Hereditary pancreatitis

INTRODUCTION — Hereditary pancreatitis refers to pancreatitis with a Mendelian pattern of inheritance. The majority of cases are caused by pathogenic variants in the PRSS1 gene. This disorder has an autosomal dominant pattern of inheritance with high penetrance and causes acute recurrent and chronic pancreatitis in both children and adults. Other cases of hereditary pancreatitis are caused by variants in SPINK1 or other genes and occasionally by multiple genetic factors.

Issues related to hereditary pancreatitis will be reviewed here. Causes and management of other types of acute recurrent or chronic pancreatitis are discussed in other UpToDate 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 – Acute pancreatitis is a syndrome of sudden pancreatic inflammation, regardless of etiology.

●Acute recurrent or chronic pancreatitis – Approximately one-third of patients with acute pancreatitis develop recurrent acute pancreatitis, and of these, approximately one-third develop chronic pancreatitis. However, approximately 40 to 50 percent of patients with chronic pancreatitis do not have clinical evidence of previous acute pancreatitis [1]. In many cases, the etiology of acute recurrent or chronic pancreatitis is complex, reflecting the interplay of complex, polygenetic risk and gene-environment interactions. (See "Causes and contributing risk factors for chronic pancreatitis in children and adolescents" and "Etiology and pathogenesis of chronic pancreatitis in adults".)

●Hereditary pancreatitis – When acute recurrent or chronic pancreatitis occurs with an autosomal dominant pattern of inheritance, then a single-gene disorder with Mendelian inheritance is likely, and cases with this demographic have been termed hereditary pancreatitis. When caused by pathogenic variants in the PRSS1 gene, this disorder has high penetrance and causes recurrent acute and chronic pancreatitis in both children and adults.

The term hereditary pancreatitis has also been used to describe some rare recessive genetic disorders including homozygous SPINK1 variants with high penetrance within families or cystic fibrosis transmembrane conductance regulator (CFTR)-related disorders when they involve pathogenic CFTR variants. We generally restrict the term "hereditary pancreatitis" to patients with an autosomal dominant inheritance pattern, as in PRSS1 gain-of-function variants, and describe recessive patterns as "familial pancreatitis." (See 'Genetics' below.)

●Familial pancreatitis – Familial pancreatitis refers to pancreatitis from any cause that occurs in a family with an incidence that is greater than would be expected by chance alone, given the size of the family and the standardized incidence of pancreatitis within a defined population. Familial pancreatitis may or may not be caused by a genetic defect.

EPIDEMIOLOGY — The epidemiology of PRSS1-associated hereditary pancreatitis varies greatly between different cities, regions, countries, and ancestral groups, likely because of founder effects and migration patterns. Furthermore, the true incidence of acute pancreatitis, recurrent acute pancreatitis, and chronic pancreatitis is not known, since 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 acute pancreatitis in children [2] but up to 30 to 80 percent of children with acute recurrent or chronic pancreatitis, depending on the genes tested and ethnicity of the population. However, a subsequent single-center study found genetic etiology in 42 percent of children with the first attack of acute pancreatitis, and more than one genetic factor was identified in a substantial proportion of those with chronic pancreatitis [3]. Furthermore, genetic testing is typically not done in people diagnosed with alcohol-associated pancreatitis; however, a study from China suggests that major genetic variants for hereditary pancreatitis are present in nearly 40 percent of these individuals [4]. (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 chronic pancreatitis (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 (typically called "hereditary") pancreatitis – This is most often associated with gain-of-function variants in the PRSS1 gene on chromosome 7q35, which encodes trypsin-1 (cationic trypsinogen) [5-7]. Rarely, autosomal dominant-appearing hereditary pancreatitis is identified in a kindred that does not have an identifiable PRSS1 mutation [8-10]. (See 'PRSS1 gene' below.)

