Clinical characteristics.

PRSS1-related hereditary pancreatitis (HP) is characterized by episodes of acute pancreatitis (AP) and recurrent acute pancreatitis (RAP: >1 episode of AP), with frequent progression to chronic pancreatitis (CP). Manifestations of acute pancreatitis can range from vague abdominal pain lasting one to three days to severe abdominal pain lasting days to weeks and requiring hospitalization.

Diagnosis/testing.

The diagnosis of PRSS1-related hereditary pancreatitis is established in a proband with episodes of AP, RAP, and/or CP and a heterozygous pathogenic gain-of-function variant in PRSS1 identified by molecular genetic testing. Note that, because of incomplete penetrance, identification of a disease-associated PRSS1 variant in an asymptomatic individual is not sufficient for a clinical diagnosis.

High-penetrance PRSS1 pathogenic variants include p.Asn29Ile and p.Arg122His, and lower-penetrance pathogenic variants include p.Arg16Val and p.Arg122Cys. Other pathogenic PRSS1 variants are recognized; these latter variants typically require additional risk factors to cause disease and do not cause autosomal dominant hereditary pancreatitis.

Management.

Treatment of manifestations: AP episodes are treated with rapid assessment of severity and fluid resuscitation as needed. Individuals with HP should be counseled not to delay in being assessed for AP since hypovolemia and shock leads to serious organ dysfunction and failure. For chronic pancreatitis, continue strategies to prevent RAP attacks. Antioxidants may have some benefit. Pancreatic enzyme replacement therapy to improve digestion in those with pancreatic insufficiency and bloating, steatorrhea, diarrhea, unexplained weight loss, and/or micronutrient deficiencies (e.g., vitamins A, D, B₁₂); treatment of glucose intolerance with a regimen typically including metformin. Management of pain can be challenging but should begin with medical therapy, with endoscopic therapies for obstructions and surgery for more severe pain – including total pancreatectomy with islet autotransplantation in selected individuals.

Prevention of primary manifestations: Avoid smoking, alcohol abuse. Recommended: a healthy diet that is low in red meat, multiple small meals if it improves symptoms, good hydration (especially during exercise), vitamins, and antioxidants. Some individuals report that moderate exercise helps control episodes of pain and reduce pain severity.

Surveillance: Referral to a surveillance program.

Agents/circumstances to avoid: Alcohol and tobacco use; dehydration; physical and emotional stress.

Evaluation of relatives at risk: Molecular genetic testing for the family-specific germline PRSS1 pathogenic variant to allow early diagnosis and prevention and/or management of symptoms.

Genetic counseling.

HP caused by gain-of-function PRSS1 pathogenic variants is inherited in an autosomal dominant manner. The proportion of PRSS1-related HP caused by a de novo pathogenic variant is unknown. Each child of an individual with autosomal dominant PRSS1-related HP has a 50% chance of inheriting the variant. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant of an affected family member has been identified. A number of other variants in the coding and noncoding regions of the PRSS1 locus are associated with risk for pancreatitis, but they typically do not cause autosomal dominant hereditary pancreatitis.

Suggestive Findings

PRSS1-related HP should be suspected in individuals with the following:

• Acute pancreatitis occurring in childhood
• Recurrent acute attacks of pancreatitis of unknown cause
• Chronic pancreatitis of unknown cause, particularly with onset before age 25 years
• A family history of recurrent acute pancreatitis, chronic pancreatitis, and/or childhood pancreatitis consistent with autosomal dominant inheritance
• A family history of pancreatitis, diabetes mellitus, or pancreatic cancer

Acute pancreatitis (AP) is characterized by sudden onset of typical epigastric abdominal pain that may radiate to the back, serum pancreatic digestive enzymes (e.g., amylase, lipase) that are more than threefold the upper limits of normal, and/or characteristic findings of pancreatic inflammation on abdominal imaging [Banks et al 2013].

Recurrent acute pancreatitis (RAP) is defined as a syndrome of multiple distinct acute inflammatory responses originating within the pancreas in individuals with genetic, environmental, traumatic, morphologic, metabolic, biologic, and/or other risk factors who experienced two or more episodes of documented acute pancreatitis, separated by at least three months [Guda et al 2018].

Chronic pancreatitis (CP) is defined as a pathologic fibro-inflammatory syndrome of the pancreas in individuals with genetic, environmental, and/or other risk factors who develop persistent pathologic responses to parenchymal injury or stress [Whitcomb et al 2016]. The features of established and advanced chronic pancreatitis include pancreatic atrophy, fibrosis, pain syndromes, duct distortion and strictures, and calcifications; pancreatic exocrine dysfunction; and pancreatic endocrine dysfunction and dysplasia [Whitcomb et al 2016].

Establishing the Diagnosis

The diagnosis of PRSS1-related HP is established in a proband by identification of a heterozygous pathogenic (or likely pathogenic) variant in PRSS1 by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous PRSS1 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of single-gene testing or use of a multigene panel:

• Single-gene testing. Sequence analysis of PRSS1 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
• A multigene panel that includes PRSS1 and other genes of interest (see Differential Diagnosis) may also be considered to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

In PRSS1-related hereditary pancreatitis (HP) the range of symptoms and disease course vary from person to person. On average, acute pancreatitis occurs by age ten years, chronic pancreatitis by age 20 years, and the incidence of pancreatic cancer rises at age 50 years.

Acute pancreatitis (sudden onset; duration <6 months) can be mild, moderate, or severe, depending on the local and systemic complications [Banks et al 2013]. Findings can range from vague abdominal pain lasting three to four days to sudden onset of severe upper abdominal pain radiating to the back with nausea, vomiting, orthostatic hypotension, confusion, and shortness of breath. Mild cases typically require one to two days of hospitalization. Severe cases may require intensive care management, result in prolonged hospitalization, and/or require six months or more to recover.

Persons with a PRSS1-related HP may also have other risk factors for pancreatitis, such as gallstones, alcohol consumption, smoking, and/or pathogenic variants in other pancreatitis-associated genes. Of note, persons with hereditary pancreatitis report that even small amounts of alcohol may sometimes trigger episodes of pain or acute pancreatitis.

