Pancreatitis associated with genetic risk factors

INTRODUCTION — Risk factors that may contribute to acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) can be categorized with the mnemonic "TIGAR-O": Toxic-metabolic, Idiopathic (when no risk factor is identified), Genetic, Autoimmune, Recurrent/Severe pancreatitis, Obstructive [1]. In many cases, more than one factor is needed to result in pancreatitis.

Genetic risk factors were previously thought to be a minor factor in ARP and CP but are increasingly recognized as cofactors in the complex etiology of these conditions. Testing for genetic risk factors has become important both to understand the individual patient's risk for future disease and to establish a basis for future treatment.

Issues related to genetic risk factors for ARP and CP will be reviewed here. Identification and management of other risk factors for ARP and CP are discussed in other topic reviews:

●(See "Clinical manifestations and diagnosis of chronic and acute recurrent pancreatitis in children".)

●(See "Causes and contributing risk factors for chronic pancreatitis in children and adolescents".)

●(See "Chronic pancreatitis: Clinical manifestations and diagnosis in adults".)

●(See "Overview of the complications of chronic pancreatitis".)

●(See "Chronic pancreatitis: Management".)

TERMINOLOGY AND CATEGORIES OF PANCREATITIS

●Acute pancreatitis (AP) – AP is a syndrome of sudden pancreatic inflammation, regardless of etiology. While the majority of cases of AP heal completely, approximately one-third of patients with AP develop acute recurrent pancreatitis. Among those with acute recurrent pancreatitis, approximately one-third develop chronic pancreatitis [2,3].

●Acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP) – ARP refers to repeated episodes of pancreatitis with good health in between. CP is a fibrosing condition with almost constant symptoms and the increased risk of both endocrine and exocrine pancreatic insufficiency. (See "Causes and contributing risk factors for chronic pancreatitis in children and adolescents" and "Etiology and pathogenesis of chronic pancreatitis in adults".)

●Hereditary pancreatitis – The term "hereditary pancreatitis" was previously used to refer to an autosomal dominant form of CP caused by the PRSS1 gene. "Familial pancreatitis" was used to refer to other forms of inherited pancreatitis. The reader may find these terms in older literature, but the complexity of the genetic risk factors for ARP and CP generally puts these terms out of use. Instead, the disorders should be described by the specific gene defect (eg, PRSS1-associated pancreatitis).

EPIDEMIOLOGY — The epidemiology of genetic risk factors for acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) varies greatly between different cities, regions, countries, and ancestral groups, likely because of founder effects and migration patterns. Furthermore, the true incidence of these risk factors, even among patients with acute pancreatitis (AP), ARP, and CP, is not known, because deep sequencing of all the important genes has not been done in most populations. For example, in 2011, it was estimated that strong genetic contributors were present in fewer than 10 percent of children with AP [4] but up to 30 to 80 percent of those with ARP or CP, depending on the genes tested and ethnicity of the population [5,6]. However, a subsequent single-center study found genetic etiology in 42 percent of children with the first attack of AP, and more than one genetic factor was identified in a substantial proportion of those with CP [7].

It is increasingly clear that genetic factors may interact with other risk factors for ARP and CP. As examples, genetic factors may influence the development of toxic-metabolic pancreatitis. A large multicenter study demonstrated an association of known genetic risk factors for pancreatitis with some cases of asparaginase-associated pancreatitis [8]. A study from China suggests that major genetic variants for SPINK1 or PRSS1 are present in nearly 40 percent of individuals with pancreatitis that had been classified as "alcohol related" [9]. (See "Causes and contributing risk factors for chronic pancreatitis in children and adolescents", section on 'Genetic'.)

GENETICS

Inheritance patterns — There are at least three different inheritance patterns for acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP) (see "Causes and contributing risk factors for chronic pancreatitis in children and adolescents", section on 'Genetic'). In addition, cases of pancreatitis without a family history may have a genetic basis (simplex case).

●Autosomal dominant – Autosomal dominant inheritance is most often associated with gain-of-function variants in the PRSS1 gene on chromosome 7q35, which encodes trypsin-1 (cationic trypsinogen) [10-12]. Rarely, autosomal dominant-appearing pancreatitis is identified in a kindred that does not have an identifiable PRSS1 mutation [13-15]. (See 'PRSS1 gene' below.)

●Autosomal recessive – Mutations in SPINK1 may present in an autosomal recessive pattern. CFTR-associated disorders include CP with minimal lung disease, and this gene may present in multiple family members. (See 'CFTR gene' below.)

●Complex mechanisms – Multiple family members may have ARP or CP associated with a combination of genetic and environmental factors. This is the case for patients with heterozygous SPINK1 mutations, in which the SPINK1 mutation probably acts as a disease modifier, lowering the threshold for developing pancreatitis from other genetic (eg, CFTR mutations) [16,17] or environmental factors (see 'SPINK1 gene' below). Some apparently sporadic cases of pancreatitis have complex genetic risk.

PRSS1 gene — Gain-of-function variants in PRSS1, which encodes cationic trypsinogen, are present in up to 80 percent of patients with autosomal dominantly inherited pancreatitis [5,18-22]. PRSS1 variants are also occasionally identified in cases of apparently idiopathic ARP or CP [23,24]. In two case series, approximately 10 percent of children with ARP had a pathogenic PRSS1 variant [7,25]. (See "Pathogenesis of acute pancreatitis" and "Causes and contributing risk factors for chronic pancreatitis in children and adolescents", section on 'Idiopathic'.)

