Disease-a-Month 60 (2014) 530–550

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Disease-a-Month journal homepage: www.elsevier.com/locate/disamonth

Chronic pancreatitis, a comprehensive review and update. Part I: Epidemiology, etiology, risk factors, genetics, pathophysiology, and clinical features Thiruvengadam Muniraj, MD, PhD, Harry R. Aslanian, MD, James Farrell, MD, Priya A. Jamidar, MBChB

Introduction Chronic pancreatitis is an irreversible condition of the pancreas characterized by chronic progressive pancreatic inflammation, fibrosis, and scarring resulting in loss of both exocrine (acinar) and endocrine (islet cells) tissue. As the definition implies, it is the inflammation-led fibrosis that culminates in CP. There are several conditions with exocrine insufficiency which need to be distinguished from CP such as post-surgical changes and Shwachman–Diamond Syndrome1 (the second most common cause for exocrine pancreatic insufficiency in children after cystic fibrosis). The anatomy of the pancreas was first described in the 17th century when the pancreatic duct was discovered (J.C. Wirsung, 1642) and the duodenal papilla was described (J.K. Brunner, 1683; C.B. Holdefreund, 1713; and A. Vater, 1750).2 The presence of fatty necrosis in acute pancreatitis was first shown by W. Balser (1882), and the autodigestive genesis was suspected by H. Chiari (1896).3 In 1788, Sir Thomas Cawley of England was the first one to describe on a “free living young man” who had died of diabetes, and on autopsy it was found that the pancreas was filled with multiple calculi. This is the first connection established between diabetes and pancreatitis.4 Paul Langerhans, who was born in Berlin in to a family of renowned physicians, is well known for pancreatic islets, and dendritic cells of the skin. In 1869, he worked on his PhD thesis on “Abdominal salivary gland” which is now known as the pancreas. During these studies he identified the “small homogeneous islands of clear cells lying throughout the gland.” After his death at the early age of 41 years (from tuberculosis), subsequent researchers magnanimously named these cells as “The islets of Langerhans”4,5 (Fig. 1). It was only in 1946 that Comfort et al.7 described the disease as chronic pancreatitis.8 Through conferences in Marseille,9,10 Cambridge,11 and Atlanta,12 the classification of acute and chronic pancreatitis has been revised several times. It has been more than two centuries since http://dx.doi.org/10.1016/j.disamonth.2014.11.002 0011-5029/& 2014 Mosby, Inc. All rights reserved.

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Fig. 1. Paul Langerhans, known for “Islets of Langerhans”4 (courtesy: Paul Langerhans Institute, Dresden.http://www.plid.de6).

chronic pancreatitis has been described; however, it remains a complex process of uncertain pathogenesis, unpredictable clinical course, and unclear management.2,13 Several autopsy-based studies and clinical–radiologic correlation led to much of our understanding of these diseases. Yet, the first genetic discovery of PRSS1 disease-causing gain-of-function variant in hereditary pancreatitis by Whitcomb et al.14 gave a new dimension to our understanding of the pathogenesis of pancreatitis (Fig. 2). The clinical spectrum of CP is very broad. Although the majority of patients present with abdominal pain, the prevalence of exocrine, and endocrine insufficiency vary. The management of CP begins with making a correct diagnosis, and during early stages of the disease, patients may

Fig. 2. Timeline of major events in understanding pancreatic disorder.

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Fig. 3. Incidence rates for pancreatitis and pancreatic cancer in the United States. Numbers in parentheses indicate approximate yearly incidence rates per 100,000 persons. The arrow indicates the relationship between benign and malignant disease.21 (Adapted with permission from Yadav.21)

only have abdominal pain and diagnosing CP may be challenging. Despite recent advances and new insights, it remains difficult to stop progression of the disease and provide adequate relief. Alcohol has multiple detrimental effects on the pancreas, and although the majority of CP cases are alcohol related, we now know that alcohol intake is not the direct cause of CP in adults, but a weak susceptibility factor, and a strong risk modifier with smoking,15 genetic,16 and environmental factors. Approximately 12% of patients with recurrent acute pancreatitis (RAP) progress to CP and this usually occurs in the setting of alcohol and smoking17 (Fig. 3). Epidemiology Chronic pancreatitis remains a major source of morbidity and represents a huge financial burden in the United States. The United States NIH database studies cite pancreatitis as the seventh most commonly noted digestive disease diagnosis on hospitalization, just after peptic ulcer disease with annual health care costs exceeding three billion dollars. This was more than that spent for Inflammatory bowel disease and hepatitis C (estimated in 2004).18 The annual incidence of CP15 ranges between 5 and 14/100,000; the prevalence of CP is about 50/100,000 persons19,20 (Fig. 3). Incidence and prevalence There seems to be a large increase in the incidence of AP and a modest increase in the incidence of CP, mainly because of an increase in the diagnosis of alcohol-related CP.19

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There is an increased incidence of obesity and rapid weight loss surgeries, which predispose to gallstone-related pancreatitis.22 A delay in cholecystectomy after an attack of AP increases the risk of recurrences.23–25 The development of RAP was the strongest predictor for a subsequent diagnosis of CP.17 The increase in detection of CP could be related to the increased availability of high-resolution cross-sectional imaging techniques and endoscopic ultrasound imaging that can detect even mild changes in the pancreas. Age and gender All though CP is seen in both genders, it is more common in men with a sex ratio (male/ female) of 4.6.20 Alcohol-related pancreatitis is more common in men, although sex differences disappear with higher levels of alcohol consumption.21 Through the North American Pancreatitis Study (NAPS), discovery of the X-linked CLDN2 gene variant, which confers allelic risk for alcoholic pancreatitis, established that men have a higher frequency of alcohol-related pancreatitis.16 Women have higher risks for pancreatitis related to gallstones, endoscopic retrograde cholangiopancreatography (ERCP), and autoimmune diseases. The prevalence increases with age and the mean age of CP is around 62 years.20 Pancreatitis in pediatric patients is often related to cystic fibrosis or other genetic mutations.14,26 In tropical countries like India, tropical calcific pancreatitis (TCP) is prevalent and is of early onset, though recent studies show idiopathic pancreatitis is becoming more common than classical tropical calcific variant.27 TCP is a form of non-alcoholic chronic pancreatitis with characteristic imaging features of multiple large intraductal calculi and association with susceptibility mutations in serine protease inhibitor Kazal type 1 (SPINK1) gene.28 In some parts of Southern India (Kerala), a very high prevalence (1 in 793) of TCP is noted.29 Race Numerous epidemiological studies have found racial differences in the incidence of pancreatic diseases.30 African-American patients have a 2- to 3-fold higher risk of pancreatitis than Caucasian patients and they have a higher frequency of alcohol-related pancreatitis.31,32 A large epidemiological study done in New York and Portugal showed that the ratio was consistent, suggesting that a component of the difference is racial rather than due to diet or environment alone.32 Hospitalization rates were significantly higher (2.4-fold) in AfricanAmerican populations (vs. Caucasians) in alcohol-related CP.33 The reasons for this racial disparity are not well understood and are currently the subject of a NAPS2 study.34 Blood group NAPS study investigators noted that A, B, and AB blood groups were not associated with a greater likelihood of having chronic pancreatitis and may in fact decrease the risk of CP in individuals who are very heavy drinkers.35

Classification of chronic pancreatitis In 1963, the Marseilles classification proposed the entities of acute and chronic pancreatitis, both with relapsing and non-relapsing variants.36 In subsequent years, further revisions and Cambridge classification, M-ANNHEIM37 were proposed to distinguish obstructive CP from other forms of CP, but still remained unclear.11,38,39 A recent classification of CP, TIGAR-O system, incorporating new insights of various risk factors is clinically relevant and most widely used. TIGAR-O system consists of six groups (Table 1) categorized as (1) Toxic–metabolic, (2) Idiopathic, (3) Genetic, (4) Autoimmune, (5) Recurrent and severe acute pancreatitis, or (6) Obstructive.