Chronic pancreatitis. Approximately half of individuals with PRSS1-related HP progress to chronic inflammation and/or irreversible morphologic changes classified as chronic pancreatitis (CP). The characteristics of CP include variable features of pancreatic atrophy, fibrosis, pain, duct distortion and strictures, and calcifications; pancreatic exocrine dysfunction; and pancreatic endocrine dysfunction and dysplasia [Whitcomb et al 2016].

Long-standing inflammation results in complications that can include the following:

• Episodic or continuous mild-to-severe abdominal pain. Pain is usually sharp and stabbing in initial attacks, becoming deep and burning as the syndrome progresses. The most psychologically distressing pain is constant chronic pain, regardless of intensity [Machicado et al 2017].
• Exocrine pancreatic insufficiency leading to maldigestion with symptoms of gas and bloating and the appearance of diarrhea, oil in the stool (steatorrhea), and/or floating stools. Other signs of maldigestion include weight loss, fat-soluble-vitamin deficiency, and protein deficiency with low albumin, prealbumin, or retinol-binding protein detected on blood testing.
• Pancreatic endocrine insufficiency manifesting initially as inappropriately elevated levels of blood glucose (glucose intolerance). Up to 48% of persons with PRSS1-related HP develop diabetes mellitus [Howes et al 2004, Rebours et al 2009], which is similar to the rates in other types of chronic pancreatitis [Bellin et al 2017]. Type 3c diabetes mellitus (pancreatogenic diabetes mellitus) is caused by loss of pancreatic tissue as a result of surgery or chronic pancreatitis; type 3c is associated with loss of both the insulin-producing beta cells and the glucagon-producing alpha cells, which results in loss of counter-regulatory hormones and risk of hypoglycemia. It is not clear what percentage of individuals with pancreatitis and diabetes have complete loss of islet cells versus beta cell dysfunction and/or peripheral insulin resistance as in typical type 2 diabetes mellitus.

Pancreatic cancer. Chronic inflammation of the pancreas is associated with an increased risk for pancreatic cancer. Persons with HP are at increased risk for pancreatic cancer because the onset of chronic pancreatitis is 20-30 years earlier than in the general population [Rebours et al 2008]. The risk of developing pancreatic cancer by age 70 years was reported to be 18.8%-40%, but a more recent study suggested that the cumulative risk of pancreatic cancer in individuals with PRSS1-related HP by age 70 years is 7.2% [Zhan et al 2018].

Genotype-Phenotype Correlations

Four gain-of-function PRSS1 variants have been associated with autosomal dominant hereditary pancreatitis. These include high-penetrance PRSS1 pathogenic variants p.Asn29Ile and p.Arg122His and lower-penetrance pathogenic variants p.Ala16Val and p.Arg122Cys. Other PRSS1 variants have been associated with disease, but typically require additional risk factors to cause disease and do not segregate as autosomal dominant hereditary pancreatitis.

Penetrance

The reported penetrance of PRSS1-related HP varies:

• 40% in Spain for p.Arg122Cys [de las Heras-Castaño et al 2009]
• 43% in Europe for p.Ala16Val [Grocock et al 2010]
• 80% in the US for p.Asn29Ile and p.Arg122His [Sossenheimer et al 1997]
• 93% in France for p.Asn29Ile and p.Arg122His [Rebours et al 2009]
• 80% [Sibert 1978] to 96% in England [Howes et al 2004] for p.Asn29Ile and p.Arg122His

The median age for diagnosis of pancreatitis in a large multifamily US cohort was seven years (IQR 3-16; range <1-73) [Shelton et al 2018].

Nomenclature

In some instances, PRSS1-related hereditary pancreatitis has been described as chronic calcific pancreatitis, familial pancreatitis, or recurrent or relapsing acute or chronic pancreatitis; however, these are clinical diagnoses and do not describe the molecular basis of the disorder.

Prevalence

A report from France estimated a population prevalence of 0.3:100,000 persons with PRSS1-related hereditary pancreatitis [Rebours et al 2009].

PRSS1-related HP is found at highly variable rates in different populations of individuals with chronic pancreatitis.

In Germany 5.0% of individuals with chronic pancreatitis had PRSS1 pathogenic variants p.Asn29Ile or p.Arg122His; additional reported variants included p.Ala16Val (2.1%), p.Arg122Cys (0.8%), and other rare variants [Rosendahl et al 2013].

In Denmark, of 12.4% of persons initially classified as having idiopathic acute and chronic pancreatitis, 9% were found to have a PRSS1 pathogenic variant (1% of all individuals with pancreatitis) [Joergensen et al 2010].

In Spain, 7.7% of individuals with chronic pancreatitis had PRSS1 pathogenic variant p.Asn29Ile [Mora et al 2009].

In the North American Pancreatitis Study II about 5% of individuals had PRSS1 variants [Phillips et al 2018].

Among children with pancreatitis, the incidence of PRSS1 pathogenic variants varies: Poland 9.6% [Sobczyńska-Tomaszewska et al 2006], Mexico 1.1% [Sánchez-Ramírez et al 2012], China 9.3% [Wang et al 2013], and Korea 9.6% [Cho et al 2016]. In India, PRSS1 variants are rare [Chandak et al 2004, Poddar et al 2017].

In the INSPPIRE cohort of 301 children primarily from the United States, 17% of individuals with recurrent acute pancreatitis and 46% of children with chronic pancreatitis had a PRSS1 pathogenic variant [Kumar et al 2016]. Furthermore, the children with a PRSS1 pathogenic variant had a younger age of onset than children with CP of other etiologies [Giefer et al 2017].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with PRSS1-related hereditary pancreatitis (HP), the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Referral to a gastroenterologist for evaluation of pancreatic exocrine function using invasive or noninvasive testing
  • Fecal elastase-1 analysis. It can be falsely positive with diarrhea but can be used while an individual is taking pancreatic enzyme replacement therapy. The test is insensitive for mild pancreatic exocrine insufficiency.
  • Secretin-stimulated pancreatic bicarbonate secretion testing, which requires intubation of the duodenum and careful measure of pancreatic bicarbonate secretion over about an hour (depending on the method). It is considered very sensitive, but only assesses duct function.
  • Cholecystokinin (CCK) and its analogs (e.g., CCK-8) or receptor agonists (e.g., cerulean); have also been used to assess acinar cell function.
  • Serum trypsinogen levels to measure pancreatic acinar cell mass [Couper et al 1995]. Levels are useful if the individual is not experiencing pain and/or an acute pancreatitis flair, as levels will be increased along with amylase and lipase [Pezzilli et al 2000].
• Diffusion-weighted MRI. Various "functional" tests have been advocated using abdominal imaging techniques, including secretin-stimulated MRI. Although diffusion-weighted MRI is probably better at detecting the structural changes of chronic pancreatitis than standard MRI [Akisik et al 2009], it does not measure function, and fluid volume cannot measure bicarbonate output.
• Referral to an endocrinologist for evaluation of pancreatic endocrine function (i.e., assessment of glucose tolerance)
• Referral to a pancreatic cancer surveillance program in persons with chronic pancreatitis and/or risk factors for pancreatic cancer (e.g., age >40 years, family history of pancreatic cancer, history of smoking)
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Medical treatment and management for PRSS1-related HP are similar to those for non-hereditary pancreatitis.