●Autosomal recessive (typically called "familial") pancreatitis – Chronic pancreatitis associated with cystic fibrosis (CF) is the most common example. Mutations in SPINK1 also may present in an autosomal recessive pattern. CFTR-associated disorders include chronic pancreatitis with minimal lung disease, and this trait may occur in multiple family members. (See 'CFTR gene' below.)

●Complex mechanisms – Multiple family members may have recurrent acute or chronic pancreatitis 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) [11,12] 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 (serine protease 1), which encodes cationic trypsinogen, are present in up to 80 percent of patients with autosomal dominant hereditary pancreatitis [13-18]. PRSS1 variants are also occasionally identified in cases of apparently idiopathic acute recurrent or chronic pancreatitis [19,20]. In two case series, approximately 10 percent of children with acute recurrent pancreatitis had a pathogenic PRSS1 variant [3,21]. (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 the major cause of pancreatic injury and immune system activation, leading to acute pancreatitis and later chronic pancreatitis. 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) [22].

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 hereditary 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 [6,7,13,17]. As an example, in a national series of 200 patients from 78 families with hereditary 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 [13]. The estimated prevalence of hereditary pancreatitis in this study was at least 0.3 per 100,000. A research website on chronic pancreatitis genetics maintains and updates a lists of the PRSS1 variants, among other genes, including functional studies to help classify the mutations [23]

The p.R122H and p.N291 variants have high penetrance (80 and 93 percent in two series) [13,24]. It remains unclear why some family members with these variants do not develop chronic pancreatitis. A possible contributing factor for the occasionally decreased penetrance of pancreatitis is the presence of variants that protect against the development of chronic pancreatitis. One such variant has been described in the PRSS2 gene (anionic trypsinogen), resulting in the loss of trypsin activity [25]. (See 'Genetic variants conferring protection from pancreatitis' below.)

Other kindreds carry pathogenic PRSS1 variants at different sites, and new variants continue to be described [19,26-30]. One type of pathogenic variant causes misfolding and intracellular retention of cationic trypsinogen, leading to chronic pancreatitis from the stress of an unfolded protein response [26], while a second stabilizes trypsinogen, protecting against autocatalytic degradation [27], and a third increases trypsin activation from trypsinogen [28]. 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 [31] and the United States [10]. The risk appears to be a dose-effect since decreased PRSS1 expression is associated with a reduced risk of pancreatitis [32].

Two synonymous variants in PRSS1 (p.Asp162= [rs6666] and p.Asn246= [rs6667]) are important because they are linked with a risk haplotype associated with chronic pancreatitis, especially in alcohol-drinking patients, known as the PRSS1-PRSS2 risk haplotype [32]. 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 to be more aggressive [33].

●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 [34,35]. 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 [14]. Thus, pathogenic variants in SPINK1 are of minimal consequence, unless there is premature and excessive activation of trypsin and inflammation. SPINK1 variants can cause familial 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 chronic pancreatitis 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) [36], but less than 1 percent of carriers develop pancreatitis [37]. Nonetheless, variants in SPINK1 increase the risk for chronic pancreatitis approximately 12-fold over the general population. In four series of patients with apparent idiopathic chronic pancreatitis, pathogenic variants in SPINK1 were detected in 15 to 23 percent [3,29,38,39]. In one of these reports, SPINK1 variants were more common in patients with idiopathic chronic pancreatitis or recurrent acute pancreatitis than in controls (19.5 versus 2.6 percent) [39]. 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 [40]. SPINK1 variants have been linked to idiopathic pancreatitis, alcoholic pancreatitis, familial pancreatitis, and tropical pancreatitis [41].

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 [41]. 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 [11,12].

CFTR gene — Pathogenic variants in the CFTR gene can cause pancreatitis with or without associated manifestations of CF. Over 2000 different genetic variants in CFTR have been identified, and disease manifestations depend on the severity of the variant and zygosity [42]. (See "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'Pancreatic disease'.)