●Molecular mechanisms – Cationic trypsin is the most abundant form of trypsin produced by the pancreas and is the primary catalyst for the conversion of pancreatic zymogens into pancreatic digestive enzymes after they are secreted into the duodenum. Premature activation of digestive enzymes in the pancreas is a major cause of pancreatic injury and immune system activation, leading to ARP and later CP. The primary defense against pancreatitis is to control trypsin activity, either through prevention of premature activation of trypsinogen to trypsin or by the destruction, inhibition, or elimination of trypsin from the pancreas. These defenses are weakened by pathogenic variants in PRSS1 or in genes coding for molecules that protect the pancreas from active trypsin (eg, SPINK1, CTRC, CFTR) [26].

Trypsin has two regulatory regions that are controlled by corresponding calcium-binding pockets, one regulating the activation site (changing trypsinogen into trypsin with the release of trypsinogen activation peptide) and the other regulating the autolysis site (leading to trypsin destruction). Nearly all of the pathogenic genetic variants associated with pancreatitis are clustered in these two regions.

●Pathogenic variants – The most common pancreatitis-associated variants in PRSS1 are p.R122H (at the autolysis site) and p.N29I [11,12,18,22]. As an example, in a national series of 200 patients from 78 families with suspected PRSS1-associated pancreatitis in France, pathogenic PRSS1 variants were detected in 68 percent; among these patients, p.R122H and p.N291 were present in 78 and 12 percent, respectively [18]. The estimated population-prevalence of PRSS1-associated pancreatitis in this study was at least 0.3 per 100,000. A research website on CP genetics maintains and updates a list of PRSS1, PRSS2, and carboxypeptidase A1 (CPA1) variants including functional studies to help classify the mutations [27].

The p.R122H and p.N291 variants have high penetrance (80 and 93 percent in two series) [18,28]. It remains unclear why some family members with these variants do not develop CP. A possible contributing factor for the occasionally decreased penetrance of pancreatitis is the presence of variants that protect against the development of CP. One such variant has been described in the PRSS2 gene (anionic trypsinogen), resulting in the loss of trypsin activity [29]. (See 'Genetic variants conferring protection from pancreatitis' below.)

Other kindreds carry pathogenic PRSS1 variants, which modify cationic trypsinogen in different ways. New variants continue to be described [23,30-34]. These variants may not have the same high penetrance that has been seen with p.R122H and p.N291 variants.

Risk of pancreatitis is also associated with copy number variants. Copy number variants are uncommon. Cases have been reported in both Europe [35] and the United States [15]. The risk appears to be a dose-effect since decreased PRSS1 expression is associated with a reduced risk of pancreatitis [36].

Two synonymous variants in PRSS1 (p.Asp162= [rs6666] and p.Asn246= [rs6667]) are important because they are linked with a risk haplotype associated with CP, especially in alcohol-drinking patients, known as the PRSS1-PRSS2 risk haplotype [36]. This haplotype is characterized by a large insertion/deletion variant that contains additional trypsinogen pseudogenes, a PRSS2 promoter and multiple T cell receptor beta gene transcripts that may increase susceptibility to pancreatitis and alter the immune response [37].

●False-positive results – PRSS1 variants that were identified through exome or genome sequencing should be confirmed through another methodology. Exome and genome sequencing may result in a PRSS1 false positive because of high homology between PRSS1 and other trypsinogen genes and pseudogenes.

In addition, there is a major technical problem in the diagnosis of PRSS1 gene variants, and especially PRSS1 p.N29I, when using next-generation "shot gun" sequencing due to an error in the human DNA reference sequence build 37 where PRSS2 was not included. Thus, the normal PRSS2 p.I29 cannot be mapped to the reference build 37 template. Because the sequenced fragments best fit the PRSS1 sequence, the normal PRSS2 p.I29 is misinterpreted as a PRSS1 p.N29I variant, resulting in an erroneously high estimate for this rare variant. We are aware of a number of patients that were incorrectly diagnosed with hereditary pancreatitis based on this error. Furthermore, next-generation sequencing genotyping was also complicated by a large insertion/deletion that requires the use of the alternate contig-containing trypsinogen genes PRSS1, PRSS3P1, PRSS3P2, TRY7, and PRSS2 rather than only PRSS1, PRSS3P1, and PRSS2 for proper sequence fragment alignment and correct mutation calls [38,39]. If an apparent PRSS1 p.N29I mutation is identified, the accuracy of the result should be verified with another testing method prior to any medical decision-making.

SPINK1 gene — SPINK1 (serine protease inhibitor Kazal type 1) encodes a pancreatic secretory trypsin inhibitor that is regulated as an acute phase reactant. It is expressed in pancreatic acinar cells during an inflammatory process where it normally serves as a critical suicide inhibitor of trypsin. Pathogenic variants in SPINK1 interfere with this protective action and predispose to pancreatitis [19]. Thus, pathogenic variants in SPINK1 are of minimal consequence, unless there is premature and excessive activation of trypsin and inflammation. SPINK1 variants can cause pancreatitis with an autosomal recessive pattern in families in which both parents have a pathogenic variant. However, the majority of patients with SPINK1 variants and CP are heterozygous, resulting in complex inheritance patterns.