Prevention of Primary Manifestations

The ability to prevent the primary manifestations of PRSS1-related HP is limited. The following recommendations are for individuals with (or at risk for) PRSS1-related HP. Following these recommendations from early childhood may help prevent attacks of acute pancreatitis:

• Low-fat diet. No formal guidelines for amount of dietary fat exist; however, some physicians recommend a low-fat diet to minimize pancreatic stimulation. If a low-fat diet is chosen, extra attention to providing fat-soluble vitamins (A, D, E, K) is needed.
• Multiple small meals. No evidence-based guidelines exist; however, small meals may minimize pancreatic exocrine stimulation.
• Good hydration. Maintaining good hydration may be helpful in minimizing attacks, especially since nausea, vomiting, and loss of appetite limit oral intake during an attack. Recognition of acute pancreatitis and prompt medical treatment with adequate intravenous hydration can be beneficial in decreasing the severity of the attack [de-Madaria et al 2018].
• Antioxidants. One small study suggested that antioxidants may be useful in reducing the likelihood of acute pancreatitis in persons at risk for hereditary pancreatitis [Uomo et al 2001].
• Exercise, yoga, and other relaxation techniques may increase quality of life in persons with pancreatitis [Sareen et al 2007]. Some individuals report that regular exercise, such as running, helps reduce the frequency of episodes of pancreatitis [Authors, unpublished].

Surveillance

Surveillance for pancreatic cancer may benefit individuals with PRSS1-related HP age 40 years and older who have long-standing chronic pancreatitis and a strong family history of pancreatic cancer [Chang et al 2014]. Because long-standing chronic pancreatitis results in pancreatic scarring and fibrosis that make assessment of abnormalities difficult [Ulrich 2001, Brand et al 2007], it is recommended that concerned individuals be referred to a surveillance program that includes biomarker research and other new techniques.

Agents/Circumstances to Avoid

Alcohol and tobacco. Smoking doubles the risk for all forms of pancreatitis, including hereditary pancreatitis [Maisonneuve et al 2005, Yadav et al 2009]. In combination, smoking and alcohol use increases the risk of developing pancreatitis eightfold [Yadav et al 2009]. Tobacco use also doubles the risk of pancreatic cancer and is associated with earlier-onset pancreatic cancer [Lowenfels et al 2001].

Dehydration worsens episodes of acute pancreatitis, and in severe cases can contribute to complications such as acute kidney injury and cardiovascular shock.

Physical and emotional stresses aggravate pancreatitis [Applebaum et al 2000]. Avoiding these stressors in individuals with PRSS1-related HP may prevent or delay worsening of symptoms and progression of disease.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by molecular genetic testing for the PRSS1 pathogenic variant in the family in order to identify as early as possible those who would benefit from screening for pancreatic exocrine and endocrine dysfunction.

Note: Predictive testing of children is appropriate in families with early-onset symptoms (i.e., onset age <25 years). In families with onset at or later than age 25 years, predictive genetic testing of asymptomatic children younger than age 16 years is not thought to be of medical benefit [Ellis et al 2001].

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

A recognition of the need for new treatments and the challenges in developing classic pharmaceutical trials for rare diseases led to an NIH workshop during PancreasFest 2018 [Abbruzzese et al 2018, Abu-El-Haija et al 2018, Forsmark et al 2018, Lowe et al 2018, Uc et al 2018].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Hereditary pancreatitis (HP) caused by gain-of-function PRSS1 pathogenic variants is inherited in an autosomal dominant manner (see Genotype-Phenotype Correlations).

Note: A number of other variants in the coding and noncoding regions of the PRSS1 locus are associated with a risk of pancreatitis, but they typically do not cause autosomal dominant hereditary pancreatitis.

Risk to Family Members

Parents of a proband

• Many individuals diagnosed with PRSS1-related HP have an affected parent.
• A proband with PRSS1-related HP may have the disorder as the result of a de novo pathogenic variant. Because simplex cases (i.e., a single occurrence in a family) have not been evaluated sufficiently to determine if the variant was de novo, the proportion of PRSS1-related hereditary pancreatitis caused by de novo pathogenic variants is unknown.
• Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include molecular genetic testing for the PRSS1 variant identified in the proband. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent.
• Although most individuals diagnosed with PRSS1-related HP have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed on the parents of the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is affected or has a PRSS1 pathogenic variant, the risk to the sibs of inheriting the variant is 50%. However, sibs who inherit a PRSS1 pathogenic variant may not develop pancreatitis because of reduced penetrance (penetrance of PRSS1 varies; see Penetrance).
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the PRSS1 pathogenic variant but are clinically unaffected, sibs of a proband are still at increased risk for PRSS1-related hereditary pancreatitis because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with PRSS1-related hereditary pancreatitis has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected, the parent's family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Prenatal Testing and Preimplantation Genetic Testing

Once the PRSS1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for PRSS1-related hereditary pancreatitis are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Introduction. Three trypsinogens are synthesized by the pancreas as digestive enzymes [Whitcomb & Lowe 2007]:

• Cationic trypsinogen (2/3s of trypsinogens) encoded by PRSS1
• Anionic trypsinogen (1/3 of trypsinogens) encoded by PRSS2
• Mesotrypsinogen (<5% of trypsinogens) encoded by PRSS3

Trypsinogens are expressed as a pre-propeptide that is processed to trypsinogen by cleavage of a signal peptide. Trypsinogen is activated to trypsin by cleavage of an eight-amino acid trypsinogen activation peptide (TAP), which is typically initiated in the intestine by the action of enterokinase. The TAP can also be cleaved by trypsin in the presence of calcium and association with a binding site formed in the activation region. Trypsin is an endopeptidase that cleaves peptide chains following an arginine or lysine residue that also serves as the master activator of pancreatic zymogens by cleaving the activation peptide of most major digestive enzymes made by the pancreas.