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Table 1 TIGAR-O system of classification of chronic pancreatitis. Etiologic risk factors associated with chronic pancreatitis: TIGAR-O classification system Toxic–metabolic Alcoholic Tobacco smoking Hypercalcemia Hyperparathyroidism Hyperlipidemia (rare and controversial) Chronic renal failure Medications Phenacetin abuse (possibly from chronic renal insufficiency) Toxins Organotin compounds (e.g. DBTC) Idiopathic Early onset Late onset Tropical Tropical calcific pancreatitis Fibrocalculous pancreatic diabetes Other Genetic Autosomal dominant Cationic trypsinogen (codon 29 and 122 mutations) Autosomal recessive/modifier genes CFTR mutations SPINK1 mutations Cationic trypsinogen (codon 16, 22, 23 mutations) Antitrypsin deficiency (possible) Autoimmune Isolated autoimmune chronic pancreatitis Syndromic autoimmune chronic pancreatitis Sjogren syndrome associated chronic pancreatitis Inflammatory bowel disease associated chronic pancreatitis Primary biliary cirrhosis associated chronic pancreatitis Recurrent and severe acute pancreatitis Postnecrotic (severe acute pancreatitis) Recurrent acute pancreatitis Vascular diseases/ischemic Postirradiation Obstructive Pancreatic divisum Sphincter of Oddi disorders (controversial) Duct obstruction (e.g. tumor) Preampullary duodenal wall cysts Posttraumatic pancreatic duct scars

Etiology of CP: Has it changed in recent years? Alcohol was long thought to be the most common cause of CP, contributing 70–80% of cases.40,41 Banks42 pointed out that the two important forms of CP were alcoholic and tropical pancreatitis. At least in the Western countries, alcohol is the most frequent associated factor of chronic pancreatitis, and in the last century, the frequency of alcohol as an etiological factor of chronic pancreatitis increased from 19%43 up to 80%. Several studies show that alcohol was the predominant cause in Europe and the Americas, whereas it was decreasing in frequency as an etiology in Japan.44 Sarles et al. interestingly identified features of CP in India that differ from the

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Table 2 Current etiologies of CP. Etiology (%)

All (n ¼ 539)

Female (n ¼ 256)

Male (n ¼ 283)

NAPS2 (US study) Alcohol Genetic Autoimmune Obstructive Other Idiopathic

44.5 8.7 2.2 8.7 7.2 28.6

28.1 12.5 2.3 12.9 9.0 35.2

59.4 5.3 2.1 4.9 5.7 22.6

All (n ¼ 893)

Female (n ¼ 233)

Male (n ¼ 660)

34 27 9 4 6 4 17

10 46 3 8 2 5 25

42 20 11 2 8 4 14

PanCrolnAISP (Italian Study) Alcohol Obstructive Alcohol þ obstructive Autoimmunity Dystrophy Herediatery/genetic Idiopathic

Western countries. Indian patients with chronic pancreatitis consume a low-fat, low-protein diet, have low rates of alcoholism, yet have a high frequency of calcific CP (TCP) at an early age.45 However, this trend in India may not continue due to rapid development, westernization of the diet, and increasing alcohol consumption. Very interestingly, the NAPS study found that the frequency of alcohol-related CP at tertiary US referral centers is lower than expected.46 Alcohol was implicated in 44.5% of CP patients and in Idiopathic CP in 28.6%. Non-alcoholic etiologies represent a large subgroup of 29%, particularly among women.46 These results were almost identical with that of the Italian study by the PanCroInfAISP Study Group, endorsing a shift away from alcohol as a highly dominant etiology47 (Table 2). The improving ability to identify rare causes of CP and the discovery of genetic mutations in recent years are also contributing to a lower percentage of cases attributed to alcohol.

Alcohol and chronic pancreatitis Though alcohol is the most widely recognized etiology of AP and CP in western populations, only 5—15% of alcoholics develop pancreatitis. Patients with alcohol-related AP are at high risk for recurrent AP48 and progression from RAP to CP, if they continue to drink alcohol and/or smoke.49–51 In a population-based study of 532 patients admitted with alcoholic AP, after a second attack of alcoholic pancreatitis, the incidence of chronic pancreatitis increased to 38% after only 2 years of follow-up and as mentioned smoking significantly enhanced the risk of progression from acute to chronic alcoholic pancreatitis.51 There is a threshold for alcoholcausing CP. If the consumption is less than 5 drinks a day, the risk of developing CP is very low. But once consumption exceeds this limit, the relationship is linear. Gorelick et al.52 have shown that alcohol does not directly cause pancreatitis, rather it has multiple effects on the pancreas including sensitizing the acinar cell to injury.53 Chronic high alcohol ingestion alters the endoplasmic reticulum (ER) stress mechanisms that protect against ER stress-induced damages54 and induce innate immune responses.28 But the role of alcohol in predisposing to apparent susceptibility to pancreatitis remained controversial until the recent discovery of the CLDN2 gene mutation.16,55 In a large survey in Japan, it was shown that initial necrosis during alcohol-related AP does not correlate with progression to CP, whereas continued consumption of alcohol strongly favored a transition to CP56 (Table 3).

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Table 3 Progression to CP influenced by continued consumption of alcohol.56 Alcohol consumption

Recurrent pancreatitis (%)

Transition to CP (%)

Complication with DM (%)

Complete cessation Decreased but occasional Decreased but daily Continue drinking as before

19.8 18.9 36.7 57.7a

13.6 12.3 23.3 40.9

14.1 14.2 30.0 37.2

a

Significant against upper 2 rows of data (P o 0.05).

Smoking and chronic pancreatitis In many epidemiological studies, after adjusting for alcohol and other risk factors, cigarette smoking has been shown to be an independent risk factor for CP with an odds ratio around 1.99– 2.68.46,57 Smoking is independently associated with complications of CP like exocrine insufficiency, development of calcifications, and ductal changes.58 Duration of smoking is more important than the dose.59 In a Danish registry of 352 AP patients, smoking was the strongest risk factor associated with progression from AP to CP.60 Cessation of smoking in the first years of diagnosis of CP has been shown to prevent development of calcifications.50 The risk of CP in smokers is linear, and while acting as an independent risk factor it is also a disease modifier, with synergistic detrimental effects in conjunction with alcohol consumption. Several experimental rat models showed that smoking increased inflammatory activity with suppression of glutathione peroxidase activity in the pancreas.61–63 In a combined model of smoking and alcohol use, worsening pancreatic ischemia and increased leukocyte infiltration was noted.64 Genetic factors in pancreatitis All these genes make trypsin more active than it should be! Once assumed to be a self-inflicted injury from alcohol, CP is now recognized as a complex disease, like inflammatory bowel disease with a genetic predisposition.6 Genetic variations in PRSS1, SPINK1, and CFTR are strongly associated with CP and to a lesser extent, CTRC and CASR.65–67 A single factor rarely causes pancreatitis, and the majority of patients with recurrent acute and chronic pancreatitis have multiple variants in a gene, or epistatic interactions between multiple genes, coupled with environmental stressors as shown in Figure 46,67 (Table 4). Are familial pancreatitis and hereditary pancreatitis the same? Familial pancreatitis (FP) FP is pancreatitis from any cause that occurs in a family with an incidence that is greater than would be expected by chance alone, and can be non-genetic or genetic. The latter includes hereditary pancreatitis which is an autosomal dominant condition. The majority of FP appears to have a complex, multigenic, interactive gene–environmental etiology with a variable number of pathological variants in genes that affect trypsin regulation, including CASR, CTRC, and CLDN2. Hereditary pancreatitis (HP)—PRSS1 (cationic trypsinogen) The first breakthrough in the approach to CP was the discovery of gain-of-function mutations in cationic trypsin gene (PRSS1) identified to be the cause of autosomal dominant or hereditary pancreatitis.14 Once trypsinogen is secreted from the acinar cells into the pancreatic duct the calcium concentrations are so high that the trypsinogen-binding sites favor increased trypsinogen activation and protect from trypsin degradation. HP is diagnosed when two or more individuals with pancreatitis in two or more generations of a family with pancreatitis is associated with a germline PRSS1 disease-causing gain-of-function

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CaSR

537

CTRC

↑ Calcium

(Alcohol)

+ Trypsinogen Typsinogen

-

PRSS1+

+ Trypsin degradation (acinar cell)

Trypsin

+

(Low pH) Secretion of bi-carb rich fluid

Injury

Trypsin wash-out into duodenum

+ CFTR

Acute Inflammatory

CLDN2 variant

Response

(Alcohol use)

+ SPINK1

Fig. 4. Genetics of pancreatitis (Trypsinogen activation and Trypsin inactivation). Premature activation of Trypsinogen within the pancreas is promoted by cationic Trypsinogen mutations (PRSS1+), active trypsin, low ph and high calcium. Calcium signaling is an important regulator for acinar cell function. CASR regulates calcium levels and alcohol dysregulates this feedback control. Trypsin degradation is blocked by high calcium level and facilitated by Chymotrypsinogen C gene (CTRC) More active trypsin within pancreas leads to pancreatic injury which triggers Acute Inflammatory Response. Inflammation up-regulates serine protease (SPINK1) expression. SPINK1 blocks active trypsin and blocks further activation of trypsinogen, thereby limiting pancreatic injury. SPINK1 is a TRYPSIN INHIBITOR during INFLAMMATION. Cystic Fibrosis Transmembrane conductance Regulator (CFTR) controls duct cells is to secrete a bicarbonate-rich fluid that flushes the trypsin out of the pancreas into the duodenum. Mutations in CFTR leads to decreased fluid secretion, reduced flushing/ trypsin wash-out. CLDN2 variant is a disease modifier acts with alcohol use leading to chronic pancreatitis (not acute), unclear mechanism. (Modified from Whitcomb, Annual Review of Medicine.6)

Table 4 Genetics in chronic pancreatitis. Gene name

Consequence

Prevalence (%)

Comments

General

CP

o0.01

2–3

2–3

8

Cationic trypsinogen (PRSS1) Pancreatic secretory trypsin inhibitor (SPINK1)

↑Trypsinogen activation and ↓trypsin degradation Failure of trypsin degradation

Chymotrypsin C (CTRC)

Failure of trypsin degradation

≤1

3–4

Risk higher in tropical/ idiopathic CP

Calcium-sensing receptor (CASR) Cystic fibrosis Transmembrane conductance (CFTR)

↑Extracellular ionized calcium Impaired flushing of pancreatic ducts leads to trypsin activation

10

18

2–3 (Δ508) 5 (Other)

6 8–9

Role in alcohol-related pancreatitis Risk in PS patients: ~25% ICP: compound heterozygotes Role of “atypical/ benign” mutations (e.g., R75Q, etc.)