Pathogenic SPINK1 variants are fairly common in the general population (2 percent of healthy individuals carry a "high-risk" variant) [40], but less than 1 percent of carriers develop pancreatitis [41]. Nonetheless, variants in SPINK1 increase the risk for CP approximately 12-fold over the general population. In four series of patients with apparent idiopathic CP, pathogenic variants in SPINK1 were detected in 15 to 23 percent [7,33,42,43]. In one of these reports, SPINK1 variants were more common in patients with idiopathic ARP or CP than in controls (19.5 versus 2.6 percent) [43]. A SPINK1 high-risk haplotype containing p.N34S is the most common variant in the United States and Europe, while a SPINK1 IVS3 +2T>C variant is also common in Japan, China, and Korea [44]. SPINK1 variants have been linked to idiopathic pancreatitis, alcohol-related pancreatitis, familial pancreatitis, and tropical pancreatitis [45].

Patients with heterozygous SPINK1 variants and pancreatitis typically have complex genetics (eg, gene x gene, gene x environment) since SPINK1, as a specific trypsin inhibitor, is only required if there is an upstream problem causing recurrent trypsin activation [45]. Thus, the SPINK1 variant probably acts as a disease modifier, lowering the threshold for developing pancreatitis from other genetic or environmental factors. The most common genetic variant seen with SPINK1 is CFTR, which is described below [16,17].

CFTR gene — Pathogenic variants in the CFTR gene can be associated with pancreatitis with or without associated pulmonary manifestations of cystic fibrosis (CF). Over 2000 different genetic variants in CFTR have been identified, and disease manifestations depend on the severity of the variant and zygosity [46]. CFTR gene variants and the conditions associated with them are catalogued in the CFTR 2 database maintained by the Cystic Fibrosis Foundation and Johns Hopkins [47]. (See "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'Pancreatic disease'.)

●Patients with CF – CF is an autosomal recessive genetic disorder caused by severe variants in the CFTR gene. Approximately 85 percent of people with CF have two severe CFTR variants [48], such as F508del/F508del (the most common allele causing disease), resulting in minimal or absent functional CFTR protein on epithelial cells of the respiratory system, digestive system, reproductive organs, and skin. Patients with these genotypes have abnormal sweat chloride measures (≥60 mmol/L) and typically develop pancreatic insufficiency early in life [49]. They rarely develop pancreatitis.

In patients with CF, the risk of acute pancreatitis (AP) is linked with less severe CFTR variants, milder phenotype, and pancreatic sufficiency [50]. Homozygous or compound heterozygous genotypes in which at least one of the CFTR gene copies is a functionally "mild" variant (or variants of variable clinical significance) result in some retained CFTR function and milder or limited pulmonary features of CF. (See "Cystic fibrosis: Clinical manifestations and diagnosis".)

●Patients without CF – In addition, there is an increased risk of ARP and CP among patients with one or two CFTR variants but who do not meet clinical criteria for a diagnosis of CF.

CFTR-related disorder is a monosymptomatic clinical entity (eg, congenital bilateral absence of the vas deferens, pancreatitis, or bronchiectasis) associated with CFTR dysfunction [51]. Patients have less than two severe CFTR variants, and the clinical and functional evidence (ie, sweat chloride values are between 30 and 59 mmol/L) does not meet diagnostic criteria for CF. A study of a commercial claims database evaluated the prevalence of a variety of conditions that were associated with 19,800 CFTR carriers, each of which were matched with five controls [52]. Fifty-seven conditions were associated with CFTR variants including pancreatitis, male infertility, bronchiectasis, diabetes, constipation, cholelithiasis, short stature, and growth faltering. Thus, identification of CFTR-associated pancreatitis should alert the clinician of the risk for other CFTR-related disorders. (See "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'CFTR-related disorder'.)

Individuals who carry a single pathogenic CFTR variant have a risk for CP that is increased three- to fourfold over the general population, although 99 percent of the carriers are healthy [53-55]. Those who do develop CP have a very high rate of coexisting SPINK1, CTRC, or more complex genotypes [16,17]. Heterozygous CFTR variants may also contribute to pancreatitis in the presence of pancreatic divisum [56,57].

Several studies have shown that carriage of one pathogenic CFTR variant, including uncommon and mild variants, is more common among patients with idiopathic CP than among controls [49,53,58]. However, in studies of populations known to be CF carriers (eg, parents of patients with CF), the prevalence of CP is only slightly increased [53,54,59]. In a longitudinal case series of children with AP, carriage of one pathogenic CFTR variant was associated with a greater risk for progression from AP to CP [7]. Together, these observations suggest that pancreatitis develops among carriers of a pathogenic CFTR variant primarily in the presence of additional genetic or environmental disease modifiers. Thus, testing is more useful in determining the etiology of early pancreatitis than for predicting pancreatitis in an asymptomatic person.

CTRC gene — Pathogenic variants in the CTRC gene confer a moderate risk for CP, usually in conjunction with other heterogeneous pancreatitis susceptibility variants, such as CFTR or SPINK1 [17,60-63]. Chymotrypsin C is a digestive enzyme that cooperates with active trypsin in solutions with lower calcium concentrations to degrade trypsin [64]. Thus, it is an intrapancreatic antitrypsin protective mechanism that complements SPINK1. Several rare variants in CTRC have been linked with CP in children [61-63], while the common p.G60G risk haplotype (where the synonymous amino acid code change is on the same chromosome as one or more variants that diminish gene expression) is associated with CP in adults, especially smokers [62].