Trypsinogen has a second calcium-binding site that persists in trypsin which, when occupied by calcium, prevents trypsin autolysis at p.Arg122 and degradation by chymotrypsin C (CTRC) binding at p.Leu81 [Szmola & Sahin-Toth 2007].

Gain-of-function variants increase conversion of trypsinogen to active trypsin, or reduce the degradation of active trypsin; thus, the amount of active, intrapancreatic trypsin is increased. Active intrapancreatic trypsin may activate other zymogens (preactivated digestive enzymes), cross-activate the immune system, and/or cause direct injury [Whitcomb 2004].

The effect of premature trypsin activation may be accentuated by loss of function in modifier genes including the genes encoding the following proteins [Chen & Ferec 2009, Whitcomb 2010]:

• Pancreatic secretory trypsin inhibitor (encoded by SPINK1)
• Chymotrypsin C (CTRC)
• Calcium-sensing receptor (CASR)
• Cystic fibrosis transmembrane conductance regulator (CFTR)

This suggestion is based on the observation that the non-PRSS1 variants are seen as part of a complex genotype more often than would be expected by chance alone.

Mechanism of disease causation. PRSS1 variants associated with disease are gain-of-function variants. Gain-of-function variants have altered regulation leading to enhanced activation or delayed/impaired inactivation. Four gain-of-function variants (see Table 3) have been associated with Mendelian inheritance.

PRSS1-specific laboratory considerations. Other disease-associated PRSS1 variants cause protein misfolding, leading to endoplasmic reticulum stress [Schnúr et al 2014]. However, the damaging effects do not appear to be sufficient to cause recurrent acute pancreatitis and chronic pancreatitis in most individuals, suggesting that additional risk factors are necessary. A common PRSS1-PRSS2 haplotype appears to affect PRSS1 expression and modify risk of pancreatitis from other factors, including alcohol [Whitcomb et al 2012, Avanthi et al 2015, Derikx et al 2015].

Copy number variants, including duplication of PRSS1 and gene conversion between PRSS1 and PRSS2, have been reported in affected individuals [Masson et al 2008a].

Revision History

• 25 April 2019 (sw) Comprehensive update posted live
• 1 March 2012 (me) Review posted live
• 5 August 2011 (ss) Initial submission

Published Guidelines / Consensus Statements

• Ellis I, Lerch MM, Whitcomb DC; Consensus Committees of the European Registry of Hereditary Pancreatic Diseases, Midwest Multi-Center Pancreatic Study Group, International Association of Pancreatology. Genetic testing for hereditary pancreatitis: guidelines for indications, counseling, consent and privacy issues. Pancreatology. 2001;1:405-15. [PubMed]
• Fink EN, Kant JA, Whitcomb DC (2007) Genetic counseling for nonsyndromic pancreatitis. Gastroenterol Clin North Am. 36:325-33. [PubMed]

