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Pancreatitis Overview

, PhD, , MS, CGC, and , MD, PhD.

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Summary

Clinical characteristics.

Pancreatitis is inflammation of the pancreas that progresses from acute (sudden onset; duration <6 months) to recurrent acute (>1 episode of acute pancreatitis) to chronic (duration >6 months). The range of symptoms and disease course vary from person to person.

  • Familial pancreatitis, defined as pancreatitis from any cause that occurs in a family with an incidence that is greater than would be expected by chance alone, can be non-genetic or genetic, the latter including autosomal dominant hereditary pancreatitis and pancreatitis syndromes characterized by pancreatitis or pancreatic insufficiency. The majority of familial pancreatitis appears to have a complex, multigenic, or gene-environmental etiology with a variable number of germline pathogenic variants in genes that affect trypsin regulation, including CASR, CTRC, and CLDN2.
  • Hereditary pancreatitis (HP) is defined as either two or more individuals with pancreatitis in two or more generations of a family (i.e., an autosomal dominant pattern of inheritance) or pancreatitis associated with a germline PRSS1 disease-causing gain-of-function variant. The phenotype of hereditary pancreatitis is increased susceptibility to acute pancreatitis, with complications such as chronic inflammation, fibrosis, and chronic pain in some affected individuals. Heterozygous pathogenic variants in PRSS1 are found in 60%-100% of families with hereditary pancreatitis, and most large families with pancreatitis spanning multiple generations; biallelic pathogenic variants in SPINK1 or biallelic pathogenic variants in CFTR result in autosomal recessive pancreatitis. Syndromes in which pancreatitis is a finding include: Pearson marrow pancreas syndrome, CEL maturity-onset diabetes of the young (CEL-MODY), and Johanson-Blizzard syndrome. Shwachman-Diamond syndrome, an autosomal recessive disorder, includes pancreatic exocrine insufficiency as well as other features.
  • Idiopathic sporadic pancreatitis is a single occurrence of pancreatitis in a family for which no etiology is identified.

Diagnosis/testing.

Establishing the diagnosis and cause of hereditary pancreatitis relies on medical history, family history, and/or molecular genetic testing, which can be either single-gene (monogenic) testing or use of a multigene panel. Although a multigene panel that includes PRSS1 along with SPINK1, CFTR, and CTRC may be considered, it should be noted that (1) the presence of isolated pathogenic variants in the latter three genes is insufficient to cause pancreatitis and (2) many variants of uncertain significance are likely to be identified.

Genetic counseling.

Hereditary pancreatitis can occur as part of a rare genetic syndrome or as an isolated finding. The risk to family members depends on the underlying etiology. Pathogenic variants associated with an increased risk for pancreatitis as an isolated finding may be inherited in an autosomal dominant, autosomal recessive, or multigene manner; such pathogenic variants may be classified as disease causing, conferring susceptibility, or disease modifiers.

Management.

Treatment of manifestations: Management for hereditary pancreatitis is currently similar to that for non-hereditary pancreatitis. Treatment of acute pancreatitis usually focuses on pain management and discontinuation of smoking and alcohol use to slow the rate of progression and to decrease the likelihood of complications, including pancreatic cancer. Treatment of chronic pancreatitis focuses on improving quality of life by managing pancreatic pain, maldigestion, and diabetes mellitus. Total pancreatectomy with islet autotransplantation (TPIAT) should be used only as a last resort to manage patients with severe manifestations of pancreatitis.

Prevention of primary manifestations: The ability to prevent the primary manifestations of hereditary pancreatitis (regardless of genetic cause) is limited.

The following recommendations (beginning in early childhood) for individuals with (or at risk for) hereditary pancreatitis can help prevent attacks of acute pancreatitis: Low-fat diet, multiple small meals, good hydration, antioxidants, and cessation/abstinence from smoking and alcohol use.

Agents/circumstances to avoid: Alcohol and tobacco use, dehydration, and physical and emotional stresses

Evaluation of relatives at risk: It is recommended that relatives at risk for PRSS1-related hereditary pancreatitis be offered molecular genetic testing for the family-specific germline PRSS1 pathogenic variant to allow early diagnosis, prevention, and management of symptoms

Definitions

Pancreatitis is characterized by inflammation of the pancreas that progresses from acute (sudden onset; duration <6 months) to recurrent acute (>1 episode of acute pancreatitis) to chronic (duration >6 months). The range of symptoms and disease course vary from person to person.