Additional genes associated with acute recurrent and chronic pancreatitis — Two genes have been reported that are associated with chronic alcohol-related pancreatitis and pediatric idiopathic CP, respectively. These are important because the mechanism is not dependent on trypsin activation and because they are either common modifier genes or confer very high risk.

●CLDN2 gene – The most important are the high-risk haplotype at the CLDN2 locus associated with CP, especially in patients with alcohol-related CP [65-67]. It confers no or small risk of AP. Instead, these variants appear to accelerate progression from AP to CP. The high-risk locus is on the X chromosome, with the haplotype-defining variant rs12688220 C in 26 percent of control alleles. Since males are hemizygous for the X chromosome, the risk appears dominant, whereas it is inherited as a recessive trait in females. If 16 percent of males and 10 percent of females are at-risk alcohol drinkers, it suggests that 4 percent of males (0.16 × 0.26) are at high risk of alcohol-related CP, compared with 0.7 percent of females (0.10 × 0.26 × 0.26).

●CPA1 gene – Carboxypeptidase A1, encoded by the CPA1 gene, is a pancreatic digestive enzyme that is second in abundance in pancreatic secretions after trypsinogen. Variants in CPA1 are linked to nonalcoholic CP, especially with early age of onset [68]. Risk of CP is unrelated to trypsin activation or failed inhibition. In a study involving 944 cases and 3938 controls in Germany, investigators performed standard DNA sequencing of all ten CPA1 exons and identified 35 novel or rare variants [68]. Functional studies showed that many of the variants had less than 20 percent of expected activity and were not secreted from experimental cells. This suggests that the mutated peptides were misfolding, causing stress inside of the endoplasmic reticulum. The low-activity variants were found in 3.1 percent of cases compared with 0.1 percent of controls (odds ratio = 25). The finding was replicated in three other groups and found to be especially prevalent in children with idiopathic CP. Newer studies of families with an autosomal dominant pancreatitis inheritance pattern in Poland and in the United States found that they had novel CPA1 p.Ser282Pro [69] or CPA1 p.K374E variants [70], further extending this association of genetics and pancreatitis.

●Other genes – Ongoing candidate gene and association studies with larger national and international cohorts continue to identify genetic variants associated with pancreatitis.

•One important gene is CEL (carboxyl-ester lipase), in which an important hybrid splice variant between CEL and the pseudogene CELP is associated with autosomal dominant pancreatitis and diabetes mellitus (MODY type 8), caused by an endoplasmic reticulum stress mechanism [71,72]. CEL has complex genetics in a region of DNA that is challenging to sequence, thereby limiting replication studies and genetic testing [71-74].

•Variants in the CASR gene (calcium-sensing receptor) are also associated with pancreatitis as a cofactor of a more complex genotype, likely associated as an activator of CFTR when duct calcium levels are too high [75,76]. The PNLIP gene (pancreatic lipase) has several variants associated with CP, especially p.F300L that is associated with pancreatitis risk in Germany and France, but it has not yet been seen in India, Japan, or the United States [77].

•Variants in the GGT1 gene (gamma-glutamyltransferase 1) are associated with CP [78] and pancreatic cancer [79]. This gene protects duct cells against oxidative stress. Variants in the UBR1 gene are associated with pancreatitis in Germany [80], although these appear to be cofactors since they are not pancreas-specific genes. UBR1 is part of the protein quality control mechanism to identify and eliminate secreted proteins that are misfolded or in the wrong cellular compartment, including zymogens in the acinar cell.

•Variants in the TRPV6 gene, which encodes a Ca(2+)-selective ion channel, were associated with early-onset idiopathic pancreatitis (before 20 years of age) in Japanese and European subjects [81].

Other genetic variants continue to be described.

Genetic variants conferring protection from pancreatitis — There are at least two genetic variants that protect people from pancreatitis. The first is the PRSS2 p.G191R variant. This introduces a trypsin cut site into anionic trypsin so that overall activity is reduced. This may be present in up to 3 percent of some populations [29,82]. Second, a protective haplotype at the PRSS1-PRSS2 locus was found that is present in approximately 42 percent of controls but only 38 percent of cases with pancreatitis, suggesting that risk was reduced by up to 40 percent [36,65]. The difference between that risk and protective haplotype in PRSS1-PRSS2 depends on which variant/haplotype is designated as the reference, with the alternative being either protective or risk.

CLINICAL PRESENTATION — Patients with genetic risk factors present similarly to other forms of pancreatitis, but some genetic risk factors may increase the chances of early-age presentation. Early-onset idiopathic chronic pancreatitis (CP) in adults is associated with the presence of genetic risk factors for pancreatitis more commonly than late-onset presentations [83]. Children presenting with acute recurrent pancreatitis (ARP) or CP before age six years more commonly had a PRSS1 or CRTC mutation [84].

The clinical presentation of patients with genetic risk factors for pancreatitis can begin with episodes of acute pancreatitis (AP) or with CP. The clinical features are similar to those seen in other causes of CP and are discussed in detail elsewhere. The primary manifestations are abdominal pain, maldigestion due to pancreatic exocrine dysfunction, and diabetes mellitus due to islet cell damage. (See "Clinical manifestations and diagnosis of chronic and acute recurrent pancreatitis in children" and "Chronic pancreatitis: Clinical manifestations and diagnosis in adults".)