Literature Cited

• Abbruzzese JL, Andersen DK, Borrebaeck CAK, Chari ST, Costello E, Cruz-Monserrate Z, Eibl G, Engleman EG, Fisher WE, Habtezion A, Kim SK, Korc M, Logsdon C, Lyssiotis CA, Pandol SJ, Rustgi A, Wolfe BM, Zheng L, Powers AC. The interface of pancreatic cancer with diabetes, obesity, and inflammation: research gaps and opportunities: summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop. Pancreas. 2018;47:516–25. [PMC free article: PMC6361376] [PubMed: 29702529]
• Abu-El-Haija M, Gukovskaya AS, Andersen DK, Gardner TB, Hegyi P, Pandol SJ, Papachristou GI, Saluja AK, Singh VK, Uc A, Wu BU. Accelerating the drug delivery pipeline for acute and chronic pancreatitis: summary of the Working Group on Drug Development and Trials in Acute Pancreatitis at the National Institute of Diabetes and Digestive and Kidney Diseases Workshop. Pancreas. 2018;47:1185–92. [PMC free article: PMC6692135] [PubMed: 30325856]
• Akisik MF, Aisen AM, Sandrasegaran K, Jennings SG, Lin C, Sherman S, Lin JA, Rydberg M. Assessment of chronic pancreatitis: utility of diffusion-weighted MR imaging with secretin enhancement. Radiology. 2009;250:103–9. [PubMed: 19001148]
• Anderson MA, Akshintala V, Albers KM, Amann ST, Belfer I, Brand R, Chari S, Cote G, Davis BM, Frulloni L, Gelrud A, Guda N, Humar A, Liddle RA, Slivka A, Gupta RS, Szigethy E, Talluri J, Wassef W, Wilcox CM, Windsor J, Yadav D, Whitcomb DC. Mechanism, assessment and management of pain in chronic pancreatitis: recommendations of a multidisciplinary study group. Pancreatology. 2016;16:83–94. [PMC free article: PMC4761301] [PubMed: 26620965]
• Applebaum SE, Kant JA, Whitcomb DC, Ellis IH. Genetic testing: counseling, laboratory and regulatory issues and the EUROPAC protocol for ethical research in multi-center studies of inherited pancreatic diseases. Med Clin N Am. 2000;84:575–88. [PubMed: 10872415]
• Avanthi SU, Ravi Kanth VV, Agarwal J, Lakhtakia S, Gangineni K, Rao GV, Reddy DN, Talukdar R. Association of claudin2 and PRSS1-PRSS2 polymorphisms with idiopathic recurrent acute and chronic pancreatitis: a case-control study from India. J Gastroenterol Hepatol. 2015;30:1796–801. [PubMed: 26110235]
• Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG, Tsiotos GG, Vege SS, et al. Classification of acute pancreatitis--2012: revision of the Atlanta classification and definitions by international consensus. Gut. 2013;62:102–11. [PubMed: 23100216]
• Bellin MD, Carlson AM, Kobayashi T, Gruessner AC, Hering BJ, Moran A, Sutherland DE. Outcome after pancreatectomy and islet autotransplantation in a pediatric population. J Pediatr Gastroenterol Nutr. 2008;47:37–44. [PubMed: 18607267]
• Bellin MD, Freeman ML, Gelrud A, Slivka A, Clavel A, Humar A, Schwarzenberg SJ, Lowe ME, Rickels MR, Whitcomb DC, Matthews JB, Amann S, Andersen DK, Anderson MA, Baillie J, Block G, Brand R, Chari S, Cook M, Cote GA, Dunn T, Frulloni L, Greer JB, Hollingsworth MA, Kim KM, Larson A, Lerch MM, Lin T, Muniraj T, Robertson RP, Sclair S, Singh S, Stopczynski R, Toledo FG, Wilcox CM, Windsor J, Yadav D, et al. Total pancreatectomy and islet autotransplantation in chronic pancreatitis: recommendations from PancreasFest. Pancreatology. 2014;14:27–35. [PMC free article: PMC4058640] [PubMed: 24555976]
• Bellin MD, Prokhoda P, Hodges JS, Schwarzenberg SJ, Freeman ML, Dunn TB, Wilhelm JJ, Pruett TL, Kirchner VA, Beilman GJ, Chinnakotla S. Age and disease duration impact outcomes of total pancreatectomy and islet autotransplant for PRSS1 hereditary pancreatitis. Pancreas. 2018;47:466–70. [PubMed: 29517634]
• Bellin MD, Whitcomb DC, Abberbock J, Sherman S, Sandhu BS, Gardner TB, Anderson MA, Lewis MD, Alkaade S, Singh VK, Baillie J, Banks PA, Conwell D, Cote GA, Guda NM, Muniraj T, Tang G, Brand RE, Gelrud A, Amann ST, Forsmark CE, Wilcox CM, Slivka A, Yadav D. Patient and disease characteristics associated with the presence of diabetes mellitus in adults with chronic pancreatitis in the United States. Am J Gastroenterol. 2017;112:1457–65. [PMC free article: PMC6168293] [PubMed: 28741615]
• Brand RE, Lerch MM, Rubinstein WS, Neoptolemos JP, Whitcomb DC, Hruban RH, Brentnall TA, Lynch HT, Canto MI, et al. Advances in counselling and surveillance of patients at risk for pancreatic cancer. Gut. 2007;56:1460–9. [PMC free article: PMC2000231] [PubMed: 17872573]
• Burton F, Alkaade S, Collins D, Muddana V, Slivka A, Brand RE, Gelrud A, Banks PA, Sherman S, Anderson MA, Romagnuolo J, Lawrence C, Baillie J, Gardner TB, Lewis MD, Amann ST, Lieb JG 2nd, O'Connell M, Kennard ED, Yadav D, Whitcomb DC, Forsmark CE, et al. Use and perceived effectiveness of non-analgesic medical therapies for chronic pancreatitis in the United States. Aliment Pharmacol Ther. 2011;33:149–59. [PMC free article: PMC3142582] [PubMed: 21083584]
• Chandak GR, Idris MM, Reddy DN, Mani KR, Bhaskar S, Rao GV, Singh L. Absence of PRSS1 mutations and association of SPINK1 trypsin inhibitor mutations in hereditary and non-hereditary chronic pancreatitis. Gut. 2004;53:723–8. [PMC free article: PMC1774044] [PubMed: 15082592]
• Chang MC, Wong JM, Chang YT. Screening and early detection of pancreatic cancer in high risk population. World J Gastroenterol. 2014;20:2358–64. [PMC free article: PMC3942839] [PubMed: 24605033]
• Chen JM, Ferec C. Chronic pancreatitis: genetics and pathogenesis. Annu Rev Genomics Hum Genet. 2009;10:63–87. [PubMed: 19453252]
• Cho SM, Shin S, Lee KA. PRSS1, SPINK1, CFTR, and CTRC pathogenic variants in Korean patients with idiopathic pancreatitis. Ann Lab Med. 2016;36:555–60. [PMC free article: PMC5011109] [PubMed: 27578509]