Claudin-2

Unclear

26

37

Penetrance—AP 80%, CP 40% Acute phase protein Risk related to one/two mutations, Risk higher in nonalcoholic CP

Present on X chromosome Increases risk of progression from acute to chronic pancreatitis

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variant. This comprises almost 2–3% of CP in the United States. The majority of affected individuals develop symptoms before the age of 20 years, and often before the age of five. Hereditary pancreatitis is associated with a marked increased risk of pancreatic adenocarcinoma with an increased relative risk ratio of 69 times.68,69 The treatment of hereditary pancreatitis is similar to that of other causes of non-hereditary chronic pancreatitis. Other syndromes manifesting as pancreatitis include Pearson marrow pancreas syndrome, CEL maturity-onset diabetes of the young (CEL-MODY), Johanson–Blizzard syndrome, and Shwachman–Diamond syndrome. SPINK-1 (trypsin inhibitor—Scavenger of Trypsin!) The serum protease inhibitor, Kazal type 1 gene (SPINK1), codes for the pancreatic secretory trypsin inhibitor. SPINK1 mutations are common in the population (approximately 2%). SPINK1 is not normally expressed in the pancreatic acinar cells and it is expressed only in the context of ongoing inflammation. It is therefore a critical feedback inhibitor of trypsin in the case of pancreas injury due to inflammation, which is typically initiated by trypsin activation.70 SPINK1 is not the primary risk factor for developing recurrent acute and chronic pancreatitis, and by themselves do not cause pancreatitis but rather represent disease-modifying failed feedback inhibition of recurrent trypsin activation.71,72 A high prevalence of SPINK1 N34S mutation is seen in Tropical calcific pancreatitis patients in India.73 In a meta-analysis, it was observed that SPINK1 mutations were a stronger risk factor in cases of CP associated with recurrent trypsin activation in idiopathic pancreatitis, and progression from alcoholic RAP to CP.74 CTRC (chymotrypsin C) Chymotrypsin C gene functions by degrading trypsin, and therefore protects the pancreas from trypsin-related injury.75 French studies indicated that the loss-of-function alterations in CTRC predispose to pancreatitis by diminishing its protective trypsin-degrading activity.76,77 CTRC mutations are responsible for 3–4% of CP and promote a higher risk for tropical CP. CaSR CaSR is a plasma membrane-bound receptor that senses extracellular calcium levels and is expressed in the parathyroid gland, bone, intestine, kidney, brain, and both acinar and duct cells of the pancreas.78,79 CaSR monitors and regulates the pancreatic juice calcium concentration by triggering ductal electrolyte and fluid secretion.80 CaSR in combination with SPINK-1 mutations increases the risk of pancreatitis,81 and CaSR mutations have been noted in CP patients with moderate to heavy alcohol consumption.82 Cystic fibrosis transmembrane conductance regulator (CFTR)—Pancreatic duct and genetic risk Mutations in CFTR, encoding the cystic fibrosis transmembrane conductance protein, are associated with cystic fibrosis (CF), an autosomal recessive disease associated with the development of CP (beginning in utero83). The primary function of duct cells is to secrete a bicarbonate-rich fluid that flushes the zymogens out of the pancreas into the duodenum. The most important molecule in the duct is CFTR, an anion channel that transports chloride and bicarbonate. Mutation of CFTR results in retention of zymogens in the duct where they can become active and begin digesting the surrounding pancreas, leading to acute pancreatitis67 (Fig. 5). The features of CFTR-associated diseases depend on the functional consequences of specific pathogenic variants on the two CFTR alleles. Cystic fibrosis is caused by two severe pathogenic variants (CFTRsev). Recent data showed that the CFTR variant p.R75Q causes a selective defect in bicarbonate conductance while maintaining chloride conductance and increases the risk of pancreatitis, but has minimal effects on the lungs. Coinheritance of p.R75Q or CF-causing CFTR variants with SPINK1 variants significantly increases the risk of ICP.84 In certain patients with idiopathic pancreatitis with no clinical evidence of CF, mutations in the CFTR gene have been identified.85 In a series of 33 patients with RAP 21% had CFTR

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Fig. 5. Genetic and environmental factors that affect acinar cells or ducts. Premature trypsin activation may occur in the acinar cell or in the duct to initiate pancreatitis. The majority of known risk factors can be classified as primarily affecting the acinar cells or pancreatic ducts. Understanding the site of likely trypsin activation and mechanism may guide preventative strategies in the future. IPMN, intraductal papillary mucinous neoplasm. (Adapted with permission from Solomon and Whitcomb.88)

mutations.85 These mutations lead to CP when additional risk factors are present.83 Recent data suggest that CFTR pathogenic variants that affect bicarbonate conductance while maintaining chloride conductance have major effects on the pancreas but minimal effects on the lungs, since the pancreas uses CFTR as a bicarbonate channel.84 There have been no genetic factors clearly associated with duct obstruction, sphincter of Oddi dysfunction, or pancreas divisum. However, a higher incidence of SPINK1 mutations and certain CFTR variants has been reported with pancreas divisum and could contribute to the development of CP.86,87 CLDN2 (CLAUDIN) Recently, a locus in a gene that codes for Claudin protein was found to be associated with a marked increase in the risk of alcohol-related RAP and CP.16 CLDN2 encodes claudin-2, a tightjunction protein that seals the space between epithelial cells. Claudin-2, which is normally expressed in the proximal pancreatic duct, is thought to facilitate the transport of water and sodium into the duct to match the chloride and bicarbonate that are actively secreted by pancreatic duct cells through CFTR. Claudin-2 is dynamically regulated, and expression is upregulated during inflammation. The CLDN2 risk variant is associated with atypical localization of claudin-2 in pancreatic acinar cells causing increased permeability (?) out of proportion with bicarbonate transport.16 A homozygous (or hemizygous in males) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. CLDN2 mutation is present in X-linked chromosome and this X chromosome linkage could partially explain the higher prevalence of alcohol-associated pancreatitis among men.16 Nearly half of all men with a diagnosis of alcoholic pancreatitis have the high-risk CLDN2 variant.16

Autoimmune diseases Celiac disease increases the risk of chronic pancreatitis by approximately 3-fold (hazard ratio ¼ 3.3).89,90 The risk of CP is increased among patients with inflammatory bowel disease,91 systemic lupus erythematosus, and other autoimmune disorders, although exact estimates are not available.

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Autoimmune pancreatitis (AIP) Less than 5% of patients with pancreatitis who undergo evaluation are diagnosed with autoimmune pancreatitis.92 Autoimmune pancreatitis (AIP) comprises two types. Type 1 AIP is a systemic disease affecting the pancreas, bile ducts, kidneys, salivary glands, retroperitoneum, and other organs. Type 1 AIP is associated with elevations in serum levels of IgG4, and with infiltration of these affected organs by IgG4-bearing plasma cells. Type 2 AIP affects only the pancreas, seen in younger patients and is not associated with IgG4 elevation.93 Among 178 patients with autoimmune pancreatitis, 433% of them had features of AP or CP at the time of presentation.94 Although autoimmune pancreatitis is considered a form of CP, it has distinct clinical and histologic features and responds well to corticosteroid therapy. The relapses are common in type 1 patients and require immune suppressants such Azathioprine or Rituximab.95 The long-term outcome of this condition is not clearly known. In a large multicenter study of 1028 patients, Hart et al.96 did not find pancreatic ductal stones and malignancy commonly developing in patients with AIP. However, some studies noted higher incidence of cancer97 especially in the 1st year after diagnosis of AIP and proposed the possibility that AIP was a paraneoplastic presentation.98