The following findings were noted in the national series of 418 patients with suspected PRSS1-associated pancreatitis from 112 families in 14 European countries [13] and 200 patients from 78 families in France [18]:

●The median ages at first symptom and diagnosis were 10 and 19 years, respectively [13,18]. Similar findings have been noted in other studies in which disease onset may be before age five [28,85]. The first symptoms occurred at a slightly older age in patients with N29I or without identified PRSS1 variants [13].

●In the French series, pancreatic pain, AP, and pseudocysts were present in 83, 69, and 23 percent, respectively, with pancreatic calcifications noted on radiologic examination in 61 percent [18].

●Exocrine pancreatic insufficiency eventually developed in 37 and 34 percent, respectively [13,18], and presented at a mean age of 29 years [18].

●Diabetes mellitus eventually developed in 48 and 26 percent, respectively [13,18], and presented at a mean age of 38 years [18]. Patients who develop diabetes typically require insulin therapy. However, the diabetes is different from typical type 1 diabetes in that the pancreatic alpha cells, which produce glucagon, are also affected (type 3c diabetes mellitus) [86]. As a result, there is an increased risk of hypoglycemia, both treatment-related and spontaneous.

●There were no differences in clinical and morphologic data according to genetic status.

The most common presentation of PRSS1-associated pancreatitis is ARP [13,18,28,87,88]. After recovery from the acute episode, affected patients may remain well for a significant duration. Some patients may present with CP without episodes of AP.

PANCREATIC CANCER

Cancer risk — PRSS1-associated pancreatitis is associated with a significantly increased risk of pancreatic cancer, although PRSS1-associated pancreatitis patients account for a very small fraction of all cases of pancreatic cancer [13,18,89,90]. Although the risk of pancreatic cancer is high compared with that of the general population, the true risk is not known, because studies are limited by referral bias and estimates have wide confidence intervals. (See "Epidemiology and nonfamilial risk factors for exocrine pancreatic cancer".)

The best available evidence suggests a cancer risk between 7 and 20 percent [13,91]. A study from the United States, representing up to 20 years for prospective follow-up of the originally identified families with PRSS1-associated pancreatitis, suggested that the risk of pancreatic cancer was indeed significantly greater than age- and sex-matched data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) registry (standardized incidence ratio [SIR] 59, 95% CI 19-138) but that the cumulative risk was only 7.2 percent (95% CI 0.0-15.4) at 70 years [91]. In a study of 112 families in Europe, the cumulative risk of developing pancreatic cancer was 18.8 percent (95% CI 8.6-29.0) at 70 years (SIR 67, 95% CI 50-82). In both studies, the risk increased markedly after age 50 [13]. Of note, pancreatic cancer is also a disease seen in older patients, and the incidence of pancreatic cancer continues to increase beyond 70 years of age.

Earlier studies suggested a much higher incidence of pancreatic cancer among patients with PRSS1-associated pancreatitis. In 1997, an international study of 246 patients (175 from the United States, 60 from Europe, and 11 from Japan) reported a cumulative risk of pancreatic cancer to age 70 years of 40 percent (SIR 53, 95% CI 9-71) [89]. These conclusions are limited because (1) the patients were seen at referral centers, (2) only five patients reached age 70 years, and (3) only two of five developed pancreatic cancer. In a separate series from France that included 200 patients from 78 families with PRSS1-associated pancreatitis, the cumulative risk of pancreatic cancer in affected family members was 10, 19, and 54 percent at ages 50, 60, and 75 years, respectively [18]. The SIR for pancreatic cancer compared with the general population was 87 (95% CI 42-113). The risk was highest in smokers and in individuals with diabetes mellitus and was much lower in nonsmokers and patients without diabetes.

The higher risk of pancreatic cancer in the older studies may be associated with a high prevalence of smoking in earlier generations, with a marked change in prevalence of smoking after the associated risks were discovered in the late 1990s. Smoking increases the risk of pancreatic cancer approximately twofold in patients with PRSS1-associated pancreatitis, which is similar to the increase in risk in the general population [92]. However, among patients with PRSS1-associated pancreatitis, smokers developed pancreatic cancer 20 years earlier than nonsmokers. (See "Epidemiology and nonfamilial risk factors for exocrine pancreatic cancer", section on 'Cigarette smoking'.)

To minimize their cancer risk, patients with all forms of chronic pancreatitis (CP) should be urged not to smoke and follow healthy lifestyles (see 'Avoidance of alcohol and tobacco' below). When pancreatic cancer does occur, it is typically in late adulthood. There is no evidence to support prophylactic procedures such as total pancreatectomy for cancer prevention.

Cancer screening — Several consensus panels have recommended screening for pancreatic cancer in individuals with PRSS1-associated pancreatitis [93-96]. These recommendations are guided largely by expert opinion since no well-powered studies have been performed to determine if screening in these patients is effective. Guidelines on screening for the familial pancreatic cancer syndrome patient that rely on imaging studies, such as magnetic resonance imaging (MRI) and/or endoscopic ultrasound, are not easily applied to PRSS1-associated pancreatitis, since the morphology of the pancreatic gland is markedly altered by CP. Nonetheless, these guidelines typically suggest initiating imaging surveillance starting at age 40 [96] or 50 [95].

Issues related to screening for pancreatic cancer in high-risk individuals with genetic risk factors for CP, including those with PRSS1-associated pancreatitis, are discussed in detail elsewhere. (See "Familial risk factors for pancreatic cancer and screening of high-risk patients", section on 'Pancreatic cancer screening'.)