• Clarke B, Slivka A, Tomizawa Y, Sanders M, Papachristou GI, Whitcomb DC, Yadav D. Endoscopic therapy is effective for patients with chronic pancreatitis. Clin Gastroenterol Hepatol. 2012;10:795–802. [PMC free article: PMC3381994] [PubMed: 22245964]
• Couper RT, Corey M, Durie PR, Forstner GG, Moore DJ. Longitudinal evaluation of serum trypsinogen measurement in pancreatic-insufficient and pancreatic-sufficient patients with cystic fibrosis. J Pediatr. 1995;127:408–13. [PubMed: 7658271]
• Decensi A, Puntoni M, Goodwin P, Cazzaniga M, Gennari A, Bonanni B, Gandini S. Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev Res (Phila). 2010;3:1451–61. [PubMed: 20947488]
• de las Heras-Castaño G, Castro-Senosiain B, Fontalba A, Lopez-Hoyos M, Sanchez-Juan P. Hereditary pancreatitis: clinical features and inheritance characteristics of the R122C mutation in the cationic trypsinogen gene (PRSS1) in six Spanish families. JOP. 2009;10:249–55. [PubMed: 19454815]
• de-Madaria E, Herrera-Marante I, González-Camacho V, Bonjoch L, Quesada-Vázquez N, Almenta-Saavedra I, Miralles-Maciá C, Acevedo-Piedra NG, Roger-Ibáñez M, Sánchez-Marin C, Osuna-Ligero R, Gracia Á, Llorens P, Zapater P, Singh VK, Moreu-Martín R, Closa D. Fluid resuscitation with lactated Ringer's solution vs normal saline in acute pancreatitis: a triple-blind, randomized, controlled trial. United European Gastroenterol J. 2018;6:63–72. [PMC free article: PMC5802674] [PubMed: 29435315]
• Derikx MH, Kovacs P, Scholz M, Masson E, Chen JM, Ruffert C, Lichtner P, Te Morsche RH, Cavestro GM, Férec C, Drenth JP, Witt H, Rosendahl J, et al. Polymorphisms at PRSS1-PRSS2 and CLDN2-MORC4 loci associate with alcoholic and non-alcoholic chronic pancreatitis in a European replication study. Gut. 2015;64:1426–33. [PubMed: 25253127]
• Dever JB, Irani S, Brandabur J, Traverso LW, Kozarek R. Outcomes of interventional ERCP in hereditary pancreatitis. J Clin Gastroenterol. 2010;44:46–51. [PubMed: 19713862]
• Drewes AM, Bouwense SAW, Campbell CM, Ceyhan GO, Delhaye M, Demir IE, Garg PK, van Goor H, Halloran C, Isaji S, Neoptolemos JP, Olesen SS, Palermo T, Pasricha PJ, Sheel A, Shimosegawa T, Szigethy E, Whitcomb DC, Yadav D. Working group for the International (IAP – APA – JPS – EPC) Consensus Guidelines for Chronic Pancreatitis. Guidelines for the understanding and management of pain in chronic pancreatitis. Pancreatology. 2017;17:720–31. [PubMed: 28734722]
• Ellis I, Lerch MM, Whitcomb DC, et al. Genetic testing for hereditary pancreatitis: guidelines for indications, counselling, consent and privacy issues. Pancreatology. 2001;1:405–15. [PubMed: 12120217]
• Etemad B, Whitcomb DC. Chronic pancreatitis: diagnosis, classification, and new genetic developments. Gastroenterology. 2001;120:682–707. [PubMed: 11179244]
• Fasanella KE, Davis B, Lyons J, Chen Z, Lee KK, Slivka A, Whitcomb DC. Pain in chronic pancreatitis and pancreatic cancer. Gastroenterol Clin North Am. 2007;36:335–64. [PubMed: 17533083]
• Fjeld K, Weiss FU, Lasher D, Rosendahl J, Chen JM, Johansson BB, Kirsten H, Ruffert C, Masson E, Steine SJ, Bugert P, Cnop M, Grützmann R, Mayerle J, Mössner J, Ringdal M, Schulz HU, Sendler M, Simon P, Sztromwasser P, Torsvik J, Scholz M, Tjora E, Férec C, Witt H, Lerch MM, Njølstad PR, Johansson S, Molven A. A recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis. Nat Genet. 2015;47:518–22. [PMC free article: PMC5321495] [PubMed: 25774637]
• Forsmark CE, Andersen DK, Farrar JT, Golden M, Habtezion A, Husain SZ, Li L, Mayerle J, Pandol SJ, Uc A, Zhu Z, Yadav D. Accelerating the drug delivery pipeline for acute and chronic pancreatitis: summary of the Working Group on Drug Development and Trials in Chronic Pancreatitis at the National Institute of Diabetes and Digestive and Kidney Diseases Workshop. Pancreas. 2018;47:1200–7. [PMC free article: PMC6196743] [PubMed: 30325858]
• Giefer MJ, Lowe ME, Werlin SL, Zimmerman B, Wilschanski M, Troendle D, Schwarzenberg SJ, Pohl JF, Palermo J, Ooi CY, Morinville VD, Lin TK, Husain SZ, Himes R, Heyman MB, Gonska T, Gariepy CE, Freedman SD, Fishman DS, Bellin MD, Barth B, Abu-El-Haija M, Uc A. Early-onset acute recurrent and chronic pancreatitis is associated with PRSS1 or CTRC gene mutations. J Pediatr. 2017;186:95–100. [PMC free article: PMC5506853] [PubMed: 28502372]
• Giri AK, Midha S, Banerjee P, Agrawal A, Mehdi SJ, Dhingra R, Kaur I, Kuman GR, Lakhotia R, Ghosh S, Das K, Mohindra S, Rana S, Bhasin DK, Garg PK, Bharadwaj D, et al. Common variants in CLDN2 and MORC4 genes confer disease susceptibility in patients with chronic pancreatitis. PLoS One. 2016;11:e0147345. [PMC free article: PMC4731142] [PubMed: 26820620]
• Grocock CJ, Rebours V, Delhaye MN, Andrén-Sandberg A, Weiss FU, Mountford R, Harcus MJ, Niemczyck E, Vitone LJ, Dodd S, Jørgensen MT, Ammann RW, Schaffalitzky de Muckadell O, Butler JV, Burgess P, Kerr B, Charnley R, Sutton R, Raraty MG, Devière J, Whitcomb DC, Neoptolemos JP, Lévy P, Lerch MM, Greenhalf W, et al. The variable phenotype of the p.A16V mutation of cationic trypsinogen (PRSS1) in pancreatitis families. Gut. 2010;59:357–63. [PubMed: 19951905]
• Guda NM, Muddana V, Whitcomb DC, Levy P, Garg P, Cote G, Uc A, Varadarajulu S, Vege SS, Chari ST, Forsmark CE, Yadav D, Reddy DN, Tenner S, Johnson CD, Akisik F, Saluja AK, Lerch MM, Mallery JS, Freeman ML. Recurrent acute pancreatitis: international state-of-the-science conference with recommendations. Pancreas. 2018;47:653–66. [PubMed: 29894415]