The association between CFTR variants and pancreatitis falls into one of four patterns:

●CF – CF is an autosomal recessive genetic disorder caused by severe variants in the CFTR gene. The presence of two severe CFTR variants, such as F508del/F508del, results in minimal or absence of 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 chronic pancreatitis and pancreatic insufficiency early in life [43]. A primary and one of the earliest features of CF is development of chronic pancreatitis in utero, with progression to pancreatic exocrine insufficiency in infancy.

The diagnosis of CF requires documenting the presence of typical clinical features of CF, genetic analysis of the CFTR gene that is consistent with CF, and an abnormal sweat chloride test or equivalent [44]. The final diagnosis is a clinical one that should be made through a qualified CF center. In patients with CF, the risk of acute pancreatitis is linked with less severe CFTR variants, milder phenotype, and pancreatic sufficiency [45]. Although some CF patients have a much milder phenotype than others, it is now recommended that clinicians avoid the use of terms like classic/nonclassic CF, typical/atypical CF, and delayed CF because these terms have no consensus definition and the terms may be confusing for families or caregivers [44]. (See "Cystic fibrosis: Clinical manifestations and diagnosis".)

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) results in some retained CFTR function and milder or limited features of CF. Affected patients have normal or borderline sweat chloride testing but may have recurrent acute or chronic pancreatitis or congenital absence of the vas deferens and/or chronic sinusitis, especially if the variant specifically alters CFTR bicarbonate conductance. The risk for chronic pancreatitis is increased 40- to 80-fold over the general population [46]. The primary example is the CFTR p.R75Q variant (discussed below), which causes a selective defect in bicarbonate secretion but does not interfere with chloride secretion as seen in classic CF [11,47]. (See "Cystic fibrosis: Overview of gastrointestinal disease", section on 'Pancreatitis'.)

●CFTR-related disorder – CFTR-related disorder has been specifically defined as a monosymptomatic clinical entity (eg, congenital bilateral absence of the vas deferens/pancreatitis/bronchiectasis) associated with CFTR dysfunction [44]. 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 [48]. 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'.)

●CFTR-related pancreas-sinus-vas deferens syndrome – A new class of CFTR variants has been identified that causes selective deficiency in bicarbonate conductance (CFTR-BD) [49]. Subjects with at least one CFTR-BD variant had increased risk of recurrent acute pancreatitis and chronic pancreatitis but also male infertility and chronic sinusitis with minimal lung disease. The sweat chloride levels are normal or slightly abnormal. The nine variants were previously classified as variable (R117H) or benign (R74Q, R75Q, R170H, L967S, L997F, D1152H, S1235R, and D1270N) based on risk of CF lung disease. These patients therefore do not meet the criteria for CF (based on sweat chloride) or CFTR-related disorders (based on multiple organ involvement) and could be considered a CFTR-related syndrome. (See "Cystic fibrosis: Overview of gastrointestinal disease", section on 'Pancreatitis'.)

●CFTR-related pancreatitis – Associated with heterozygous pathogenic CFTR variants (ie, CF carriers) who have sweat chloride values <30 mmol/L and are therefore normal. The risk for chronic pancreatitis in this group is increased three- to fourfold over the general population, although 99 percent of the carriers are healthy [47,50,51]. Those who do develop chronic pancreatitis have a very high rate of coexisting SPINK1, CTRC, or more complex genotypes [11,12]. Heterozygous CFTR variants may also contribute to pancreatitis in the presence of pancreatic divisum [52,53].

Several studies have shown that carriage of one pathogenic CFTR variant, including uncommon and mild variants, is more common among patients with idiopathic chronic pancreatitis than among controls [43,50,54]. However, in studies of populations known to be CF carriers (eg, parents of patients with CF), the prevalence of chronic pancreatitis is only slightly increased [50,51,55]. In a longitudinal case series of children with acute pancreatitis, carriage of one pathogenic CFTR variant was associated with a greater risk for progression from acute to chronic pancreatitis [3]. 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 chronic pancreatitis, usually in conjunction with other heterogeneous pancreatitis susceptibility variants, such as CFTR or SPINK1 [12,56-59]. Chymotrypsin C is a digestive enzyme that cooperates with active trypsin in solutions with lower calcium concentrations to degrade trypsin [60]. Thus, it is an intrapancreatic antitrypsin protective mechanism that complements SPINK1. Several rare variants in CTRC have been linked with chronic pancreatitis in children [57-59], 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 chronic pancreatitis in adults, especially smokers [58].