Acute pancreatitis is diagnosed in the presence of two of the following three findings [Banks et al 2006]:

  • Sudden onset of typical epigastric abdominal pain
  • Elevation of serum amylase or lipase more than three times the upper limits of normal [Neoptolemos et al 2000]
  • Characteristic findings of acute pancreatitis such as pancreatic edema, fat stranding, peripancreatic fluid collections on abdominal imaging [O’Connor et al 2011, Banks et al 2013]

Manifestations of acute pancreatitis can range from vague abdominal pain lasting one to three days to severe abdominal pain, systemic inflammation, and multi-organ failure lasting days to weeks and requiring hospitalization with care in an intensive care unit.

Continued injury increases fibrosis and advances the clinical manifestations from acute pancreatitis to chronic pancreatitis.

Chronic pancreatitis is a continuing inflammatory disease of the pancreas characterized by irreversible morphologic changes that typically cause pain and/or permanent loss of function [Etemad & Whitcomb 2001]. Chronic pancreatitis is a syndrome of various disorders causing pancreatic inflammation lasting more than six months with irreversible pancreatic changes documented by one of the following:

  • Abdominal imaging (inflammatory masses; pancreatic parenchyma and ductal calcifications; pseudocysts)
  • Functional studies (pancreatic exocrine insufficiency with maldigestion of food; pancreatic endocrine insufficiency with diabetes mellitus with destruction of the islets [type 3c])
  • Histologic changes (atrophy, fibrosis, and/or sclerosis)

Chronic pancreatitis typically manifests as episodic or continuous mild to severe abdominal pain, and progresses to exocrine pancreatic insufficiency leading to maldigestion and/or pancreatic endocrine insufficiency (glucose intolerance progressing to diabetes mellitus type 3c).

Pain, the primary complaint of persons with chronic pancreatitis, originates in the abdomen in response to pancreatic injury. Pain character, frequency, and severity are highly variable due to multiple causes. As the disease progresses pain may convert to constant neuropathic pain, which is not controlled even by major interventions such as spinal block or total pancreatectomy.

Pancreatic cancer risk is increased after age 50 years in those with long-standing chronic inflammation of the pancreas. Persons with hereditary pancreatitis are at high risk because their onset of chronic pancreatitis is 20-30 years earlier than in sporadic forms of chronic pancreatitis. Although earlier studies estimated life-time risk of pancreatic cancer at nearly 40%, this was in populations with high rates of smoking. For non-smokers the lifetime risk may be below 20% [Rebours et al 2008, Rebours et al 2009].

Familial pancreatitis is defined as 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 incidence of pancreatitis within a defined population. Familial pancreatitis can have a genetic and/or a non-genetic etiology; thus, familial pancreatitis includes autosomal dominant hereditary pancreatitis (with or without an identified PRSS1 pathogenic variant) as well as pancreatitis syndromes characterized by pancreatitis or pancreatic insufficiency.

Hereditary pancreatitis (HP) is defined as EITHER two or more individuals with pancreatitis in two or more generations of a family (i.e., an autosomal dominant pattern of inheritance) OR pancreatitis associated with a known germline pathogenic variant [Whitcomb & Lowe 2010].

Idiopathic sporadic pancreatitis. An individual with no family history of pancreatitis is referred to as a simplex case (i.e., a single occurrence of pancreatitis in a family). Pancreatitis in a simplex case may be due to environmental, metabolic, or genetic causes (e.g., autosomal recessive inheritance). If no etiology is identified in a simplex case, the pancreatitis is considered to be idiopathic sporadic pancreatitis.

Causes of Hereditary Pancreatitis

Hereditary pancreatitis (HP), a disease of recurrent injury to the pancreas, is most often caused by abnormal regulation of trypsin, the master regulator of pancreatic digestive enzyme activation. In HP, inflammation is initiated by injury to the pancreas secondary to germline pathogenic variants in genes that affect trypsin regulation [Whitcomb & Ulrich 1999, Yadav & Whitcomb 2010].