• Howes N, Lerch M, Greenhalf W, Stocken DD, Ellis I, Simon P, Truninger K, Ammann R, Cavallini G, Charnley RM, Uomo G, Delhaye M, Spicak J, Drumm B, Jansen J, Mountford R, Whitcomb DC, Neoptolemos JP, et al. Clinical and genetic characteristics of hereditary pancreatitis in Europe. Clin Gastroenterol Hepatol. 2004;2:252–61. [PubMed: 15017610]
• Joergensen MT, Brusgaard K, Crüger DG, Gerdes AM, Schaffalitzky de Muckadell OB. Genetic, epidemiological, and clinical aspects of hereditary pancreatitis: a population-based cohort study in Denmark. Am J Gastroenterol. 2010;105:1876–83. [PubMed: 20502448]
• Kobayashi T, Manivel JC, Carlson AM, Bellin MD, Moran A, Freeman ML, Bielman GJ, Hering BJ, Dunn T, Sutherland DE. Correlation of histopathology, islet yield, and islet graft function after islet autotransplantation in chronic pancreatitis. Pancreas. 2011;40:193–9. [PubMed: 21404456]
• Kumar S, Ooi CY, Werlin S, Abu-El-Haija M, Barth B, Bellin MD, Durie PR, Fishman DS, Freedman SD, Gariepy C, Giefer MJ, Gonska T, Heyman MB, Himes R, Husain SZ, Lin TK, Lowe ME, Morinville V, Palermo JJ, Pohl JF, Schwarzenberg SJ, Troendle D, Wilschanski M, Zimmerman MB, Uc A. Risk factors associated with pediatric acute recurrent and chronic pancreatitis: lessons from INSPPIRE. JAMA Pediatr. 2016;170:562–9. [PMC free article: PMC5317277] [PubMed: 27064572]
• Le Maréchal C, Masson E, Chen JM, Morel F, Ruszniewski P, Levy P, Férec C. Hereditary pancreatitis caused by triplication of the trypsinogen locus. Nat Genet. 2006;38:1372–4. [PubMed: 17072318]
• Lowe ME, Goodman MT, Coté GA, Glesby MJ, Haupt M, Schork NJ, Singh VK, Andersen DK, Pandol SJ, Uc A, Whitcomb DC. Accelerating the drug delivery pipeline for acute and chronic pancreatitis: summary of the Working Group on Drug Development and Trials in Recurrent Acute Pancreatitis at the National Institute of Diabetes and Digestive and Kidney Diseases Workshop. Pancreas. 2018;47:1193–9. [PMC free article: PMC6195328] [PubMed: 30325857]
• Lowenfels AB, Maisonneuve P, Whitcomb DC, Lerch MM, DiMagno EP. Cigarette smoking as a risk factor for pancreatic cancer in patients with hereditary pancreatitis. JAMA. 2001;286:169–70. [PubMed: 11448279]
• Machicado JD, Amann ST, Anderson MA, Abberbock J, Sherman S, Conwell DL, Cote GA, Singh VK, Lewis MD, Alkaade S, Sandhu BS, Guda NM, Muniraj T, Tang G, Baillie J, Brand RE, Gardner TB, Gelrud A, Forsmark CE, Banks PA, Slivka A, Wilcox CM, Whitcomb DC, Yadav D. Quality of life in chronic pancreatitis is determined by constant pain, disability/unemployment, current smoking, and associated co-morbidities. Am J Gastroenterol. 2017;112:633–42. [PMC free article: PMC5828017] [PubMed: 28244497]
• Maisonneuve P, Lowenfels AB, Mullhaupt B, Cavallini G, Lankisch PG, Andersen JR, Dimagno EP, Andrén-Sandberg A, Domellöf L, Frulloni L, Ammann RW. Cigarette smoking accelerates progression of alcoholic chronic pancreatitis. Gut. 2005;54:510–4. [PMC free article: PMC1774435] [PubMed: 15753536]
• Masson E, Le Maréchal C, Chandak GR, Lamoril J, Bezieau S, Mahurkar S, Bhaskar S, Reddy DN, Chen JM, Férec C. Trypsinogen copy number mutations in patients with idiopathic chronic pancreatitis. Clin Gastroenterol Hepatol. 2008a;6:82–8. [PubMed: 18063422]
• Masson E, Le Maréchal C, Delcenserie R, Chen JM, Férec C. Hereditary pancreatitis caused by a double gain-of-function trypsinogen mutation. Hum Genet. 2008b;123:521–9. [PubMed: 18461367]
• Mora J, Comas L, Ripoll E, Gonçalves P, Queraltó JM, González-Sastre F, Farré A. Genetic mutations in a Spanish population with chronic pancreatitis. Pancreatology. 2009;9:644–51. [PubMed: 19657220]
• Pezzilli R, Talamini G, Gullo L. Behaviour of serum pancreatic enzymes in chronic pancreatitis. Dig Liver Dis. 2000;32:233–7. [PubMed: 10975774]
• Phillips AE, LaRusch J, Greer P, Abberbock J, Alkaade S, Amann ST, Anderson MA, Baillie J, Banks PA, Brand RE, Conwell D, Coté GA, Forsmark CE, Gardner TB, Gelrud A, Guda N, Lewis M, Money ME, Muniraj T, Sandhu BS, Sherman S, Singh VK, Slivka A, Tang G, Wilcox CM, Whitcomb DC, Yadav D. Known genetic susceptibility factors for chronic pancreatitis in patients of European ancestry are rare in patients of African ancestry. Pancreatology. 2018;18:528–35. [PMC free article: PMC8715541] [PubMed: 29859674]
• Poddar U, Yachha SK, Borkar V, Srivastava A, Saraswat VA. Clinical profile and treatment outcome of chronic pancreatitis in children: a long-term follow-up study of 156 cases. Scand J Gastroenterol. 2017;52:773–8. [PubMed: 28276824]
• Pongprasobchai S, DiMagno EP. Treatment of exocrine pancreatic insufficiency. In: Forsmark CE, ed. Pancreatitis and Its Complications. Totowa, NJ: Humana Press; 2005:295-310.
• Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–33. [PMC free article: PMC4731925] [PubMed: 26656846]
• Rebours V, Boutron-Ruault MC, Schnee M, Férec C, Le Maréchal C, Hentic O, Maire F, Hammel P, Ruszniewski P, Lévy P. Risk of pancreatic adenocarcinoma in patients with hereditary pancreatitis: a national exhaustive series. Am J Gastroenterol. 2008;103:111–9. [PubMed: 18184119]
• Rebours V, Boutron-Ruault MC, Schnee M, Férec C, Le Maréchal C, Hentic O, Maire F, Hammel P, Ruszniewski P, Lévy P. The natural history of hereditary pancreatitis: a national series. Gut. 2009;58:97–103. [PubMed: 18755888]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Rosendahl J, Landt O, Bernadova J, Kovacs P, Teich N, Bödeker H, Keim V, Ruffert C, Mössner J, Kage A, Stumvoll M, Groneberg D, Krüger R, Luck W, Treiber M, Becker M, Witt H. CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated? Gut. 2013;62:582–92. [PubMed: 22427236]