Pathogenesis The pathogenesis of chronic pancreatitis is still not understood.99 It was postulated that the hypersecretion of protein, not compensated for by an increase in ductal bicarbonate secretion, may be a contributing factor.100 And this further leads to proteinaceous ductal plugs from increased secretion of pancreatic proteins, which act as a nidus for calcification, leading to stone formation within the duct system. This results in formation of ductal epithelial lesions, which scar and obstruct the ducts, thereby causing inflammatory changes and cell loss due to fibrosis. Whatever the etiology of CP, the basic pathophysiology involves progressive fibrotic destruction as a response to inflammation. Whitcomb67 has proposed a simple model that CP results from two hits (Fig. 3). The first hit is the acute pancreatitis (AP), which initiates the injury process by activation of the immune system. This injury is linked to premature activation of trypsin and trypsin-independent mechanisms. The second hit in the progression to CP is a modification of the normal inflammatory response, leading to sustained activation of pancreatic stellate cells and fibrosis. The first hit comes from factors that cause injury (TIGAR-O), whereas the second hit involves factors that promote inflammation, which could include various responses of the immune and autonomic and sensory nervous systems, acinar and duct cell stress responses, cell regeneration and transdifferentiation, tissue remodeling, dysplasia, altered anatomy, and other factors (Fig. 6). Different genetic variants can affect each of these different steps.67 This model gives us as clear understanding of areas where we could intervene and alter the course of the disease (Fig. 7).

Stellate cells mediate fibrosis in CP Pancreatic stellate cells (PSC) play an important role in fibrogenesis. PSC are activated either directly due to toxic factors like alcohol or by chemokines such as transforming growth factor beta (TGF-beta), platelet-derived growth factor (PDGFR) released during pancreatic necroinflammation resulting in the formation of collagen, and other extracellular matrix (ECM) proteins in the interstitial spaces and acinar cells destroyed or duct cells are injured and deformed.101 This ultimately leads to progressive loss of the lobular morphology and structure of the pancreas, resulting in deformation of the large ducts and severe changes in the arrangement and composition of the islets.102 The fibrotic destruction of the pancreatic gland is irreversible, and the morphological and structural changes lead to functional impairment of both exocrine and endocrine functions, eventually leading to malnutrition and/or diabetes.

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Fig. 6. Factors contributing to the development of pancreatitis. The first hit increases susceptibility to injury, whereas the second hit affects the immune response (and includes leukocytes, such as M2 macrophages) to promote stellate cellassociated fibrosis. Alcohol could injure the pancreas via its effects on acinar cells, but it is probably more important in the second group as a modifier of the immune response. For example, it could promote a Th17-cell response or act directly on stellate cells (dashed lines). Altered trypsin functions in acinar cells or ducts could also initiate disease. In either case, similar second hit factors then contribute to the development of fibrosis (via variants in SPINK1 and/or CTRC). Severe AP involves widespread pancreatic necrosis (approximately 90% of tissue), which leads directly to scarring and fibrosis in the recovery phase. Obese patients could have areas of adipose tissue that contain local necrosis of acinar tissue, which has been linked to lipotoxicity. Progressive fibrosis could occur in patients with RAP. Other pathways include AIP, in which the pathway to fibrosis is less well understood. (Adapted with permission from Whitcomb.67)

Fig. 7. Progression of pancreatic injury. CP is illustrated as a syndrome that develops over time (left to right). (A) Individuals may live for years with multiple susceptibility factors. Patients at very high risk may be candidates for prevention strategies, such as avoiding alcohol. (B) When a stochastic event leads to pancreatic injury, it initiates the Sentinel Acute Pancreatitis Event (SAPE) with intra-pancreatic immune system activation. Management includes identification of actionable risk and prevention of RAP. (C) Factors such as alcohol, smoking, and genetic mutations or presently unidentified factors affect the specialized cells of the pancreas and infiltrating cells to cause various complications. Research efforts are focusing on identifying risk, mechanisms, and biomarkers of the progression pathways. (Adapted with permission from Whitcomb.67)

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Clinical manifestations Patients with CP often have complex symptoms, which result from pancreatic parenchymal destruction and pancreatic duct distortion. These include abdominal pain, exocrine pancreatic insufficiency leading to steatorrhea, malnutrition, gut dysmotility, and endocrine insufficiency leading to diabetes type 3c. Side effects to medication further contribute to a reduced quality of life (QOL). Histopathologic and autopsy studies show increased prevalence of pancreatic fibrosis in alcoholic patients103 and as the presence of fibrosis reduces the severity of acute inflammatory episodes,104 there could be a significant number of asymptomatic patients with CP. Abdominal pain Pain is one of the typical and frequent symptoms of chronic pancreatitis (CP), with a reported prevalence of 50–85%.105,106 Abdominal pain in CP has a wide spectrum. Classically, the pain is described as epigastric, often with radiation to the back. Pain is often post-prandial and associated with nausea and vomiting. Early in the disease course, pain is often episodic, which may then progress along with the disease to become continuous pattern and course of pain symptoms is highly variable among patients with chronic pancreatitis. Up to 20–45% of patients having objective evidence of pancreatic endocrine or exocrine dysfunction may not have pain. Thus, pain is not a prerequisite for the diagnosis of chronic pancreatitis. Why does pain occur? Pain mechanisms in patients with chronic pancreatitis are incompletely understood and probably multifactorial. Many different hypotheses have been proposed to explain the development of pain in CP ranging from elevation of ductal pressure from strictures or increased parenchymal pressure, cysts, hypertrophy of intra-pancreatic nerves, neuropathic changes, or tissue injury due to oxidative stress.106,107 Pain may be modified by psychosocial factors often associated with the etiology of the pancreatitis, such as alcohol use. Pancreatic duct hypertension In the past, it was thought that there existed a direct relationship between pancreatic duct hypertension due to blockage and pain.108 Subsequent studies showed increased pancreatic duct pressure measured by manometry in patients with CP undergoing a surgical pancreatic drainage procedure when compared with controls without CP undergoing surgery for different reasons.109,110 However, in many studies comparing CP patients with pain and without pain, there was no difference in pressure levels and therefore, the link between ductal hypertension and pain in CP remains hypothetical, which has implications for both surgical and endoscopic therapy.111–114 Pancreatic parenchymal hypertension Chronic pancreatitis was once considered as a compartment syndrome with high intrapancreatic tissue pressure due to impeded drainage and an inelastic capsule.115 While some studies showed higher intra-pancreatic pressures in patients with pain than in patients without pain, and this intra-pancreatic hypertension was reversed following surgical drainage,116 many subsequent studies did not replicate these findings.117 So far, there is no conclusive evidence to suggest this hypothetical theory of parenchymal hypertension as a cause of the pain. Does pain correlate with pancreas morphology in imaging? In a MRI-based Dutch study, it was observed that pancreas parenchymal fibrosis was not associated with pain or other clinical symptoms and questioned the relevance of pancreas

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abnormalities to guide treatment.119 Interestingly, only one of the disease-related variables, that is the etiology of CP, correlated with pain.107,120 None of the morphologic parameters, from calcifications to ductal dilation, were related to the pain severity score. These results indicate the likely importance of extra-pancreatic factors, most notably the prior diagnosis of an affective spectrum disorder or other chronic pain syndrome. In some small studies it is evident, that changes in atrophy and ductal-related parameters were associated with exocrine and endocrine insufficiency, but pain is independent of imaging pathology.119 In the recent large study of 518 (well phenotyped) CP patients (NAPS2), the most common imaging finding was pancreatic duct dilation (68%), followed by atrophy (57%), calcifications (55%), pancreatic duct irregularity (51%), and pancreatic pseudocysts (32%). The most common individual pain pattern was constant mild pain with episodes of severe pain, as reported in 45% of patients. Interestingly, there was no association of imaging findings with any specific pain pattern, concluding that the CP pain pattern and severity are independent of structural variants observed by abdominal imaging techniques.121 CP pain is centrally mediated There are increasing numbers of studies that underscore the importance of central mechanisms in chronic pancreatic pain and introduce a novel concept to describe pain in CP as a “predominantly neuropathic,” “mixed-type” pain118 (Fig. 8). In many of the patients with CP, the pain processing in the central nervous system is abnormal, with changes in cortical projections and mimics that seen in neuropathic pain disorders.122,123 A recent study from Denmark, identified by performing brainstem evoked potentials in CP patients that the sustained pain in CP leads to functional reorganization of the insular cortex.124 Recent studies have shown sensitization of visceral nerves in chronic pancreatitis, suggesting that Nerve Growth factors and receptors like TRPV1 may be an exciting new target for treating the pain of chronic pancreatitis.125 This explains why chronic pancreatitis patients demonstrate pronounced generalized deep hyperalgesia, despite opioid therapy126 Patients with CP exhibit enhanced pain sensitivity due to impaired inhibitory pain modulation to somatic and visceral stimulation in areas distant from the pancreas, which is at least in part mediated by impaired descending modulation of painful input.127 Therapy therefore should focus not only on the pancreas but also on the sensitization of the central nervous system.127 The lack of direct correlation between pancreatic morphology and the burden of pain in CP and the significant central component of pain is further evidenced by outcomes following pancreatic resections. Even with surgical resection including total pancreatectomy, pain relief is not universal and up to 50% may still require narcotics at 1 year after these procedures.128–130 Exocrine pancreatic insufficiency Pancreatic exocrine insufficiency (PEI) is an important cause of maldigestion and malabsorption, and is a major complication in chronic pancreatitis. PEI can be defined as a reduction in pancreatic enzyme activity in the intestinal lumen to a level that is below the threshold required to maintain normal digestion. Symptomatic PEI does not occur until 90% of pancreatic exocrine function is lost.131 Therefore, the demonstration of moderately reduced bicarbonate output in sensitive tests of pancreatic secretion, such as the secretin/cholecystokinin-stimulation test, is a reliable indicator of chronic pancreatitis (CP) but does not necessarily indicate significant PEI.132 The prevalence of PEI seems to vary widely. In tertiary care referral centers, approximately 40–50% of patients with CP have PEI. However, in community practice, the diagnosis of PEI and CP are often missed especially when mild and in the absence of associated pain. The primary symptom of PEI is steatorrhea, which is loose, fatty, pale malodourous stool resulting from fat malabsorption. Unabsorbed fat and oil droplets (depending on diet) in stool