Under acinar cell stress (e.g., hyperstimulation, intracellular hypercalcemia), intracellular trypsinogen is likely converted to trypsin, which activates other digestive enzymes causing injury. Injury releases immune system-activating molecules that cause an initial acute inflammatory response, followed by recruitment of tissue macrophages and activated pancreatic stellate cells. Recurrent injury leads to chronic pancreatitis and fibrosis, mediated by pancreatic stellate cells.

The phenotype of HP is increased susceptibility to acute pancreatitis, with secondary features of chronic pancreatitis (including pancreatic fibrosis, chronic pain, maldigestion and diabetes mellitus [Type 3c]) occurring in at least 50%. The risk of pancreatic cancer risk is also increased; the life-time risk of pancreatic cancer in non-smokers and families without a strong history of pancreatic cancer is less than 20%.

Genes in which Pathogenic Variants are Associated with Hereditary Pancreatitis

PRSS1. A heterozygous pathogenic variant PRSS1, which results in autosomal dominant inheritance of pancreatitis, is found in 60%-100% of families with hereditary pancreatitis [LaRusch & Whitcomb 2011] (see PRSS1-Related Hereditary Pancreatitis).

Although the clinical manifestations of PRSS1-related hereditary pancreatitis and non-PRSS1-related HP are not significantly different, the typical age of onset of non-PRSS1-related HP is later than that of PRSS1-related HP (which is ~10 years).

PRSS1 encodes trypsin-1 (cationic trypsinogen) a major pancreatic digestive enzyme that also catalyzes activation of other pancreatic zymogens to active enzymes, a process that normally occurs in the intestine. HP-causing PRSS1 pathogenic variants typically result in a trypsin protein that is either prematurely activated or resistant to degradation. Note that duplication of PRSS1 (resulting in a presumed 50% or greater increase of baseline trypsin protein) also causes HP, but may be under-recognized because such variants are not always identified by clinical testing [Chen et al 2008; Masson et al 2008c; LaRusch et al 2012; Author, personal observation].

SPINK1. Pathogenic variants in SPINK1, encoding serine protease inhibitor, Kazel-type 1, can lead to autosomal recessive pancreatitis.

In the United States, Europe, and India a high-risk haplotype containing SPINK1 p.Asn34Ser (NM_003122.3:c.101A>G) is common, with a minor allele frequency as high as 3%.

In China, Japan, and Korea the SPINK1 splice variant (c.194+2T>C, also known as IVS3+2T>C) is common.

SPINK1 serves as a trypsin inhibitor that is upregulated by inflammation (an acute phase protein). Since SPINK1 encodes a protein that guards the pancreas from the effects of recurrent or persistent trypsin activation, it is not a typical susceptibility gene for acute pancreatitis, but rather a susceptibility gene for the chronic pancreatitis that follows acute pancreatitis. It is not known if biallelic SPINK1 pathogenic variants alone are sufficient to cause recurrent acute or chronic pancreatitis, but multiple families with biallelic SPINK1 pathogenic variants in affected family members have been documented. (See SPINK1 discussion related to complex genotypes.)

CFTR. Pathogenic variants in CFTR, encoding the cystic fibrosis transmembrane conductance protein, are associated with recurrent acute and chronic pancreatitis. Indeed, CF is defined (and the severity of CFTR variants estimated) by the effect of variants on the pancreas. CFTR is the most important molecule for fluid secretion in the pancreatic duct cell. The primary function of duct cells is to secrete a bicarbonate-rich fluid that flushes the zymogens out of the pancreas into the duodenum. Dysfunction of CFTR results in retention of zymogens in the duct where they can become active and begin digesting the surrounding pancreas, leading to acute pancreatitis.

The features of CFTR-associated diseases depend on the functional consequences of specific pathogenic variants on the two CFTR alleles, as well as variants in modifier genes and effects of environmental factors. Cystic fibrosis is caused by two severe pathogenic variants (CFTRsev). Recent data suggest that CFTR pathogenic variants that affect bicarbonate conductance while maintaining chloride conductance (e.g., p.Arg75Gln (NM_000492.3:c.224G>A) have major effects on the pancreas but minimal effects on the lungs since the pancreas uses CFTR as a bicarbonate channel [Schneider et al 2011]. The functional effect of CFTR genotypes is determined by the least severe pathogenic variant; thus, either two bicarbonate-defective (BD) variants (CFTRBD / CFTRBD) or one BD and one severe variant (CFTRBD / CFTRsev) can result in a monogenic pancreatitis-predominant disorder.