• Sánchez-Ramírez CA, Flores-Martínez SE, García-Zapién AG, Montero-Cruz SA, Larrosa-Haro A, Sánchez-Corona J. Screening of R122H and N29I mutations in the PRSS1 gene and N34S mutation in the SPINK1 gene in Mexican pediatric patients with acute and recurrent pancreatitis. Pancreas. 2012;41:707–11. [PubMed: 22699143]
• Sareen S, Kumari V, Gajebasia KS, Gajebasia NK. Yoga: a tool for improving the quality of life in chronic pancreatitis. World J Gastroenterol. 2007;13:391–7. [PMC free article: PMC4065893] [PubMed: 17230607]
• Schnúr A, Beer S, Witt H, Hegyi P, Sahin-Tóth M. Functional effects of 13 rare PRSS1 variants presumed to cause chronic pancreatitis. Gut. 2014;63:337–43. [PMC free article: PMC3681892] [PubMed: 23455445]
• Shalimar Midha S, Hasan A, Dhingra R, Garg PK. Long-term pain relief with optimized medical treatment including antioxidants and step-up interventional therapy in patients with chronic pancreatitis. J Gastroenterol Hepatol. 2017;32:270–7. [PubMed: 27061119]
• Shelton CA, Umapathy C, Stello K, Yadav D, Whitcomb DC. Hereditary pancreatitis in the United States: survival and rates of pancreatic cancer. Am J Gastroenterol. 2018;113:1376–84. [PMC free article: PMC6708435] [PubMed: 30018304]
• Sibert JR. Hereditary pancreatitis in England and Wales. J Med Genet. 1978;15:189–201. [PMC free article: PMC1013676] [PubMed: 671483]
• Sobczyńska-Tomaszewska A, Bak D, Oralewska B, Oracz G, Norek A, Czerska K, Mazurczak T, Teisseyre M, Socha J, Zagulski M, Bal J. Analysis of CFTR, SPINK1, PRSS1 and AAT mutations in children with acute or chronic pancreatitis. J Pediatr Gastroenterol Nutr. 2006;43:299–306. [PubMed: 16954950]
• Sossenheimer MJ, Aston CE, Preston RA, Gates LK Jr, Ulrich CD, Martin SP, Zhang Y, Gorry MC, Ehrlich GD, Whitcomb DC. Clinical characteristics of hereditary pancreatitis in a large family, based on high-risk haplotype. The Midwest Multicenter Pancreatic Study Group (MMPSG). Am J Gastroenterol. 1997;92:1113–6. [PubMed: 9219780]
• Sutton JM, Schmulewitz N, Sussman JJ, Smith M, Kurland JE, Brunner JE, Salehi M, Choe KA, Ahmad SA. Total pancreatectomy and islet cell autotransplantation as a means of treating patients with genetically linked pancreatitis. Surgery. 2010;148:676–85. [PubMed: 20846557]
• Szmola R, Sahin-Toth M. Chymotrypsin C (caldecrin) promotes degradation of human cationic trypsin: identity with Rinderknecht's enzyme Y. Proc Natl Acad Sci U S A. 2007;104:11227–32. [PMC free article: PMC2040881] [PubMed: 17592142]
• Uc A, Andersen DK, Borowitz D, Glesby MJ, Mayerle J, Sutton R, Pandol SJ. Accelerating the drug delivery pipeline for acute and chronic pancreatitis-knowledge gaps and research opportunities: overview summary of a National Institute of Diabetes and Digestive and Kidney Diseases workshop. Pancreas. 2018;47:1180–4. [PMC free article: PMC6201320] [PubMed: 30325855]
• Ulrich CD. Pancreatic cancer in hereditary pancreatitis – consensus guidelines for prevention, screening, and treatment. Pancreatology. 2001;1:416–22. [PubMed: 12120218]
• Uomo G, Talamini G, Rabitti PG. Antioxidant treatment in hereditary pancreatitis. A pilot study on three young patients. Dig Liver Dis. 2001;33:58–62. [PubMed: 11303976]
• Wang W, Sun XT, Weng XL, Zhou DZ, Sun C, Xia T, Hu LH, Lai XW, Ye B, Liu MY, Jiang F, Gao J, Bo LM, Liu Y, Liao Z, Li ZS. Comprehensive screening for PRSS1, SPINK1, CFTR, CTRC and CLDN2 gene mutations in Chinese paediatric patients with idiopathic chronic pancreatitis: a cohort study. BMJ Open. 2013;3:e003150. [PMC free article: PMC3773632] [PubMed: 24002981]
• Whitcomb DC. Genetic aspects of pancreatitis. Annu Rev Med. 2010;61:413–24. [PubMed: 20059346]
• Whitcomb DC. Mechanisms of disease: advances in understanding the mechanisms leading to chronic pancreatitis. Nat Clin Pract Gastroenterol Hepatol. 2004;1:46–52. [PubMed: 16265044]
• Whitcomb DC, Frulloni L, Garg P, Greer JB, Schneider A, Yadav D, Shimosegawa T. Chronic pancreatitis: an international draft consensus proposal for a new mechanistic definition. Pancreatology. 2016;16:218–24. [PMC free article: PMC6042966] [PubMed: 26924663]
• Whitcomb DC, LaRusch J, Krasinskas AM, Klei L, Smith JP, Brand RE, Neoptolemos JP, Lerch MM, Tector M, Sandhu BS, Guda NM, Orlichenko L, Alkaade S, Amann ST, Anderson MA, Baillie J, Banks PA, Conwell D, Coté GA, Cotton PB, DiSario J, Farrer LA, Forsmark CE, Johnstone M, Gardner TB, Gelrud A, Greenhalf W, Haines JL, Hartman DJ, Hawes RA, Lawrence C, Lewis M, Mayerle J, Mayeux R, Melhem NM, Money ME, Muniraj T, Papachristou GI, Pericak-Vance MA, Romagnuolo J, Schellenberg GD, Sherman S, Simon P, Singh VP, Slivka A, Stolz D, Sutton R, Weiss FU, Wilcox CM, Zarnescu NO, Wisniewski SR, O'Connell MR, Kienholz ML, Roeder K, Barmada MM, Yadav D, Devlin B. Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis. Nat Genet. 2012;44:1349–54. [PMC free article: PMC3510344] [PubMed: 23143602]
• Whitcomb DC, Lowe ME. Human pancreatic digestive enzymes. Dig Dis Sci. 2007;52:1–17. [PubMed: 17205399]
• Yadav D, Hawes RH, Brand RE, Anderson MA, Money ME, Banks PA, Bishop MD, Baillie J, Sherman S, DiSario J, Burton FR, Gardner TB, Amann ST, Gelrud A, Lawrence C, Elinoff B, Greer JB, O'Connell M, Barmada MM, Slivka A, Whitcomb DC, et al. Alcohol consumption, cigarette smoking, and the risk of recurrent acute and chronic pancreatitis. Arch Intern Med. 2009;169:1035–45. [PMC free article: PMC6785300] [PubMed: 19506173]
• Zhan W, Shelton CA, Greer PJ, Brand RE, Whitcomb DC. Germline variants and risk for pancreatic cancer: a systematic review and emerging concepts. Pancreas. 2018;47:924–36. [PMC free article: PMC6097243] [PubMed: 30113427]