteinases (MMP). Once activated, PSC initially help to remodel the parenchyma through the removal of matrix proteins by MMP. PSC not only produce MMP but also the inhibitors of MMP called tissue inhibitors of metalloproteinases (TIMP). A balance of these two factors likely affects the progression toward fibrosis. The destruction of the matrix releases growth factors and cytokines that signal adjacent cells and stimulate parenchymal healing through interactions of the immune and exocrine and endocrine pancreatic cells. PSC not only orchestrate the destruction of matrix but also help orchestrate the regeneration of the framework to allow regenerating acinar and duct cells to proliferate and repopulate the parenchyma. However, if PSC remain activated through repeated injury to the pancreas or aberrant cell signaling from adjacent cells such as macrophages, a pathogenic response can ensue. The response perpetuates the remodeling of the ECM and replaces acinar tissue with fibrosis, leading to the loss of pancreatic

exocrine function. PSC in CP models have been shown to respond to adjacent macrophages that produce higher levels of TGFβ and PDGFβ suggesting that the macrophage-

PSC interaction may be important in regulating pancreatic fibrogenesis [38]. PSC communicate with cytokine- producing T cells (Th22 and Th17) by expressing their receptors in order to promote fibrosis in CP [39,47]. STAT3 activation is a prominent signaling molecule found in activated PSC, and the inhibition of the Jak/STAT pathway via ruxolitinib has been shown to reduce the severity of experimental CP[59], suggesting a potential therapeutic strategy for CP.

Conclusions

There are several risk factors and progressive steps that lead to the histopathological disease known as CP. They include a sentinel pancreatic event in a susceptible host that perpetuates a progressive low- grade injury. The injury results in pancreatic fibrosis and loss of physiologic function. Alternatively, several repeated injury events of acute pancreatitis may lead to chronic injury and fibrotic replacement of the pancreatic parenchyma. Several animal models have been developed to help target specific aspects of injury and disease progression for the study of CP. Although healthy caution is indicated when using animal models to mimic disease states in humans, with careful attention to the limitations of the experimental model, one may begin to understand aspects of this complex, multifaceted disease. The animal model systems used most frequently are cost- effective rodent models of pancreatic injury leading to inflammation and fibrosis reminiscent of histologic changes in CP (e.g., duct ligation, chemical or biological exposures)[60–65]. However, for certain etiologies such as CFTR disease, the rodent models do not mimic the human condition, and other models (such as the porcine or ferret model for CFTR) must be used. Genetic models of CP exist and include overexpression or reduced expression of genes that allow the histopathologic appearance of CP. Beyond animal models, our understanding of CP would be enhanced by the characterization of heterogeneous human microenvironments using unbiased analysis techniques.

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Natural History ofRecurrent Acute andChronic Pancreatitis

Rohit Das1, Jorge D. Machicado2, and Dhiraj Yadav

Division of Gastroenterology & Hepatology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

Division of Gastroenterology & Hepatology, Department of Medicine, University of Michigan, Ann Arbor, MI, USA

Introduction

Pancreatitis, especially chronic, is a low prevalence disease. Consequently, the focus of epidemiologic studies of pancreatitis has primarily been to define the disease at the level of individual patients. In the past two decades, the importance of understanding the distribution of risk factors and disease at the population level has been recognized. This has enabled determination of disease estimates and understand the relationship between acute pancreatitis (AP) and chronic pancreatitis (CP) at the population level. Demonstration that subsets of patients with AP develop recurrent acute pancreatitis (RAP) and/or progress to CP provides empiric evidence that these conditions represent stages of a disease continuum. Knowledge of the risks and factors associated with disease progression will help in risk stratification, prediction, and developing strategies for altering the natural history of disease.

This chapter will focus on the burden of disease, natural course and survival of AP, RAP, and CP. For AP, the emphasis will not be on the severity and outcome of the initial attack, but rather the risk of readmissions, recurrences, and progression to CP. In CP, the prevalence and natural history of clinical features, i.e., pain, endocrine and exocrine insufficiency, bone health, and the risk of pancreatic cancer will be discussed. Finally, we will summarize available data on the quality of life.