Additional genes associated with acute recurrent and chronic pancreatitis — Two genes have been reported that are associated with chronic alcoholic pancreatitis and pediatric idiopathic chronic pancreatitis, 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 chronic pancreatitis, especially in patients with alcohol-related chronic pancreatitis [61-63]. It confers no or small risk of acute pancreatitis. Instead, these variants appear to accelerate progression from acute pancreatitis to chronic pancreatitis. The high-risk locus is on the X chromosome, with the haplotype-defining variant rs12688220 C in 26 percent of control alleles. Since men are hemizygous for the X chromosome, the risk appears dominant, whereas it is inherited as a recessive trait in women. If 16 percent of men and 10 percent of woman are at-risk alcohol drinkers, it suggests that 4 percent of men (0.16 x 0.26) are at high risk of alcoholic chronic pancreatitis, as compared with 0.7 percent of women (0.10 x 0.26 x 0.26).

●CPA1 gene – Carboxypeptidase A1, encoded by the CPA1 gene, is a pancreatic digestive enzyme that is second in abundance in pancreatic juice after trypsinogen. Variants in CPA1 are linked to nonalcoholic chronic pancreatitis, especially with early age of onset [64]. Risk of chronic pancreatitis 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 [64]. 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 chronic pancreatitis. 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 [65] or CPA1 p.K374E variants [66], 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 [67,68]. CEL has complex genetics in a region of DNA that is challenging to sequence, thereby limiting replication studies and genetic testing [67-70].

•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 [71,72]. The PNLIP gene (pancreatic lipase) has several variants associated with chronic pancreatitis, 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 [73].

•Variants in the GGT1 gene (gamma-glutamyltransferase 1) are associated with chronic pancreatitis [74] and pancreatic cancer [75]. This gene protects duct cells against oxidative stress. Variants in the UBR1 gene are associated with pancreatitis in Germany [76], 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 [77].

Other genetic variants continue to be described, although these are beyond the scope of this review.

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 [25,78]. 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 [32,61]. 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 autosomal dominant hereditary pancreatitis typically present clinically with recurrent acute pancreatitis in childhood or early adolescence, chronic pancreatitis in late adolescence or early adulthood, and an increased risk for pancreatic cancer beginning in the fifth decade of life. However, individuals who carry the PRSS1 variants p.N29I or p.R122H may have their index attack at any age between 1 year and >60 years of age.

The clinical presentation of patients with hereditary pancreatitis, familial pancreatitis, and sporadic pancreatitis with a strong genetic etiology (simplex case) can begin with episodes of acute pancreatitis or with chronic pancreatitis. The clinical features are similar to those seen in other causes of chronic pancreatitis 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 hereditary pancreatitis from 112 families in 14 European countries [8] and 200 patients with hereditary pancreatitis from 78 families in France [13]:

●The median ages at first symptom and diagnosis were 10 and 19 years, respectively [8,13]. Similar findings have been noted in other studies in which disease onset may be before age five [24,79]. The first symptoms occurred at a slightly older age in patients with N29I or without identified PRSS1 variants [8].

●In the French series, pancreatic pain, acute pancreatitis, and pseudocysts were present in 83, 69, and 23 percent, respectively, with pancreatic calcifications noted on radiologic examination in 61 percent [13].

●Exocrine pancreatic insufficiency eventually developed in 37 and 34 percent, respectively [8,13], and presented at a mean age of 29 years [13].