GENETIC TESTING — Genetic testing is an important component of the evaluation for many patients with acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP). Testing for genetic risk factors be overseen by a qualified genetic counselor with expertise in this area [40,97,98]. (See "Etiology and pathogenesis of chronic pancreatitis in adults", section on 'Idiopathic' and "Causes and contributing risk factors for chronic pancreatitis in children and adolescents", section on 'Idiopathic'.)

Indications for genetic testing

●Symptomatic patients – Genetic testing for pancreatitis susceptibility genes is medically necessary and should be performed in patients with pancreatitis and one or more of the following [40,99,100]:

•A second episode of pancreatitis in a person under age 35 years old (including children) despite appropriate therapeutic interventions (eg, clearing the biliary tree in gallstone-associated pancreatitis)

•A family history of ARP, idiopathic CP, or childhood pancreatitis without a known cause

•Relatives known to carry gene variants associated with pancreatitis (eg, PRSS1 variants)

•ARP and CP

•Evidence of a CFTR-associated disorder (eg, male infertility or bronchiectasis)

•Unexplained exocrine or endocrine pancreatic insufficiency

•Patients eligible for approved research protocols

Practice varies regarding genetic testing for patients with ARP or CP and other risk factors (eg, heavy alcohol use, duct obstruction, or medications). Some clinicians defer genetic testing for this group. However, genetic testing is increasingly included in the evaluation, recognizing that multiple risk factors can contribute to disease expression. Most clinicians do not test for genetic factors in individuals with a single episode of acute pancreatitis (AP), although some may do so if there is a family history of pancreatitis, pancreatic cancer, or previous episodes of undiagnosed severe abdominal pain.

●Asymptomatic patients – Testing of asymptomatic individuals (predictive testing) can be considered for individuals who have a first-degree relative with a known pathologic PRSS1 variant but should only be undertaken after expert genetic counseling. Predictive testing is generally not recommended for asymptomatic individuals under 16 years of age [100]. If a family carries a known pathogenic variant, negative test results in a family member essentially eliminate the risk of PRSS1-associated pancreatitis in that individual [101]. A positive test result confers approximately 80 percent risk of developing pancreatitis. If an individual remains free of symptoms, the residual risk of developing pancreatitis is 25 percent at age 20 and 10 percent at age 30 [102].

By contrast, predictive testing of SPINK1 or CFTR variants in asymptomatic individuals is of minimal value because pathogenic variants are common and most patients with these variants do not develop disease [40].

Testing strategy and interpretation — Most laboratories that offer genetic testing for pancreatic diseases include the major variants for Mendelian disorders linked to PRSS1, SPINK1, CFTR, and CTRC. More comprehensive tests that include over a dozen genes are also available to detect additional risk genes and variants in gene regulatory elements. An updated list of laboratories that perform this testing is available at the Genetic Testing Registry website.

All patients in whom genetic testing is performed should be offered genetic counseling prior to and after testing. An overview of the issues to be addressed by genetic counselors has been published [100,103].

Interpretation is as follows:

●PRSS1 – The most common autosomal dominant, gain-of-function variants in PRSS1 include p.A16V, p.N29I, p.R122H, and p.R122C, with p.A16V having a low penetrance. In addition, PRSS1 copy number variants are associated with autosomal dominant pancreatitis. Other PRSS1 gene variants may also be associated with pancreatitis because of protein misfolding in the endoplasmic reticulum of Golgi including p.D19A, p.D22G, p.K23R, p.K23I, p.K23I_I24insIDK, p.N29I, p.N29T, p.V39A, p.D100H, p.L104V or P, p.R116C, p.R122H, p.R122C, p.S124F, p.C139F, and p.G208A [104]. Co-inheritance of other risk alleles appears to increase risk and worsen severity. Knowledge of the type of PRSS1 variant may affect choice of treatment, either focused on limiting trypsin activity or on managing the unfolded protein response.

●CFTR – Genetic testing for CFTR variants is also indicated in patients with unexplained ARP and CP or those with signs/symptoms of a CFTR-related disorder. Many clinicians would start with sweat chloride testing, if not already done. CFTR-associated pancreatitis includes the variants that cause cystic fibrosis (CF) but also gene variants previously thought to be benign (eg, R75Q). Therefore, complete gene sequencing should be considered, especially if the patient has recurrent sinusitis or male infertility. Interpretation of results must be done in the context of clinical setting. Patients with two severe CFTR variants, or a severe and mild-variable CFTR variant, should be referred to a CF center for formal testing because management requires a structured, multidisciplinary approach. Of note, patients with types IV and V and some other variants appear to be responsive to CFTR potentiators [105-107].

●SPINK1 – Pathogenic SPINK1 variants are believed to limit the inflammation-associated feedback inhibition of intrapancreatic trypsin activity. Heterozygous SPINK1 variants are benign, unless there is a problem causing recurrent intrapancreatic trypsin activation. Homozygote or compound heterozygote SPINK1 variants cause sufficient loss of trypsin inhibiting function to explain the etiology of recurrent pancreatitis. Heterozygous SPINK1 variants typically cause pancreatitis only if they are associated with another predisposing factor, such as pathogenic variants in CFTR, CaSR, or CTRC [75], or biliary obstruction. Patients with pathogenic SPINK1 variants typically have a more severe clinical course compared with those with other causes of ARP and a more rapid progression from ARP to CP [7,108]. Inactivating variants in CaSR also cause familial hypocalciuric hypercalcemia, which is also associated with pancreatitis when present with pathogenic CFTR variants, heavy alcohol use, or other risks. (See "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia", section on 'Familial hypocalciuric hypercalcemia'.)