Natural History After First Attack ofAP

Disease Burden, Etiology, andSeverity

AP is one of the leading gastrointestinal causes of hospitalization in the United States [1]. The estimated incidence of AP in recent studies is 30–50 per 100,000

population. AP affects all age groups, but is most frequent in middle-

aged and older individuals[2]. Gallstones and excessive alcohol consumption account for about 60–70% of all cases, the latter being more common in men when compared to women. Other etiologies include metabolic factors (hypertriglyceridemia, hypercalcemia), endoscopic retrograde cholangiopancreatography (ERCP), medications, genetic mutations (PRSS1, SPINK1, CFTR, CTRC), obstructive causes (such as pancreatic duct stricture, etc.), and trauma. In 10–25% patients no identifiable etiology is found on evaluation[2]. The two main determinants of mortality in AP are the presence of infected necrosis and organ failure, especially when persistent (>48 h) or involving more than one organ[3]. The risk of death increases with age and comorbidities[4]. Increased morbidity is seen in patients with local complications who do not have organ failure[5].

Readmissions

After the first attack of AP, about 20–30% patients are readmitted to hospital (Table40.1). The reason for readmission differs based on time since discharge from the hospital. Vipperla etal.[6] differentiated between early (<30days after index AP) and late (>30days) readmissions and found that early readmissions were more likely due to smoldering symptoms from AP and/or local complications, whereas late admissions were more likely to be due from recurrent AP episodes. Younger age, alcohol use and/or alcohol-

related etiology, non- private medical insurance, increased length of stay during index admission, and discharge to long- term care facilities have been identified as predictors of readmissions[6–8].

The Pancreatitis Activity Scoring System (PASS) was

developed in 2017 as a tool to measure disease activity

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

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Table40.1 Summary ofrecent studies examining rates andrisk factors forreadmission after afirst attack ofacute pancreatitis.

Readmission rate (%)

Author, year, design Cohort size Follow- up time (months)

Yadav etal., 2014[7] Retrospective

Vipperla etal., 2014[6] Retrospective

Garg etal., 2018[8] Retrospective

CP: chronic pancreatitis.

5239 39.0 22 40 15 32 Unclear Younger age Alcoholic etiology

127 36.0 34 60 29 59 1.3 Younger age Male gender

243816 Unclear 16 Not stated Unclear Younger age

Time to readmission (months) Risk factors for readmissionOverall Alcoholic Biliary Idiopathic

Subsequent diagnosis of CP

Alcoholic or idiopathic etiology Severe disease at index attack

private medical insurance

NonDischarge to longfacilities Increased length of stay

term care

Natural History ofRecurrent Acute andChronic Pancreatitis

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and better predict the prognosis of AP. PASS incorporates organ failure, systemic inflammatory response syndrome (SIRS), abdominal pain, opiate requirement and diet tolerance, with each component having a different weight according to their prognostic importance[9]. In a prospective study examining the predictive utility of PASS, a score of >60was highly associated with readmission within 30days of AP discharge[10].

These data suggest that focused discharge planning may reduce the risk of early readmissions— i.e., ensuring that the patients’ symptoms are well controlled and they have received counseling for behavior modification. In patients with severe AP, close follow- up with relevant specialists (e.g., nutrition, gastroenterologist, surgeon) is helpful to determine the need and timing of crosssectional imaging, duration of enteral feeds, and “step up” therapy. Many patients with severe AP need short- term stay at a transitional care facility or rehabilitation unit prior to safe discharge home.

First Recurrence

The risk of recurrent AP (RAP) after the first attack has been evaluated in several, mostly retrospective, population and nonpopulation based studies (Table40.2). The overall risk of a subsequent attack of AP is ~20% during a median follow- up period ranging from 4 to 8 years. Similar to the first attack, among patients with a second attack of AP, alcohol, gallstones, and idiopathic are the most common etiologies[11–13]. When compared with the first attack of AP, subsequent recurrence is generally milder with an overall lower mortality[14].

The risk of recurrent attack is highest among patients with alcohol etiology (35–40%) followed by idiopathic and biliary AP (both 10–20%)[11–13]. Takeyama etal. noted that the risk of subsequent recurrence was directly related to continued alcohol consumption— the risk was highest in patients who continued drinking at the same level, and lowest among patients who stopped drinking completely[15]. Contrary to what many physicians may believe, counseling against alcohol consumption has a significant impact on patient behavior. This was tested empirically in a randomized controlled trial (RCT), where repeated counseling of patients led to a significant decrease in the risk of abdominal pain attacks, AP episodes and hospitalizations[16].