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Fig. 8. Neural pain in chronic pancreatitis.118

that stick to the toilet bowl or difficult to flush are highly suggestive of PEI in appropriate patients.133,134 Despite PEI, carbohydrate and protein digestion are well maintained, as the digestive system is capable of compensating for PEI. In contrast, lipid digestion largely depends on pancreatic lipase, and exogenous pancreatic enzyme replacement therapy (PERT) is needed to rescue the functional status.133 Intra-gastric lipid digestion usually contributes only 10% and the remaining 90% depends on pancreatic lipase for digestion. Furthermore, the diseased pancreas does not secrete enough bicarbonate. Bicarbonate protects pancreatic enzymes from denaturation by gastric acid and establishes an optimal pH for lipase activity.135 This is compounded by the acidic environment of the stomach; however, proton pump inhibitor (PPI) therapy may be beneficial.

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Other clinical symptoms related to PEI include malnutrition related to malabsorption; decreased muscle mass; weight loss; fat soluble vitamin deficiencies A, D, E, and K; and metabolic bone disease secondary to osteoporosis. Osteoporosis in CP—One in four CP patients have osteoporosis even without PEI CP causes Vit D deficiency as a result of fat malabsorption and osteoporosis risk is three times higher than the general population. This is noticed even in exocrine-sufficient patients.136 As smoking and alcohol are also among the main risk factors for osteoporosis, CP patients with an alcohol and smoking history are at a much higher risk.137,138 Osteoporosis occurs not only due to Vit D malabsorption, but also due to chronic inflammation stimulating osteoclastic activity.139 In a retrospective cohort study, low trauma fractures are seen in CP (4.8%) with a prevalence greater than controls and Crohn’s disease patients; comparable with other “high-risk” GI diseases140 (Fig. 9). A recent meta-analysis showed that almost one of four patients with chronic pancreatitis have osteoporosis, and almost two-thirds of patients have either osteoporosis or osteopenia. These complications are underappreciated and there is an urgent need for bone health management guidelines for CP patients.141,142 Chronic pancreatitis and diabetes—pancreatogenic (type 3c) diabetes More than half of all patients with chronic pancreatitis (CP) develop diabetes mellitus (DM)143 due to the loss of complete islet cell mass, not just beta cells as in type 1 DM (T1DM), or due to insulin resistance, as in type 2 DM (T2DM).144 This type of diabetes with loss of islets due to pancreatic disease is classified as a form of secondary diabetes by the American Diabetes Association (ADA) and by the World Health Organization, and is defined as pancreatogenic diabetes or apancreatic diabetes mellitus, also called as type 3c DM (T3cDM).145 While T3cDM can result from several conditions such as acute and chronic pancreatitis of any etiology, hemochromatosis, cystic fibrosis, fibrocalculous pancreatopathy, pancreatic trauma leading to loss of pancreatic tissue, pancreatectomy, pancreatic agenesis, and pancreatic cancer, the most common underlying disease is CP, accounting for about 75–80% of T3cDM patients.143 A unique characteristic of patients with T3cDM is that they also lose counter-regulatory hormones, such as glucagon and pancreatic polypeptide, and are therefore more susceptible to hypoglycemia.146 T3cDM accounts for 5–10% of the Western diabetic populations. However, in a patient first presenting with diabetes, chronic pancreatitis as a potential causative condition is often ignored.147 T3cDM carries a high risk for pancreatic carcinoma. We know that due to PEI there is a mismatch (asynchrony) between food ingestion and nutrient absorption, which makes these patients further prone to hypoglycemia. Also, PEI causes malabsorption, which releases higher levels of gut hormones including GLP-1, and therefore use of insulin secretagogues and incretin therapy are likely useless.146,148,149 A 2012 consensus statement proposed that an absent

Fig. 9. Low trauma fractures in CP. (Adapted with persmission from Tignor et al.140)

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pancreatic polypeptide response to mixed-nutrient ingestion is a specific indicator of type 3c diabetes and this should prompt an initial evaluation with fasting glucose and HbA1c.150

Clinical features from complications Patients may present with clinical manifestations due to complications such as chronic pseudocysts, biliary obstruction, gastric outlet obstruction, duodenal fibrosis, pancreatic fistula, ascites, pleural effusion, splenic vein thrombosis, gastric varices, GI bleeding, and pancreatic cancer. These complications will be discussed in the second part of this review. References 1. Whitcomb DC. The genetics of Shwachman-Diamond syndrome. Gastroenterology. 2003;125:1541–1543. 2. Sachs M. Study of the pancreas and its inflammatory diseases from the 16th-19th century. Zentralbl Chir. 1993;118: 702–711. 3. H. C. Ueber selbstverdauung des menschlichen pankreas. Zeitschrift fur Heilkunde. 1896;17:69–96. 4. Beger HG, Warshaw AL, Büchler MW, et al. (eds.) The Pancreas: An Integrated Textbook of Basic Science, Medicine, and Surgery. 2nd ed. Wiley-Blackwell; 2008. 5. Drozdov I, Modlin IM, Kidd M, Goloubinov VV. From Leningrad to London: the saga of Kulchitsky and the legacy of the enterochromaffin cell. Neuroendocrinology. 2009;89:1–12. 6. Whitcomb DC. Genetic aspects of pancreatitis. Annu Rev Med. 2010;61:413–424. 7. Comfort MW, Gambill EE, Baggenstoss AH. Chronic relapsing pancreatitis; a study of twenty-nine cases without associated disease of the biliary or gastro-intestinal tract. Gastroenterology. 1946;6:239 [passim]. 8. Pitchumoni CS. Chronic pancreatitis: a historical and clinical sketch of the pancreas and pancreatitis. Gastroenterologist. 1998;6:24–33. 9. Sarles H. Revised classification of pancreatitis—Marseille 1984. Dig Dis Sci. 1985;30:573–574. 10. Singer MV, Gyr K, Sarles H. Revised classification of pancreatitis. Report of the Second International Symposium on the Classification of Pancreatitis in Marseille, France, March 28-30, 1984. Gastroenterology. 1985;89:683–685. 11. Sarner M, Cotton PB. Classification of pancreatitis. Gut. 1984;25:756–759. 12. Banks PA, Bollen TL, Dervenis C, et al. Classification of acute pancreatitis—2012: revision of the Atlanta classification and definitions by international consensus. Gut. 2013;62:102–111. 13. Steer ML, Waxman I, Freedman S. Chronic pancreatitis. N Engl J Med. 1995;332:1482–1490. 14. Whitcomb DC, Preston RA, Aston CE, et al. A gene for hereditary pancreatitis maps to chromosome 7q35. Gastroenterology. 1996;110:1975–1980. 15. Yadav D, Whitcomb DC. The role of alcohol and smoking in pancreatitis. Nat Rev Gastroenterol Hepatol. 2010;7: 131–145. 16. Whitcomb DC, LaRusch J, Krasinskas AM, et al. Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis. Nat Genet. 2012;44:1349–1354. 17. Yadav D, OʼConnell M, Papachristou GI. Natural history following the first attack of acute pancreatitis. Am J Gastroenterol. 2012;107:1096–1103. 18. Go VLW, Everhart JE: Pancreatitis. In: Everhart JE, ed. Digestive diseases in the United States: epidemiology and impact. US Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases Washington, DC: US Government Printing Office, 1994; 2009; pp. 691–712. 19. Yadav D, Timmons L, Benson JT, Dierkhising RA, Chari ST. Incidence, prevalence, and survival of chronic pancreatitis: a population-based study. Am J Gastroenterol. 2011;106:2192–2199. 20. Hirota M, Shimosegawa T, Masamune A, et al. The seventh nationwide epidemiological survey for chronic pancreatitis in Japan: Clinical significance of smoking habit in Japanese patients. Pancreatology. 2014;14:490–496. 21. Yadav D, Lowenfels AB. The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology. 2013;144: 1252–1261. 22. Bonfrate L, Wang DQ, Garruti G, Portincasa P. Obesity and the risk and prognosis of gallstone disease and pancreatitis. Best Pract Res Clin Gastroenterol. 2014;28:623–635. 23. Sandzen B, Haapamaki MM, Nilsson E, Stenlund HC, Oman M. Cholecystectomy and sphincterotomy in patients with mild acute biliary pancreatitis in Sweden 1988-2003: a nationwide register study. BMC Gastroenterol. 2009;9: 80. 24. Nguyen GC, Rosenberg M, Chong RY, Chong CA. Early cholecystectomy and ERCP are associated with reduced readmissions for acute biliary pancreatitis: a nationwide, population-based study. Gastrointest Endosc. 2012;75: 47–55. 25. Nebiker CA, Frey DM, Hamel CT, Oertli D, Kettelhack C. Early versus delayed cholecystectomy in patients with biliary acute pancreatitis. Surgery. 2009;145:260–264. 26. Bottino R, Bertera S, Grupillo M, et al. Isolation of human islets for autologous islet transplantation in children and adolescents with chronic pancreatitis. J Transplant. 2012;2012:642787. 27. Balakrishnan V, Unnikrishnan AG, Thomas V, et al. Chronic pancreatitis. A prospective nationwide study of 1086 subjects from India. JOP. 2008;9:593–600. 28. Subhash R, Iyoob VA, Natesh B. Tropical calcific pancreatitis. Clin Gastroenterol Hepatol. 2012;10:A30.