Syndromes that Include Pancreatitis or Pancreatic Insufficiency

Pathogenic variants in several genes are associated with rare disorders in which pancreatitis or pancreatic insufficiency is part of their complex phenotype [Durie 1996, Lerch et al 2006].

SBDS. Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder caused by biallelic SBDS pathogenic variants, which appear to affect RNA function. Clinical features include short stature, skeletal abnormalities, exocrine pancreatic insufficiency, and hematologic dysfunction resulting in multiple infections and risk of myeloid leukemias [Boocock et al 2003].

Mitochondrial (mt) DNA deletions. Pearson marrow pancreas syndrome is a severe disorder caused by deletions of mtDNA resulting in defective oxidative phosphorylation. Clinical features involve the hematopoietic system with severe, transfusion-dependent macrocytic anemia, exocrine pancreas dysfunction with features of chronic pancreatitis, and liver and kidney dysfunction [Rötig et al 1990]. Diabetes mellitus and adrenal dysfunction can also be observed [Hopewell et al 1990]. Children who survive develop features of Kearns-Sayre syndrome, an encephalomyopathy with ophthalmoplegia, retinal degeneration, ataxia, and endocrine abnormalities [Becher et al 1999].

CEL. Pathogenic variants and tandem repeat variants in CEL, encoding carboxyl ester lipase, are associated with both pancreatic exocrine, endocrine dysfunction, and chronic pancreatitis in a syndrome referred to as CEL-maturity onset diabetes of the young (CEL-MODY) (see MODY Overview) This disorder presents with diabetes mellitus, pancreatic lipomatosis, and exocrine dysfunction without the severe malnutrition seen in cystic fibrosis. Inheritance is autosomal dominant [Raeder et al 2006]. It is managed as other types of diabetes mellitus and pancreatic dysfunction.

UBR1. Johanson-Blizzard syndrome (OMIM 243800) is an autosomal recessive disorder that includes congenital exocrine pancreatic inflammation and insufficiency, multiple malformations such as nasal wing aplasia, and (frequently) intellectual disability [Zenker et al 2005]. The disorder is caused by biallelic pathogenic variants in UBR1 (a gene involved in protein synthesis) that result in either loss of gene expression or expression of a nonfunctional gene product.

Complex Multigenic Disorders

The majority of kindreds with familial pancreatitis without risk associated with a single locus (e.g., PRSS1, CFTR, or SPINK1) are small, with two to four affected individuals. These families and simplex cases (i.e., a single occurrence in a family) are increasingly found to have complex, multigenic, or gene-environmental disorders with a variable number of germline pathogenic variants in genes that affect trypsin regulation.

Recently, research studies suggest that at least one third of recurrent acute and chronic pancreatitis results from complex genetic mechanisms [Whitcomb, NAPS2 study 2014, unpublished]. Although the most common genotypes are complex SPINK1/CFTR variants, a growing list of common, low-risk variants are now recognized as being significant contributors to pancreatic disease. The paradigm appears to be a combination of a variant in a gene that increases the risk of recurrent trypsin activation (e.g., PRSS1, CFTR) plus a variant in a gene that protects the pancreas from active trypsin or chronic inflammation (e.g., SPINK1).

In rare instances families with apparent autosomal dominant inheritance do not have an identified PRSS1 pathogenic variant. In one such family, multiple pathogenic variants in PRSS1, SPINK1, and CFTR were identified in different combinations in affected members [LaRusch et al 2012].

The traditional method of determining the effect of the second class of genes in complex multigenic disorders is calculation of an odds ratio, which reflects the frequency of the variant in the disorder divided by the frequency of the variant in the population. However, in order for a variant to be detected as a disease modifier (e.g., one that worsens the severity of recurrent trypsin activation), the variant must be common within the population so that the co-inheritance of injury-causing pathogenic variants and defective-protection pathogenic variants is also common. Thus, the importance and effect of these variants is not accurately reflected by an odds ratio, but rather by the likelihood that the disease will progress from recurrent mild injury to end-stage disease.