After an attack of biliary pancreatitis, the risk of recurrence can be dramatically reduced by early cholecystectomy. This has been demonstrated in RCTs, as well as in meta- analyses of published data [17]. In patients with mild biliary pancreatitis, cholecystectomy should be considered as close to the attack of AP as possible, preferably during the same admission. In patients with severe AP, cholecystectomy should be delayed until resolution of

inflammatory changes in the pancreas/pancreatic area. In patients with pancreatic/peripancreatic collections that need drainage, a surgical approach (preferably laparoscopic or minimally invasive) to address this along with a cholecystectomy should be considered [18]. In patients with another known etiology, i.e., medications, hypertriglyceridemia, hypercalcemia, etc., addressing the inciting cause will decrease the risk of recurrence[19].

Tobacco abuse has been a consistent association with the risk of recurrent AP (odds ratio 1.5–2) [11,13,20]. Therefore, after an attack of AP, patients should be informed about this risk and counseled for tobacco cessation. This will be especially relevant in patients in whom the cause was alcohol, hypertriglyceridemia, genetic or idiopathic, or if the AP attack was moderate to severe. Individual studies have also shown that age and severity of initial attack may also play a role in recurrent attacks[11,13,20].

The burden of recurrent AP at a population level is not well defined. Using information on the total number of admissions for AP in the USA and applying the incident AP rates from California, approximate number of recurrent attacks can be estimated[1,21]. Among the 275,000 annual admissions for AP in the USA, approximately 150,000–160,000 would be incident attacks, while the remaining 115,000–125,000would represent RAP (first or subsequent recurrences), readmissions for ongoing symptoms or complications of AP, or acute CP.

Subsequent Recurrences

Alcohol is the most common etiology of subsequent recurrences, followed by idiopathic pancreatitis, genetic causes, hypertriglyceridemia, and underlying CP as other important causes. The role of pancreas divisum and sphincter of Oddi dysfunction in causing initial or recurrent AP attacks is controversial[22].

Approximately one- third of patients who have a recurrence after the first attack of AP will have one or more subsequent recurrences. Burden of recurrent AP was further quantified in in two previous studies. Among 562 patients with a first attack of alcoholic AP who survived the index admission, Sand et al. reported at least one recurrence in 260 (46%) patients. Among these patients, 133 (51%) had only one recurrence, 49 (19%) had two recurrences, 39 (15%) had three recurrences, and 39 (15%) had four or more recurrences[23]. Among patients who underwent a cholecystectomy for presumed biliary pancreatitis, Trna et al. noted the risk of subsequent attacks to be related to the presence of abnormal liver function tests and documentation of gallbladder stones or sludge. Among patients who did not have either, 26% had a second attack, and 9% had a third attack of AP[24]. Although few empiric data is available, the risk of

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Table40.2 Summary ofrecent studies examining therate andrisk factors fordevelopment ofrecurrent acute pancreatitis (RAP) after afirst attack ofacute pancreatitis.

RAP rate (%)

Follow- up

Author, year Cohort size

Lankisch etal., 2009[12] Prospective 532 8.0 17 33 12 14 Unclear Younger age Alcoholic

Yadav etal., 2012[13] Retrospective 7456 3.3 29 52 18 26 7.2 Younger age Alcoholic

Bertilsson etal., 2015[11] Retrospective 1457 4.2 23 37 17 24 5.1 Alcoholic etiology Severe

Ahmed Ali etal., 2016[20] Prospective 669 4.8 17 Not stated 5.0 Younger age Idiopathic

time (years)

Time to recurrence (months) Risk factors for RAPOverall Alcoholic Biliary Idiopathic

etiology Male gender

etiology Tobacco use

disease at index attack Tobacco use

etiology Tobacco abuse Severe disease at index attack

Natural History ofRecurrent Acute andChronic Pancreatitis

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multiple attacks of AP seems high in patients with genetic mutations (e.g., PRSS1, CFTR)[25]. The risk of recurrences would also be higher in patients with uncommon causes of AP, such as hypertriglyceridemia, hypercalcemia, etc., especially if the underlying cause is not corrected, but definitive data on the burden of attacks in these patients is limited.