T. Muniraj et al. / Disease-a-Month 60 (2014) 530–550

547

29. Balaji LN, Tandon RK, Tandon BN, Banks PA. Prevalence and clinical features of chronic pancreatitis in southern India. Int J Pancreatol. 1994;15:29–34. 30. Tao N, Sussman S, Nieto J, Tsukamoto H, Yuan JM. Demographic characteristics of hospitalized patients with alcoholic liver disease and pancreatitis in los angeles county. Alcohol Clin Exp Res. 2003;27:1798–1804. 31. Yang AL, Vadhavkar S, Singh G, Omary MB. Epidemiology of alcohol-related liver and pancreatic disease in the United States. Arch Intern Med. 2008;168:649–656. 32. Lowenfels AB, Maisonneuve P, Grover H, et al. Racial factors and the risk of chronic pancreatitis. Am J Gastroenterol. 1999;94:790–794. 33. Yadav D, Muddana V, OʼConnell M. Hospitalizations for chronic pancreatitis in Allegheny County, Pennsylvania, USA. Pancreatology. 2011;11:546–552. 34. Whitcomb DC, Yadav D, Adam S, et al. Multicenter approach to recurrent acute and chronic pancreatitis in the United States: the North American Pancreatitis Study 2 (NAPS2). Pancreatology. 2008;8:520–531. 35. Greer JB, LaRusch J, Brand RE, OʼConnell MR, Yadav D, Whitcomb DC. ABO blood group and chronic pancreatitis risk in the NAPS2 cohort. Pancreas. 2011;40:1188–1194. 36. Sarles H. Pancreatitis Symposium.Marseilles, France: Karger; 1965. 37. Schneider A, Lohr JM, Singer MV. The M-ANNHEIM classification of chronic pancreatitis: introduction of a unifying classification system based on a review of previous classifications of the disease. J Gastroenterol. 2007;42: 101–119. 38. Singer MV, Gyr K, Sarles H. [2d symposium on the classification of pancreatitis. Marseilles, 28-30 March 1984]. Acta Gastroenterol Belg. 1985;48:579–582. 39. Sarles H. Definitions and classifications of pancreatitis. Pancreas. 1991;6:470–474. 40. Pezzilli R, Lioce A, Frulloni L. Chronic pancreatitis: a changing etiology? JOP. 2008;9:588–592. 41. Yamada. Textbook of Gastroenterology. Wiley-Blackwell; 2008. 42. Banks PA. Epidemiology, natural history, and predictors of disease outcome in acute and chronic pancreatitis. Gastrointest Endosc. 2002;56:S226–S230. 43. OʼSullivan JN, Nobrega FT, Morlock CG, Brown AL Jr, Bartholomew LG. Acute and chronic pancreatitis in Rochester, Minnesota, 1940 to 1969. Gastroenterology. 1972;62:373–379. 44. Otsuki M. Chronic pancreatitis in Japan: epidemiology, prognosis, diagnostic criteria, and future problems. J Gastroenterol. 2003;38:315–326. 45. Sarles H, Cros RC, Bidart JM. A multicenter inquiry into the etiology of pancreatic diseases. Digestion. 1979;19: 110–125. 46. Cote GA, Yadav D, Slivka A, et al. Alcohol and smoking as risk factors in an epidemiology study of patients with chronic pancreatitis. Clin Gastroenterol Hepatol. 2011;9:266–273 [quiz e27]. 47. Frulloni L, Gabbrielli A, Pezzilli R, et al. Chronic pancreatitis: report from a multicenter Italian survey (PanCroInfAISP) on 893 patients. Dig Liver Dis. 2009;41:311–317. 48. Pelli H, Lappalainen-Lehto R, Piironen A, Sand J, Nordback I. Risk factors for recurrent acute alcohol-associated pancreatitis: a prospective analysis. Scand J Gastroenterol. 2008;43:614–621. 49. Nordback I, Pelli H, Lappalainen-Lehto R, Jarvinen S, Raty S, Sand J. The recurrence of acute alcohol-associated pancreatitis can be reduced: a randomized controlled trial. Gastroenterology. 2009;136:848–855. 50. Talamini G, Bassi C, Falconi M, et al. Smoking cessation at the clinical onset of chronic pancreatitis and risk of pancreatic calcifications. Pancreas. 2007;35:320–326. 51. Lankisch PG, Breuer N, Bruns A, Weber-Dany B, Lowenfels AB, Maisonneuve P. Natural history of acute pancreatitis: a long-term population-based study. Am J Gastroenterol. 2009;104:2797–2805 [quiz 806]. 52. Katz M, Carangelo R, Miller LJ, Gorelick F. Effect of ethanol on cholecystokinin-stimulated zymogen conversion in pancreatic acinar cells. Am J Physiol. 1996;270:G171–G175. 53. Lerch MM, Gorelick FS. Models of acute and chronic pancreatitis. Gastroenterology. 2013;144:1180–1193. 54. Pandol SJ, Gorelick FS, Gerloff A, Lugea A. Alcohol abuse, endoplasmic reticulum stress and pancreatitis. Dig Dis. 2010;28:776–782. 55. Derikx MH, Kovacs P, Scholz M, et al. Polymorphisms at PRSS1-PRSS2 and CLDN2-MORC4 loci associate with alcoholic and non-alcoholic chronic pancreatitis in a European replication study. Gut. 2014. doi:10.1136/ gutjnl-2014-307453. 56. Takeyama Y. Long-term prognosis of acute pancreatitis in Japan. Clin Gastroenterol Hepatol. 2009;7:S15–S17. 57. Law R, Parsi M, Lopez R, Zuccaro G, Stevens T. Cigarette smoking is independently associated with chronic pancreatitis. Pancreatology. 2010;10:54–59. 58. Luaces-Regueira M, Iglesias-Garcia J, Lindkvist B, et al. Smoking as a risk factor for complications in chronic pancreatitis. Pancreas. 2014;43:275–280. 59. Sadr-Azodi O, Andren-Sandberg A, Orsini N, Wolk A. Cigarette smoking, smoking cessation and acute pancreatitis: a prospective population-based study. Gut. 2012;61:262–267. 60. Nojgaard C, Becker U, Matzen P, Andersen JR, Holst C, Bendtsen F. Progression from acute to chronic pancreatitis: prognostic factors, mortality, and natural course. Pancreas. 2011;40:1195–1200. 61. Wittel UA, Pandey KK, Andrianifahanana M, et al. Chronic pancreatic inflammation induced by environmental tobacco smoke inhalation in rats. Am J Gastroenterol. 2006;101:148–159. 62. Jianyu H, Guang L, Baosen P. Evidence for cigarette smoke-induced oxidative stress in the rat pancreas. Inhal Toxicol. 2009;21:1007–1012. 63. Wittel UA, Singh AP, Henley BJ, et al. Cigarette smoke-induced differential expression of the genes involved in exocrine function of the rat pancreas. Pancreas. 2006;33:364–370. 64. Hartwig W, Werner J, Ryschich E, et al. Cigarette smoke enhances ethanol-induced pancreatic injury. Pancreas. 2000;21:272–278. 65. Larusch J, Whitcomb DC. Genetics of pancreatitis with a focus on the pancreatic ducts. Minerva Gastroenterol Dietol. 2012;58:299–308.