Other genes in which variants have been considered as possible modifiers include the following.

CASR encodes the calcium sensing receptor (CASR), a plasma membrane receptor that senses calcium levels outside the cell and then activates a variety of regulator actions inside the cell. Although first identified in the parathyroid gland in “calcium syndromes” caused by loss-of-function or gain-of-function variants [Pidasheva et al 2004], this receptor is now known to be used throughout the body by different cells in different ways:

  • Loss-of-function CASR pathogenic variants are commonly seen in the pancreas with CFTR pathogenic variants, suggesting that a failure to detect elevated calcium levels in the pancreatic duct triggers CFTR channel opening and duct flushing.
  • Gain-of-function pathogenic variants are linked with alcoholic pancreatitis, suggesting that CASR pathogenic variants on the acinar cell are linked to intracellular hypercalcemia in combination with the effects of alcohol on calcium regulation [LaRusch & Whitcomb 2011].

CTRC encodes chymotrypsin C (CTRC), a low-abundance pancreatic digestive enzyme that is synthesized with PRSS1 [Beer et al 2013]. CTRC plays an important role in degrading prematurely activated trypsin within the pancreas. Several studies have associated pathogenic variants in CTRC with chronic pancreatitis [Masson et al 2008a, Rosendahl et al 2008, Chang et al 2009]. Of note, loss-of-function CTRC pathogenic variants do not appear to cause chronic pancreatitis but rather are seen in combination with other trypsin-activating variants including heterozygous CFTR or SPINK1 variants [Rosendahl et al 2013].

CLDN2 encodes claudin-2, a tight-junction protein that seals the space between epithelial cells, which differs from most other claudins in that it forms water pores and sodium channels (rather than a true tight junction that is permeable to water or solute). Claudin-2, which is normally expressed in the proximal pancreatic duct, is thought to facilitate the transport of water and sodium into the duct to match the chloride and bicarbonate that are actively secreted by pancreatic duct cells through CFTR. Claudin-2 is dynamically regulated, and expression is upregulated during inflammation.

The first genome-wide association study (GWAS) to study pancreatitis identified a high-risk locus near CLDN2 on the X chromosome [Whitcomb 2012]. The high-risk variant is common with a minor allele frequency of 0.26 and was strongly associated with alcohol-related chronic pancreatitis rather than recurrent acute pancreatitis. The CLDN2-risk variant is associated with atypical localization of claudin-2 in pancreatic acinar cells. These results could partially explain the high frequency of alcohol-related pancreatitis in men (male hemizygote frequency is 0.26) compared to women (female homozygote frequency is 0.07). Nearly half of all men with a diagnosis of alcoholic pancreatitis have the high-risk CLDN2 variant.

CPA1 encodes carboxypeptidase A1, the second most abundant pancreatic digestive enzyme protein after trypsinogen, contributing up to 10% of the total secreted protein. Mutation of CPA1 is associated with nonalcoholic chronic pancreatitis, especially with an early age of onset [Witt et al 2013]. Risk for chronic pancreatitis (which is unrelated to trypsin activation) appears to be related to endoplasmic reticulum stress from pathogenic variants that alter protein folding, triggering the unfolded protein response. Sequence analysis of all ten CPA1 exons in 944 cases from Germany and 3,938 controls revealed 35 different pathogenic variants. Functional studies in the laboratory showed that many of the variants had less than 20% of expected activity and were not secreted from experimental cells, suggesting that the mutated peptides were misfolding, causing stress inside the endoplasmic reticulum. The low-activity mutated proteins were found in 3.1% of cases compared to 0.1% of controls (OR = 25). The finding, which was replicated in three other groups, was especially prevalent in children with idiopathic chronic pancreatitis.

See Genetic Risk Factors that Predispose to Pancreatitis (pdf) for additional information regarding genetic risk factors that predispose to pancreatitis; Tables 1-5 summarize some of the most common variants (and their phenotypic consequences) that may either cause HP or contribute to multigenic inheritance.