Only a minority of patients with unexplained pancreatitis have a genotype that is a sufficiently strong risk factor to explain their condition. These may include PRSS1 p.R122H, CFTR p.F508del with a class IV or V variant, or homozygous SPINK1 pN34S haplotypes.

The majority of patients with unexplained pancreatitis will have complex genotypes in which none of the factors alone are necessary or sufficient to cause pancreatitis by themselves but in combination are pathogenic. These patients may have a genetic risk factor as well as an obstructive or toxic metabolic risk factor. In this case, the data are best interpreted with a precision medicine paradigm, where the focus is on the underlying mechanistic disorders in specific cells or systems where symptoms of a disorder arise from a combination of genetic variant-associated alterations in normal function and environmental, metabolic, or lifestyle stressors [109]. The goal is to diagnose the underlying disorder (eg, CFTR dysfunction) and provide targeted holistic treatment before the disorder causes sufficient pathology to meet consensus criteria for irreversible CP [110]. Thus, clinical context, biomarkers, and information from an adequate gene-sequencing panel are needed for interpretation of complex disorders from a precision medicine perspective and to provide guidance beyond a typical "genetic report" of classic Mendelian diseases.

MANAGEMENT — Management of acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) follows many of the principles for CP of other causes. However, some therapies may be contraindicated in individuals with genetic risk factors. (See "Chronic pancreatitis: Management".)

Avoidance of alcohol and tobacco — We suggest that any patient with a genetic risk factor for ARP and CP abstain from alcohol and tobacco for life, although data are limited.

The best data for these risk factors are for individuals with PRSS1-associated pancreatitis (eg, the PRSS1 variants p.R122H, p.N29I), members of affected families, and individuals in whom a specific pathogenic PRSS1 variant has been identified. Alcohol intake has been associated with exacerbations, and there is no known quantity of alcohol that is safe for this group of patients [18,88]. Other possible triggers for exacerbations include emotional stress and dietary fat. In addition, smoking is a strong independent risk factor for CP [111,112] and increases the risk of pancreatic cancer [92].

Alcohol and tobacco use also increase the risk of progressing to end-stage CP for patients with risk variants in the CLDN2 gene locus, the high-risk PRSS1-PRSS2 haplotype, or CTRC p.G60G risk haplotypes [36,62]. (See 'Genetics' above.)

CFTR modulator therapy — Several small molecules are now available that modulate the CFTR protein to make it a more effective transmembrane conduction regulator. These molecules may hold promise for individuals with CFTR-associated pancreatitis. Case series have demonstrated that some people with CF and recurrent episodes of pancreatitis have experienced relief of pancreatitis episodes while on modulators [105,113]. These patients probably had moderately impaired pancreatic function at baseline and modulator therapy improved CFTR function sufficiently to put the patient out of the risk range for pancreatitis [50]. Conversely, a few people with CF have developed pancreatitis on modulators [114,115]. These patients had more severe pancreatic insufficiency at baseline and modulator therapy improved CFTR function, moving them into the risk range for pancreatitis. Both effects are likely the result of increased CFTR function in the pancreatic acinus. Clinicians managing people with CF should be aware of these possibilities. Clinical trials are necessary to determine whether CFTR modulators have a role in therapy of patients with ARP or CP. (See "Cystic fibrosis: Treatment with CFTR modulators" and "Cystic fibrosis: Hepatobiliary disease", section on 'Considerations related to CFTR modulator therapy'.)

Endoscopic retrograde cholangiopancreatogram and pancreatic surgery — Endoscopic retrograde cholangiopancreatogram (ERCP) procedures may relieve pain in individuals with pancreatitis associated with genetic risk factors, although the effect may not be permanent [116]. If repeated ERCP procedures are needed for pain relief, an alternative strategy is pancreatectomy with islet autotransplantation. Surgical draining procedures or other surgical interventions should be used judiciously in people with genetic risk factors for pancreatitis. There is a high risk of pancreatitis recurrence in the remaining pancreatic tissue.

Pancreatectomy

●Pancreatectomy with islet autotransplantation – We generally offer pancreatectomy with islet autotransplantation for younger patients with severe features of ARP or CP.

This procedure is most likely to be beneficial for younger patients who have functional islet cells, for whom it may preserve islet function and relieve intractable, narcotic-dependent pancreatic pain [117,118]. Outcomes based on case series show moderate levels of success. As an example, in a series of 75 children undergoing this procedure, 90 percent experienced sustained improvement in pancreatic pain and almost all of these patients were successfully weaned from narcotics [119]. Insulin independence was achieved in 41 percent of patients (31 of 75 subjects). Insulin independence was typically achieved during the first 12 months after the transplant procedure and was sustained for at least three years in most (28 of 31 subjects). Factors predicting insulin independence included younger age (<12 years), male sex, and the number of islets transplanted. In a small series of younger children (ages three to eight years), outcomes were somewhat better, with 82 percent achieving insulin independence with median follow-up 2.2 years and all patients experiencing pain relief [120]. These outcomes are generally better than in series of adults undergoing the same procedure [117,118].