548

T. Muniraj et al. / Disease-a-Month 60 (2014) 530–550

66. Shelton CA, Whitcomb DC. Genetics and treatment options for recurrent acute and chronic pancreatitis. Curr Treat Options Gastroenterol. 2014;12:359–371. 67. Whitcomb DC. Genetic risk factors for pancreatic disorders. Gastroenterology. 2013;144:1292–1302. 68. Weiss FU. Pancreatic cancer risk in hereditary pancreatitis. Front Physiol. 2014;5:70. 69. Klein AP, Hruban RH, Brune KA, Petersen GM, Goggins M. Familial pancreatic cancer. Cancer J. 2001;7:266–273. 70. Witt H, Luck W, Hennies HC, et al. Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nat Genet. 2000;25:213–216. 71. Khalid A, Finkelstein S, Thompson B, et al. A 93 year old man with the PRSS1 R122H mutation, low SPINK1 expression, and no pancreatitis: insights into phenotypic non-penetrance. Gut. 2006;55:728–731. 72. Pfutzer RH, Barmada MM, Brunskill AP, et al. SPINK1/PSTI polymorphisms act as disease modifiers in familial and idiopathic chronic pancreatitis. Gastroenterology. 2000;119:615–623. 73. Bhatia E, Choudhuri G, Sikora SS, et al. Tropical calcific pancreatitis: strong association with SPINK1 trypsin inhibitor mutations. Gastroenterology. 2002;123:1020–1025. 74. Aoun E, Chang CC, Greer JB, Papachristou GI, Barmada MM, Whitcomb DC. Pathways to injury in chronic pancreatitis: decoding the role of the high-risk SPINK1 N34S haplotype using meta-analysis. PLoS One. 2008;3: e2003. 75. Szmola R, Sahin-Toth M. Chymotrypsin C (caldecrin) promotes degradation of human cationic trypsin: identity with Rinderknechtʼs enzyme Y. Proc Natl Acad Sci U S A. 2007;104:11227–11232. 76. Rosendahl J, Witt H, Szmola R, et al. Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis. Nat Genet. 2008;40:78–82. 77. Masson E, Chen JM, Scotet V, Le Marechal C, Ferec C. Association of rare chymotrypsinogen C (CTRC) gene variations in patients with idiopathic chronic pancreatitis. Hum Genet. 2008;123:83–91. 78. Riccardi D, Brown EM. Physiology and pathophysiology of the calcium-sensing receptor in the kidney. Am J Physiol Renal Physiol. 2010;298:F485–F499. 79. Bruce JI, Yang X, Ferguson CJ, et al. Molecular and functional identification of a Ca2 þ (polyvalent cation)-sensing receptor in rat pancreas. J Biol Chem. 1999;274:20561–20568. 80. Racz GZ, Kittel A, Riccardi D, Case RM, Elliott AC, Varga G. Extracellular calcium sensing receptor in human pancreatic cells. Gut. 2002;51:705–711. 81. Felderbauer P, Klein W, Bulut K, et al. Mutations in the calcium-sensing receptor: a new genetic risk factor for chronic pancreatitis? Scand J Gastroenterol. 2006;41:343–348. 82. Muddana V, Lamb J, Greer JB, et al. Association between calcium sensing receptor gene polymorphisms and chronic pancreatitis in a US population: role of serine protease inhibitor Kazal 1type and alcohol. World J Gastroenterol. 2008;14:4486–4491. 83. Sharer N, Schwarz M, Malone G, et al. Mutations of the cystic fibrosis gene in patients with chronic pancreatitis. N Engl J Med. 1998;339:645–652. 84. Schneider A, Larusch J, Sun X, et al. Combined bicarbonate conductance-impairing variants in CFTR and SPINK1 variants are associated with chronic pancreatitis in patients without cystic fibrosis. Gastroenterology. 2011;140: 162–171. 85. Cohn JA, Friedman KJ, Noone PG, Knowles MR, Silverman LM, Jowell PS. Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. N Engl J Med. 1998;339:653–658. 86. Pezzilli R. Pancreas divisum and acute or chronic pancreatitis. JOP. 2012;13:118–119. 87. Garg PK, Khajuria R, Kabra M, Shastri SS. Association of SPINK1 gene mutation and CFTR gene polymorphisms in patients with pancreas divisum presenting with idiopathic pancreatitis. J Clin Gastroenterol. 2009;43:848–852. 88. Solomon S, Whitcomb DC. Genetics of pancreatitis: an update for clinicians and genetic counselors. Curr Gastroenterol Rep. 2012;14:112–117. 89. Ludvigsson JF, Montgomery SM, Ekbom A. Risk of pancreatitis in 14,000 individuals with celiac disease. Clin Gastroenterol Hepatol. 2007;5:1347–1353. 90. Sadr-Azodi O, Sanders DS, Murray JA, Ludvigsson JF. Patients with celiac disease have an increased risk for pancreatitis. Clin Gastroenterol Hepatol. 2012;10:1136–1142 (e3). 91. Pitchumoni CS, Chari S. Ulcerative colitis and autoimmune pancreatitis. J Clin Gastroenterol. 2013;47:469. 92. Sugumar A, Chari ST. Autoimmune pancreatitis. J Gastroenterol Hepatol. 2011;26:1368–1373. 93. Kamisawa T, Chari ST, Lerch MM, Kim MH, Gress TM, Shimosegawa T. Recent advances in autoimmune pancreatitis: type 1 and type 2. Gut. 2013;62:1373–1380. 94. Sah RP, Pannala R, Chari ST, et al. Prevalence, diagnosis, and profile of autoimmune pancreatitis presenting with features of acute or chronic pancreatitis. Clin Gastroenterol Hepatol. 2010;8:91–96. 95. Hart PA, Topazian MD, Witzig TE, et al. Treatment of relapsing autoimmune pancreatitis with immunomodulators and rituximab: the Mayo Clinic experience. Gut. 2013;62:1607–1615. 96. Hart PA, Kamisawa T, Brugge WR, et al. Long-term outcomes of autoimmune pancreatitis: a multicentre, international analysis. Gut. 2013;62:1771–1776. 97. Huggett MT, Culver EL, Kumar M, et al. Type 1 autoimmune pancreatitis and IgG4-related sclerosing cholangitis is associated with extrapancreatic organ failure, malignancy, and mortality in a prospective UK cohort. Am J Gastroenterol. 2014;109:1675–1683. 98. Shiokawa M, Kodama Y, Yoshimura K, et al. Risk of cancer in patients with autoimmune pancreatitis. Am J Gastroenterol. 2013;108:610–617. 99. Stevens T, Conwell DL, Zuccaro G. Pathogenesis of chronic pancreatitis: an evidence-based review of past theories and recent developments. Am J Gastroenterol. 2004;99:2256–2270. 100. Sahel J, Sarles H. Modifications of pure human pancreatic juice induced by chronic alcohol consumption. Dig Dis Sci. 1979;24:897–905. 101. Apte MV, Haber PS, Darby SJ, et al. Pancreatic stellate cells are activated by proinflammatory cytokines: implications for pancreatic fibrogenesis. Gut. 1999;44:534–541.