Diabetes andExocrine Insufficiency After AP

Recent data have documented that AP increases the risk of diabetes mellitus (DM) and exocrine pancreatic insufficiency (EPI) irrespective of severity. In two populationbased studies patients with mild AP were about two times more likely to develop DM than age- and sexmatched controls[26,27]. In a systematic review of 24 prospective studies, the pooled prevalence of newly diagnosed DM after the first episode of AP was reported to be 23% (95% CI 16–31%), and increased with the duration of follow-

up[28]. The risk of DM after AP is greater in patients with severe AP, necrotizing pancreatitis and in those with alcohol etiology. The mechanisms leading to DM are not well defined.

With regards to EPI, a meta- analysis of 39 studies reported that the pooled prevalence of EPI after an index episode of AP was 35% and the prevalence was greater during the time of AP hospitalization [29]. The risk of EPI increased with disease severity, presence of necrosis, and alcohol etiology.

disease progression have been alcohol etiology, tobacco abuse, and RAP. The association with severity of AP is less consistent and has been noted in some studies.

Lankisch etal. noted that progression to CP occurred almost exclusively in patients with alcohol etiology[12]. However, in other studies progression was also noted with nonalcoholic or idiopathic CP, albeit at a lower rate. The role of tobacco, especially in combination with alcohol in disease progression is important. Ali etal. reported that while the cumulative risk of progression to CP overall was 7.6%, it was 18% among current smokers, and increased to 30% in current smokers who also had alcohol etiology[20]. Therefore, including the counseling of tobacco cessation along with alcohol abstinence should be emphasized. Genetic factors also seem to play a role in the development of CP, but outside of hereditary pancreatitis, little empiric data is available[25].

Perhaps the strongest risk factor for disease progression is RAP, and the risk of progression in these patients is ~30–40%. Bertilsson etal. noted that among patients who transitioned to CP, 74% had at least two AP attacks, and 54% had more than two attacks. When compared with alcohol or tobacco (hazard ratio between 2 and 3), the risk of progression to CP in RAP is much higher (hazard ratio ~6)[11].

Natural History ofChronic Pancreatitis

Quality ofLife After AP

Several studies have demonstrated that AP deleteriously impacts quality of life. In a single- center prospective study of 91 patients, patients who experienced AP had a significantly lower physical healthcare- related quality of life (HRQOL) as compared to controls even after 14 months of AP [30]. Factors associated with lower physical HRQOL included the presence of ongoing abdominal pain and use of analgesics, disability, and smoking. Multiorgan failure was the only disease- related factor associated with a lower physical HRQOL.

Progression toCP

Many studies evaluating the natural history after a first attack of AP have determined the risk of progression to CP (Table40.3)[11–13,20]. In a meta- analysis of 14 studies consisting of 8492 patients, Sankaran etal. reported that following a sentinel attack of AP the pooled prevalence of RAP was 22% (38% for alcohol etiology, 17% for biliary etiology) and of CP was 10%[31]. The three factors consistently shown to have an independent effect on

Disease Burden, Demographics, andEtiology

Recent population studies estimate that the incidence of CP ranges from 4 to 14 per 100,000 per year, and the prevalence ranges from 42 to 73 per 100,000 population[19,32]. The prevalence of CP peaks at the age of 45–55 years and has a male predominance[32]. Alcohol is the most common cause of CP worldwide (frequency ~40–70%), followed by idiopathic etiology (frequency ~20–30%)[19]. Smoking is a well-

recognized factor for CP and works in a dose- dependent manner— the risk of CP is fivefold greater in those smoking over 35 packyears compared to never smokers [33]. The role of genetic factors is increasingly recognized and mutations in some susceptibility genes (PRSS1, SPINK1, CFTR, CTRC, CPA, CASR) are found in 10–15% of CP patients. Alcoholic CP is seen more commonly in men, while the other etiologies are more evenly distributed in both sexes[33]. The diagnosis of CP is preceded by AP in at least 50% of patients[34]. This has been well demonstrated in patients with hereditary and alcoholic CP, in whom AP precedes the progression of CP by 10years[19].

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