Familial Pancreatitis of Unknown Cause

In 60% of families with familial pancreatitis in which no PRSS1 pathogenic variant is identified, the genetic cause is as yet unknown.

Possible explanations for failure to identify a genetic cause to date:

  • “Missed” risk factors. Some genetic risk factors were not identified by testing methods used in the past. For example, pathogenic variant panels or variant screening that may miss rare or private pathogenic variants; classic sequencing techniques that may miss deep intronic pathogenic variants (e.g., CFTR c.3717+12191C>T) and copy number variants (e.g., PRSS1 duplication). Massively parallel sequencing approaches may help to identify rare or private pathogenic variants as well as provide the opportunity to identify variants in newly identified risk genes.
  • Unknown genetic risk factors. Even when correcting for potentially “missed” pathogenic variants, it is likely that there are pathogenic variants in genes that have not been discovered. While genotyping technologies are expanding to include copy number analysis and full gene sequencing, a substantial effort is also being made to identify novel risk factors in pancreatitis. Techniques such as analysis of large genome-wide association studies (GWAS) [Whitcomb et al 2012] and massively parallel exome/genome sequencing [LaRusch et al 2012] are now being applied with the goal of identifying novel risk factors for HP.
  • Phenocopies. Instances in which environmental factors mimic known genetic diseases are likely to be rare for a multigenerational family not living together. As environmental toxicity is a known etiology for pancreatitis, the possibility of a phenocopy mimicking familial pancreatitis cannot be completely ruled out [Khurana & Barkin 2001, Nitsche et al 2012].

Establishing the Diagnosis and Cause of Hereditary Pancreatitis in a Proband

The clinical findings, morphologic features, and laboratory findings of hereditary pancreatitis are the same as those of alcohol-related chronic pancreatitis; thus, establishing the diagnosis and cause of hereditary pancreatitis relies on medical history, family history, and/or molecular genetic testing. Of note, establishing the cause of HP informs recurrence risk counseling for family members and may inform future therapeutic options.

Medical History

Attention should be paid to: unexplained documented episode(s) of acute pancreatitis in childhood; recurrent acute attacks of pancreatitis of unknown cause; evidence for chronic pancreatitis; and history of alcohol use and tobacco smoking. In addition, the medical history should include signs and symptoms of pancreatitis-associated syndromes such as cystic fibrosis (CF), atypical CF, or Shwachman-Diamond syndrome (SDS).

The medical history may be able to exclude alternate etiologies of pancreatitis, such as biliary pancreatitis, hyperlipidemia, autoimmune disorders, obstructive pancreatitis, medications, infections, or cystic fibrosis (see CFTR-Related Disorders).

Early-onset pancreatitis (age <30 years) is often indicative of pancreatitis with an underlying genetic etiology (i.e., an autosomal dominant pathogenic variant or multiple complex pathogenic variants) [Pfützer et al 2000, Lee et al 2011], whereas late-onset pancreatitis may indicate a complex pathology with both genetic and environmental causes.

Family History

The presence in a family of two or more individuals with pancreatitis in two or more generations raises the suspicion of hereditary pancreatitis; it is appropriate to obtain a three-generation family history with attention to other relatives with signs and symptoms of acute or chronic pancreatitis.

Documentation of relevant findings in relatives can be accomplished through review of their medical records including the results of molecular genetic testing, laboratory testing, imaging studies, and operative reports. Furthermore, it is prudent to determine if any relatives have the diagnosis of cystic fibrosis (see CFTR-Related Disorders).

Note: Ongoing and high levels of alcohol and tobacco use in affected family members may indicate an alcohol-related etiology, but there is demonstrated genetic risk involved with substantial overlap with familial and idiopathic pancreatitis, such that excessive alcohol use does not exclude consideration of genetic causes of pancreatitis.

Molecular Genetic Testing

Molecular genetic testing is indicated in a proband with pancreatitis and at least one of the following:

  • An unexplained documented episode of acute pancreatitis in childhood
  • Recurrent acute attacks of pancreatitis of unknown cause
  • Chronic pancreatitis of unknown cause, particularly with onset before age 25 years
  • A history of at least one relative with recurrent acute pancreatitis, chronic pancreatitis of unknown cause, or childhood pancreatitis of unknown cause

Note: Although genetic testing techniques have advanced and additional genetic risk factors have been identified in the last ten years, the issues of privacy, consent, and clinical suitability for genetic testing for hereditary pancreatitis have not significantly changed; thus, the original consensus document [Ellis et al 2001] is still applicable and guidelines are reflected in this GeneReview [Ellis 2004, Solomon & Whitcomb 2012].