T. Muniraj et al. / Disease-a-Month 60 (2014) 530–550

549

102. Brock C, Nielsen LM, Lelic D, Drewes AM. Pathophysiology of chronic pancreatitis. World J Gastroenterol. 2013;19: 7231–7240. 103. Agrawal P, Vaiphei K. Histomorphological features of pancreas and liver in chronic alcoholics—an analytical study in 390 autopsy cases. Indian J Pathol Microbiol. 2014;57:2–8. 104. Acharya C, Cline RA, Jaligama D, et al. Fibrosis reduces severity of acute-on-chronic pancreatitis in humans. Gastroenterology. 2013;145:466–475. 105. Ammann RW, Muellhaupt B. The natural history of pain in alcoholic chronic pancreatitis. Gastroenterology. 1999;116:1132–1140. 106. Fasanella KE, Davis B, Lyons J, et al. Pain in chronic pancreatitis and pancreatic cancer. Gastroenterol Clin North Am. 2007;36:335–364 (ix). 107. Ceyhan GO, Bergmann F, Kadihasanoglu M, et al. Pancreatic neuropathy and neuropathic pain—a comprehensive pathomorphological study of 546 cases. Gastroenterology. 2009;136:177–186.e1. 108. White TT, Bourde J. A new observation on human intraductal pancreatic pressure. Surg Gynecol Obstet. 1970;130: 275–278. 109. Okazaki K, Yamamoto Y, Ito K. Endoscopic measurement of papillary sphincter zone and pancreatic main ductal pressure in patients with chronic pancreatitis. Gastroenterology. 1986;91:409–418. 110. Laugier R. Dynamic endoscopic manometry of the response to secretin in patients with chronic pancreatitis. Endoscopy. 1994;26:222–227. 111. Novis BH, Bornman PC, Girdwood AW, Marks IN. Endoscopic manometry of the pancreatic duct and sphincter zone in patients with chronic pancreatitis. Dig Dis Sci. 1985;30:225–228. 112. Rolny P, Arleback A, Jarnerot G, Andersson T. Endoscopic manometry of the sphincter of Oddi and pancreatic duct in chronic pancreatitis. Scand J Gastroenterol. 1986;21:415–420. 113. Ugljesic M, Bulajic M, Milosavljevic T, Stimec B. Endoscopic manometry of the sphincter of Oddi and pancreatic duct in patients with chronic pancreatitis. Int J Pancreatol. 1996;19:191–195. 114. Vestergaard H, Kruse A, Rokkjaer M, Frobert O, Thommesen P, Funch-Jensen P. Endoscopic manometry of the sphincter of Oddi and the pancreatic and biliary ducts in patients with chronic pancreatitis. Scand J Gastroenterol. 1994;29:188–192. 115. Ebbehoj N, Svendsen LB, Madsen P. Pancreatic tissue pressure: techniques and pathophysiological aspects. Scand J Gastroenterol. 1984;19:1066–1068. 116. Ebbehoj N, Borly L, Bulow J, Rasmussen SG, Madsen P. Evaluation of pancreatic tissue fluid pressure and pain in chronic pancreatitis. A longitudinal study. Scand J Gastroenterol. 1990;25:462–466. 117. Manes G, Buchler M, Pieramico O, Di Sebastiano P, Malfertheiner P. Is increased pancreatic pressure related to pain in chronic pancreatitis? Int J Pancreatol. 1994;15:113–117. 118. Demir IE, Tieftrunk E, Maak M, Friess H, Ceyhan GO. Pain mechanisms in chronic pancreatitis: of a master and his fire. Langenbecks Arch Surg. 2011;396:151–160. 119. Frokjaer JB, Olesen SS, Drewes AM. Fibrosis, atrophy, and ductal pathology in chronic pancreatitis are associated with pancreatic function but independent of symptoms. Pancreas. 2013;42:1182–1187. 120. Strate T, Bachmann K, Busch P, et al. Resection vs drainage in treatment of chronic pancreatitis: long-term results of a randomized trial. Gastroenterology. 2008;134:1406–1411. 121. Mel Wilcox M C, Yadav Dhiraj MD MPH, Tian Ye, et al. Chronic pancreatitis pain pattern and severity are independent of abdominal imaging findings. Clin Gastroenterol Hepatol. 2014. 122. Drewes AM, Krarup AL, Detlefsen S, Malmstrom ML, Dimcevski G, Funch-Jensen P. Pain in chronic pancreatitis: the role of neuropathic pain mechanisms. Gut. 2008;57:1616–1627. 123. Dimcevski G, Sami SA, Funch-Jensen P, et al. Pain in chronic pancreatitis: the role of reorganization in the central nervous system. Gastroenterology. 2007;132:1546–1556. 124. Olesen SS, Frokjaer JB, Lelic D, Valeriani M, Drewes AM. Pain-associated adaptive cortical reorganisation in chronic pancreatitis. Pancreatology. 2010;10:742–751. 125. Schwartz ES, Christianson JA, Chen X, et al. Synergistic role of TRPV1 and TRPA1 in pancreatic pain and inflammation. Gastroenterology. 2011;140:1283–1291(e1-2). 126. Buscher HC, Wilder-Smith OH, van Goor H. Chronic pancreatitis patients show hyperalgesia of central origin: a pilot study. Eur J Pain. 2006;10:363–370. 127. Olesen SS, Brock C, Krarup AL, et al. Descending inhibitory pain modulation is impaired in patients with chronic pancreatitis. Clin Gastroenterol Hepatol. 2010;8:724–730. 128. Morgan K, Owczarski SM, Borckardt J, Madan A, Nishimura M, Adams DB. Pain control and quality of life after pancreatectomy with islet autotransplantation for chronic pancreatitis. J Gastrointest Surg. 2012;16: 129–133 [discussion 33-4]. 129. Shapiro AM, Ricordi C, Hering BJ, et al. International trial of the Edmonton protocol for islet transplantation. N Engl J Med. 2006;355:1318–1330. 130. Lieb JG 2nd, Forsmark CE. Review article: pain and chronic pancreatitis. Aliment Pharmacol Ther. 2009;29: 706–719. 131. DiMagno EP, Go VL, Summerskill WH. Relations between pancreatic enzyme ouputs and malabsorption in severe pancreatic insufficiency. N Engl J Med. 1973;288:813–815. 132. Lindkvist B. Diagnosis and treatment of pancreatic exocrine insufficiency. World J Gastroenterol. 2013;19: 7258–7266. 133. Whitcomb DC. Pancrelipase delayed-release capsules for the treatment of pancreatic insufficiency. Gastroenterol Hepatol. 2011;7:253–255. 134. Dominguez-Munoz JE. Pancreatic exocrine insufficiency: diagnosis and treatment. J Gastroenterol Hepatol. 2011;26 (suppl 2):12–16. 135. DiMagno EP, Malagelada JR, Go VL, Moertel CG. Fate of orally ingested enzymes in pancreatic insufficiency. Comparison of two dosage schedules. N Engl J Med. 1977;296:1318–1322.

550

T. Muniraj et al. / Disease-a-Month 60 (2014) 530–550

136. Sikkens EC, Cahen DL, Koch AD, et al. The prevalence of fat-soluble vitamin deficiencies and a decreased bone mass in patients with chronic pancreatitis. Pancreatology. 2013;13:238–242. 137. Duggan SN, OʼSullivan M, Hamilton S, Feehan SM, Ridgway PF, Conlon KC. Patients with chronic pancreatitis are at increased risk for osteoporosis. Pancreas. 2012;41:1119–1124. 138. Haaber AB, Rosenfalck AM, Hansen B, Hilsted J, Larsen S. Bone mineral metabolism, bone mineral density, and body composition in patients with chronic pancreatitis and pancreatic exocrine insufficiency. Int J Pancreatol. 2000;27: 21–27. 139. Tilg H, Moschen AR, Kaser A, Pines A, Dotan I. Gut inflammation and osteoporosis: basic and clinical concepts. Gut. 2008;57:684–694. 140. Tignor AS, Wu BU, Whitlock TL, et al. High prevalence of low-trauma fracture in chronic pancreatitis. Am J Gastroenterol. 2010;105:2680–2686. 141. Duggan SN, Smyth ND, Murphy A, Macnaughton D, OʼKeefe SJ, Conlon KC. High prevalence of osteoporosis in patients with chronic pancreatitis: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2014;12: 219–228. 142. Pezzilli R, Andriulli A, Bassi C, et al. Exocrine pancreatic insufficiency in adults: a shared position statement of the Italian Association for the Study of the Pancreas. World J Gastroenterol. 2013;19:7930–7946. 143. Ewald N, Kaufmann C, Raspe A, Kloer HU, Bretzel RG, Hardt PD. Prevalence of diabetes mellitus secondary to pancreatic diseases (type 3c). Diabetes Metab Res Rev. 2012;28:338–342. 144. Whitcomb DC. Chronic pancreatitis, type 3c diabetes, and pancreatic cancer risk. JOP. 2014;15:2773. 145. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2009;32(suppl 1):S62–S67. 146. Whitcomb DC. Diabetes and cancer: the problem of reverse causality and missing links. JOP. 2014;15:2772. 147. Ewald N, Hardt PD. Diagnosis and treatment of diabetes mellitus in chronic pancreatitis. World J Gastroenterol. 2013;19:7276–7281. 148. Cui Y, Andersen DK. Pancreatogenic diabetes: special considerations for management. Pancreatology. 2011;11: 279–294. 149. Knop FK, Vilsboll T, Larsen S, et al. Increased postprandial responses of GLP-1 and GIP in patients with chronic pancreatitis and steatorrhea following pancreatic enzyme substitution. Am J Physiol Endocrinol Metab. 2007;292: E324–E330. 150. Rickels MR, Bellin M, Toledo FG, et al. Detection, evaluation and treatment of diabetes mellitus in chronic pancreatitis: recommendations from PancreasFest 2012. Pancreatology. 2013;13:336–342.