●Diabetes mellitus eventually developed in 48 and 26 percent, respectively [8,13], and presented at a mean age of 38 years [13]. 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) [80]. 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 autosomal dominant hereditary pancreatitis is recurrent acute pancreatitis [8,13,24,81,82]. After recovery from the acute episode, affected patients may remain well for a significant duration. Some patients may present with chronic pancreatitis without episodes of acute pancreatitis.

PANCREATIC CANCER

Cancer risk — Hereditary pancreatitis is associated with a significantly increased risk of pancreatic cancer, although hereditary pancreatitis patients account for a very small fraction of all cases of pancreatic cancer [8,13,83,84]. 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 [8,85]. A study from the United States, representing up to 20 years for prospective follow-up of the originally identified families with hereditary 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 [85]. 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 [8]. 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 hereditary 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) [83]. 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 hereditary 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 [13]. 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 hereditary pancreatitis, which is similar to the increase in risk in the general population [86]. However, among patients with hereditary 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 hereditary pancreatitis 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. Thus, we do not generally recommend radical prophylactic procedures such as total pancreatectomy.

Cancer screening — Several consensus panels have recommended screening for pancreatic cancer in individuals with hereditary pancreatitis [87-90]. 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 hereditary pancreatitis, since the morphology of the pancreatic gland is markedly altered by chronic pancreatitis. Nonetheless, these guidelines typically suggest initiating imaging surveillance starting at age 40 [90] or 50 [89].

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

DIAGNOSIS — The diagnosis of hereditary pancreatitis is based upon the clinical history and/or genetic testing in patients with idiopathic acute pancreatitis, recurrent acute pancreatitis, or chronic pancreatitis. Laboratory and radiographic testing are used as biomarkers to confirm pancreatic involvement and stage the disease as recurrent acute or chronic pancreatitis. Clinicians should recognize the autosomal dominant inheritance patterns that are typical of PRSS1 gain-of-function variants. Patients without a clear family history may initially be thought to have idiopathic pancreatitis [7], and genetic testing becomes the basis of diagnosis in symptomatic patients. (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'.)

Genetic testing — Genetic testing is medically necessary for the evaluation of patients with idiopathic acute pancreatitis, recurrent acute pancreatitis, and chronic pancreatitis after the major causes of acute pancreatitis, such as gallstone disease, heavy alcohol use, duct obstruction, and medications, have been excluded [91-93]. Genetic testing is also recommended for patients with clinical evidence of a pancreatitis-associated disorder or possible chronic pancreatitis in which the etiology is unclear, especially in younger patients, as outlined in a clinical guideline from the American College of Gastroenterology [94].

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. An overview of the issues to be addressed by genetic counselors has been published [95,96].

Symptomatic patients — Genetic testing for pancreatitis susceptibility genes should be performed in patients with pancreatitis and one or more of the following [36,95]:

●Episode of pancreatitis as a child that is well documented and otherwise unexplained

●Idiopathic chronic pancreatitis, particularly when the onset of pancreatitis occurs before 25 years of age

●A family history of recurrent acute pancreatitis, idiopathic chronic pancreatitis, or childhood pancreatitis without a known cause

●Relatives known to carry gene variants associated with hereditary pancreatitis (ie, PRSS1 variants)

●Recurrent attacks of acute pancreatitis for which there is no identifiable cause

●Possible chronic pancreatitis (ie, clinical evidence of chronic pancreatitis that does not meet diagnostic criteria), especially in younger patients

●Evidence of a pancreatitis-associated disorder (eg, male infertility or bronchiectasis)

●Patients eligible for approved research protocols

All patients in whom genetic testing is performed should be offered genetic counseling prior to and after testing [36,97,98].

●Testing for single gene defects – Genetic testing is most commonly limited to the PRSS1, SPINK1, CFTR, and CTRC genes, although 12-gene panels and more extensive analyses are now available. Interpretation is as follows:

•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 hereditary 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 [99]. 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.