The established guidelines for genetic testing for pancreatic diseases focus on the monogenic, classic Mendelian approach; in the future, however, when the complex genetics of pancreatic disease and the role of variants in modifier genes are better understood and the cost of genotyping technology decreases, the recommendations will need updating.

Approach 1: Single-Gene Testing for Familial Pancreatitis with an Autosomal Dominant Inheritance Pattern

Currently it is recommended that sequence analysis be performed to identify a heterozygous PRSS1 pathogenic variant, the most common cause of hereditary pancreatitis (See PRSS1- Related Hereditary Pancreatitis.) Deletion/duplication analysis to detect the known duplication of PRSS1 may be appropriate when the evidence of autosomal dominant HP is strong and no pathogenic variant has been identified by sequence analysis of PRSS1 or multigene panel testing (see Approach 2).

Of note, PRSS1 has very high homology with other trypsinogen genes and pseudogenes, and the pathogenic variants often result from gene conversion events between trypsinogen genes or pseudogenes (see Chen & Ferec [2000]). Regardless of the sequencing method employed, primers must be carefully chosen and validated to amplify the fragment for the correct gene and transcript. Thus a multi-step method is required to verify the presence of a pathogenic variant in PRSS1 [Masson et al 2008b].

Approach 2: Multigene Panels for Familial Pancreatitis with an Autosomal Dominant Inheritance Pattern

Use of a multigene panel comprising PRSS1, SPINK1, CFTR, and CTRC (and possibly additional genes as they are discovered and understood) may be appropriate. This approach recognizes that:

  • Multiple genetic risk factors, such as variants in CFTR and SPINK1, are common, and various combinations of these genetic risk factors may be seen in different generations of one family [LaRusch et al 2012].
  • The dropping cost of genotyping makes the initial simultaneous testing of multiple genes cost-effective compared to the sequential testing of multiple genes, which typically also involves multiple clinical visits and counseling sessions.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

General Interpretation of Genetic Test Results

PRSS1. Identification of a heterozygous PRSS1 pathogenic variant confirms a diagnosis of hereditary pancreatitis, informs treatment, and enables variant-specific testing of at-risk family members. See PRSS1-Related Hereditary Pancreatitis.

SPINK1, CFTR, or CTRC. A subset of variants in SPINK1, CFTR and CTRC are known to be pathogenic, and discovery of combinations of these variants is strong evidence of disease association. If the person has one SPINK1, CFTR, or CTRC variant, and it segregates in a family with those with disease, the variant may be pathogenic and associated with another factor.

  • SPINK1 pathogenic variants have been identified in approximately 20% of small families with hereditary pancreatitis who do not have a PRSS1 germline pathogenic variant. Homozygosity or compound heterozygosity for p.Asn34Ser confers a high risk for autosomal recessive hereditary pancreatitis (see Genes in which Pathogenic Variants are Associated with Hereditary Pancreatitis, SPINK1); additionally p.Asn34Ser is associated with early-onset, more aggressive disease in persons with additional pathogenic variants in other genes (see Supplemental Gene Information – pdf).
  • CFTR pathogenic variants have been identified in approximately 25% of families who do not have a PRSS1 pathogenic variant. (Note: The frequency of CFTR deletions in hereditary pancreatitis has not been investigated.) For example, the CFTR variant p.Arg75Gln, which predisposes to hereditary pancreatitis by impairing the conductance of bicarbonate rather than chloride, is not associated with lung disease and typical cystic fibrosis [Schneider et al 2011, Rosendahl et al 2013]. However, the odds ratio for p.Arg75Gln is 1.5, the allele frequency is high in the general population, and the allele is only significant in the presence of a second pathogenic variant as a recessive trait (see Supplemental Gene Information).
    Individuals with symptoms of pancreatitis and a heterozygous CFTR pathogenic variant – without a SPINK1, CTRC, or CASR pathogenic variant – should be evaluated for additional manifestations of a CFTR-related disorder, such as bronchiectasis, infertility in males, and chronic sinusitis in the event that an undetected second pathogenic CFTR variant is present.
    Individuals with biallelic CFTR pathogenic variants consistent with atypical cystic fibrosis (CF) should be referred to a CF center for formal functional testing (e.g., sweat test) before the diagnosis of cystic fibrosis is confirmed.
  • CTRC. Pathogenic variants identified in a small number of persons with idiopathic chronic pancreatitis are usually linked to another trypsin-activating variant (see Complex Multigenic Disorders, CTRC; Supplemental Gene Information).
  • CPA1. Pathogenic variants are generally amino acid substitutions that cause misfolding, which is difficult to predict without functional studies. See Witt et al [2013] for information on specific variants.