Arguments against this procedure are that it is irreversible, is associated with multiple risks, and has not been proven to protect islet cells and delay development of diabetes. Furthermore, the risk of cancer occurs late in life; the published risk may be higher than real risk because of selection bias. Finally, new treatments are being evaluated that may further reduce risk of pancreatitis and pancreatic cancer. Enthusiasm for doing this procedure should therefore be tempered with caution.

Two conferences were held to debate the role of total pancreatectomy with islet autotransplantation in management of disabling ARP or painful CP, and these produced recommendations for follow-up of these patients [121,122].

●Pancreatectomy without islet transplantation – Pancreatectomy without islet autotransplantation is occasionally performed if there is a risk of malignant cells being infused with islets. This may be the case in older patients with long-standing CP (eg, those who have had CP for 20 years or more) to treat pain or reduce the risk of developing pancreatic cancer. Screening for pancreatic cancer in these high-risk patients can be particularly difficult because the pancreas is scarred and disfigured [93]. However, most such patients can be managed with islet autotransplantation if there are functioning islet cells and there is judged to be little or no cancer risk; if successful, the islet infusion will reduce the severity of postoperative diabetes. No cases of pancreatic cancer have yet been reported after islet autotransplantation [123].

PROGNOSIS — The mortality rate compared with the general population is significantly increased in patients with genetic risk factor-associated pancreatitis who develop pancreatic cancer [124]. In contrast, mortality does not appear to be increased in patients without pancreatic cancer.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic pancreatitis and pancreatic exocrine insufficiency".)

SUMMARY AND RECOMMENDATIONS

●Genes involved in pancreatitis

•Autosomal dominant hereditary pancreatitis is usually caused by pathogenic variants in PRSS1. In some cases, the PRSS1 variant may promote premature activation of trypsinogen or interfere with the inactivation of trypsin. (See 'PRSS1 gene' above.)

•Other forms of pancreatitis with a genetic basis are associated with homozygous or compound heterozygous variants in SPINK1, CFTR, CTRC, or other genes such as CPA1 in children and CLDN2 in adults, especially in men with alcohol-related pancreatitis. (See 'Genetics' above.)

●Clinical presentation – Most patients with pancreatitis associated with genetic risk factors present before 20 years of age with acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP). As many as one-third of patients progress to develop pancreatic insufficiency and/or diabetes mellitus. Affected individuals have increased risk of developing pancreatic cancer, especially if they smoke or have diabetes mellitus. (See 'Clinical presentation' above and 'Pancreatic cancer' above.)

●Symptomatic patients – Clinical indications for genetic testing in patients with pancreatitis include:

•ARP or CP, particularly if beginning <35 years of age

•Pancreatitis in a patient with a family history of pancreatitis or pancreatic cancer

•Pancreatitis and clinical evidence of a CFTR-associated disorder (eg, male infertility or bronchiectasis)

Such patients should be tested for variants in PRSS1, SPINK1, CFTR, and CTRC as a minimum, plus additional risk genes if the inheritance pattern is less clear and if no other etiology can be identified. (See 'Indications for genetic testing' above.)

●Asymptomatic patients – For children under age 16 with a family history of CP but no clinical symptoms, we suggest not performing genetic testing (Grade 2C). For patients older than age 16, genetic testing for PRSS1 can be considered if there is a family history of a known pathogenic PRSS1 variant and if testing is desired by the patient after expert genetic counseling. For patients without clinical symptoms suggestive of pancreatic disease, testing for SPINK1 or CFTR is not clinically useful, because a heterozygous variant for one of these genes only slightly increases the risk for CP. However, CFTR variant carriers may also be at increased risk for a variety of other disorders as well. (See 'Indications for genetic testing' above and 'CFTR gene' above.)

●Management of CP

•Supportive care – Management of genetic risk factor-associated pancreatitis is similar to that for other causes of ARP and CP. Affected individuals should exercise, focus on a healthy lifestyle, and avoid consuming alcohol and smoking cigarettes. (See 'Management' above and "Chronic pancreatitis: Management".)

•Pancreatectomy – In children or adults with severe pain and high opioid use associated with ARP or CP, but with residual islet function, we suggest pancreatectomy with islet autotransplantation (Grade 2C). Pancreatectomy can markedly improve the quality of life in selected patients, but the procedure is irreversible, is associated with significant perioperative risk, has uncertain long-term consequences related to islet cell function in the liver, and results in complete pancreatic exocrine insufficiency that requires lifelong, full-dose pancreatic enzyme replacement therapy. (See 'Pancreatectomy' above.)

•Cancer risk and surveillance – CP associated with genetic risk factors is associated with a significantly increased risk of pancreatic cancer. The cumulative risk of developing pancreatic cancer within 70 years appears to be between 7 and 20 percent (with wide confidence intervals), but this statistic includes patients with other risk factors for pancreatic cancer, including smoking, diabetes, and a family history of cancer. Smokers from pancreatic cancer-prone families develop cancer on average a decade earlier than nonsmokers. Patients who do not smoke and have not developed diabetes likely have less than a 20 percent chance of developing pancreatic cancer. Consensus panels have recommended screening for pancreatic cancer in individuals with CP, but there is no consensus as to the optimal age to start screening. (See 'Pancreatic cancer' above.)

In older patients with long-standing inflammation and diabetes mellitus, pancreatectomy with or without islet autotransplantation should be considered if the patient has a high level of concern about pancreatic cancer. (See 'Pancreatectomy' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David C Whitcomb, MD, PhD, who contributed to earlier versions of this topic review.