•Genetic testing for CFTR variants is also indicated in patients with unexplained recurrent acute pancreatitis and chronic pancreatitis or those with signs/symptoms of a CFTR-related disorder. 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 [100-102].

•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 [71]. Patients with pathogenic SPINK1 variants typically have a more severe clinical course compared with those with other causes of recurrent acute pancreatitis and a more rapid progression from recurrent acute to chronic pancreatitis [3,103]. 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'.)

●Pancreatitis from multiple genetic and environmental risks – Only a minority of patients with unexplained pancreatitis have Mendelian genetic syndromes that are adequately explained by pathogenic genetic variants such as a 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. 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 [104]. 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 chronic pancreatitis [105]. 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.

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 individuals under 16 years of age [95]. If a family carries a known pathogenic variant, negative test results in a family member essentially eliminate the risk of hereditary pancreatitis in that individual [106]. 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 [107].

By contrast, predictive testing of SPINK1 or CFTR variants in presymptomatic individuals is of minimal value because pathogenic variants are common and most patients with these variants do not develop disease [36].

MANAGEMENT — Management of hereditary pancreatitis follows many of the principles for chronic pancreatitis of other causes. (See "Chronic pancreatitis: Management".)

Avoidance of alcohol and tobacco — Among patients with hereditary pancreatitis (eg, the PRSS1 variants p.R122H, p.N29I), several environmental triggers have been associated with exacerbations, including alcohol abuse, emotional stress, and dietary fat [13,82]. There is no known quantity of alcohol that is safe for patients with hereditary pancreatitis, so patients are typically counseled to abstain from consuming any alcoholic beverages. In addition, smoking is a strong independent risk factor for chronic pancreatitis [108,109] and increases the risk of pancreatic cancer [86]. Thus, patients with hereditary pancreatitis, members of affected families, and individuals in whom a specific pathogenic PRSS1 variant has been identified should be counseled to avoid these triggers.

Patients with recurrent acute and chronic pancreatitis are also at greater risk of progressing to end-stage chronic pancreatitis in conjunction with alcohol and tobacco use if they have risk variants in the CLDN2 gene locus, the high-risk PRSS1-PRSS2 haplotype, or CTRC p.G60G risk haplotypes [32,58]. Identification of these variants should be included in counseling since these patients should abstain from both alcohol and smoking for life. (See 'Genetics' above.)

Antioxidants and analgesics — One two-year crossover study of antioxidants and analgesics in three children from the same Italian hereditary pancreatitis family suggested significant improvement in pain with the antioxidants [110]. We have observed similar improvement in a subset of patients with nonalcoholic pancreatitis [111], although the components, dose, and frequency have not been standardized. Antioxidants have also been found to be useful in a cohort of patients from India, where the prevalence of the SPINK1 p.N34S haplotype is high, although the cohort was not genotyped [112].

Pancreatic surgery — A small study from Austria reported the outcomes of 12 pediatric patients aged 4 to 15 years with hereditary pancreatitis who were managed with a step-up approach of endoscopic retrograde cholangiopancreatogram (ERCP), followed by surgery when necessary [113]. The etiology included SPINK1, CFTR, and PRSS1 variants, and some children had no pathogenic variants. Patients underwent early ERCP for management of pain. Obstructive etiologies were identified in 10 patients, and 8 patients were successfully treated endoscopically, with both pain control and elimination of recurrent acute pancreatitis. Two patients underwent surgical drainage procedures because of technical failure of the ERCP. Overall, good pain control was achieved using the step-up approach. While this is a very small and highly heterogeneous group for a clinical study, this report suggests that endoscopic therapy may play an important role in selected patients with hereditary pancreatitis caused by obstructions.

Pancreatectomy

●Pancreatectomy with islet autotransplantation – We generally offer pancreatectomy with islet autotransplantation for younger patients with severe features of recurrent acute or chronic pancreatitis. The typical candidate is a child with an established genetic cause for chronic pancreatitis (a pathogenic PRSS1 variant or multiple SPINK1 variants), severe pain leading to narcotic dependence, and residual islet cell function. However, there is ongoing debate about the use of this procedure for chronic pancreatitis, patient selection, and timing. The optimal timing for this procedure requires consideration of the disability of the patient from pancreatitis, the exclusion of treatable etiologies, prognosis, and islet cell mass. Earlier surgery may provide more islets and diminish months of suffering, but the procedure is also irreversible, is associated with uncommon but serious risk, and commits the patient to a lifetime of full-dose pancreatic enzyme replacement therapy. Furthermore, the long-term survival of islets and consequences of islets in the liver are not fully defined, and the clock begins as soon as the procedure is performed. (See "Surgery for chronic pancreatitis", section on 'Diffuse parenchymal disease'.)

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 [114,115]. 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 [116]. 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 [117]. These outcomes are generally better than in series of adults undergoing the same procedure [114,115].

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 recurrent acute pancreatitis or painful chronic pancreatitis, and these produced recommendations for follow-up of these patients [118,119].

●Pancreatectomy without islet transplantation – Older patients with long-standing chronic pancreatitis (eg, those who have had chronic pancreatitis for 20 years or more) are occasionally candidates for total pancreatectomy 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 [87]. Islet autotransplantation is not done in patients with long-standing chronic pancreatitis in some centers, because of precancerous lesions and potential cancers [120], and there is concern that these malignant cells may be reinfused with the islets. Furthermore, the potential benefit of islet autotransplantation is limited if the patient has marked fibrosis or is already diabetic. However, other centers have performed islet autotransplantation on these patients, and no cases of pancreatic cancer development have yet been reported [121].

A patient's level of concern about pancreatic cancer varies substantially. A high level of patient concern may outweigh the risk and expense of performing a total pancreatectomy. Thus, the decision as to whether or not to perform total pancreatectomy in these older patients should be individualized, depending on the patient's values and preferences and particularly their level of concern about pancreatic cancer. However, note that more recent data suggest that the incidence of cancer up to age 70 in these patients is likely lower than previously estimated, well below 10 percent [85]. (See "Chronic pancreatitis: Management", section on 'Surgical resection'.)

PROGNOSIS — The mortality rate compared with the general population is significantly increased in patients with hereditary pancreatitis who develop pancreatic cancer [122]. 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 hereditary 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 alcoholic pancreatitis. (See 'Genetics' above.)

●Clinical presentation – Most patients with PRSS1-associated hereditary pancreatitis present before 20 years of age with recurrent acute or chronic pancreatitis. Approximately one-third of patients progress to develop pancreatic insufficiency and/or diabetes mellitus. Affected individuals have a markedly 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 for hereditary pancreatitis include:

•Unexplained pancreatitis in a child

•Unexplained recurrent acute or chronic pancreatitis in older individuals

•Pancreatitis in a patient with a family history that suggests hereditary pancreatitis

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

•Possible chronic pancreatitis (ie, clinical evidence of chronic pancreatitis that does not meet diagnostic criteria) in which the etiology is unclear, especially in younger patients

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 'Symptomatic patients' above.)

●Asymptomatic patients – For children under age 16 with a family history of chronic pancreatitis 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 chronic pancreatitis. However, CFTR variant carriers may also be at increased risk for a variety of other disorders as well. (See 'Asymptomatic patients' above and 'CFTR gene' above.)

●Management of chronic pancreatitis

•Supportive care – Patients with hereditary pancreatitis should exercise, focus on a healthy lifestyle, take multivitamins and antioxidants, and avoid consuming alcohol and smoking cigarettes. Management of hereditary pancreatitis is otherwise similar to that for other causes of acute and chronic pancreatitis. (See 'Management' above and "Chronic pancreatitis: Management".)

•Pancreatectomy – In children or adults with severe pain and opioid addiction due to chronic pancreatitis, 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 – Hereditary pancreatitis 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 hereditary pancreatitis, 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.