Other genes. Variants in additional genes recently associated with pancreatitis, in general:

  • Are relatively low-risk alleles (e.g., odds ratio <2),
  • Have not been identified in independent cohorts, and
  • Do not have functional studies to demonstrate a plausible molecular mechanism.

Note: Often, only a single pathogenic variant in SPINK1, CFTR, or CTRC is identified in a family with HP; the variant will generally (but not exclusively) segregate with disease. Although such variants may be a risk factor for HP, additional unidentified modifying factors also contribute to disease. Of note, the majority of individuals with a single pathogenic variant in these genes do not have pancreatitis.

For further information about SPINK1, CFTR, and CTRC see Genetic Risk Factors that Predispose to Pancreatitis and Supplemental Gene Information (pdfs).

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Modes of Inheritance

Acute and chronic pancreatitis may present as part of a syndrome or as an isolated finding.

Isolated Pancreatitis

Variants associated with increased risk of isolated pancreatitis may be inherited in an autosomal dominant, autosomal recessive, or multigene manner; such variants may be classified as pathogenic (disease causing), conferring susceptibility, or disease modifiers. In those with PRSS1 allelic variants, pancreatitis may appear to be sporadic because of non-penetrance, adoption, or paternity issues; in those with allelic variants in CFTR, SPINK1, CTRC, and other genes pancreatitis may appear to be sporadic because of small family size, chance, or non-penetrance in sibs.

For all situations, genetic testing can only determine if a person has or has not inherited a variant that confers high risk for disease. Genetic testing cannot determine if the individual will develop disease, the age of disease onset, or disease severity.

The assessment of risk to family members of developing pancreatitis depends on several variables: genetic risk factors, smoking, alcohol use, gender, and developmental differences such as pancreas divisum (incomplete pancreatic duct development resulting in two duct systems rather than one, with most of the pancreas draining through a high-resistance papilla), as well as unknown environmental and genetic risk factors. Thus, risk assessment needs to be tailored to each individual and his/her family.

Autosomal dominant inheritance. PRSS1-related hereditary pancreatitis is inherited in an autosomal dominant manner.

Autosomal recessive inheritance. Pancreatitis caused by biallelic pathogenic variants in CTRC, CFTR, or SPINK1 is inherited in an autosomal recessive manner.

Digenic inheritance. Pancreatitis caused by double heterozygosity (i.e., presence of a heterozygous pathogenic variant at each of two separate genetic loci) is inherited in a digenic manner.

Multigene inheritance. Identification of multiple risk variants in any combination of the pancreatitis-associated genes indicates complex disease; genetic counseling should be handled on a case-by-case basis. Specific combinations of genetic factors may be epistatic, while others are additive. No systematic approach is available to predict the effects of most of these complex genotypes.

The severity of disease and prognosis depends on the number of variants and the relationship of the specific variants to disease causation, as well as environmental and stochastic factors; however, multigenic pancreatitis is unlikely to be inherited in an autosomal dominant fashion.

Single variant. A single variant in CTRC, CFTR, or SPINK1 may be the only identified pathogenic variant in a kindred with apparent hereditary pancreatitis, segregates exclusively with disease, and contribute to the disease manifestations in the family. However, because the vast majority of individuals heterozygous for a pathogenic variant in one of these known pancreatitis-related genes are healthy, disease pathogenesis is likely due to additional unknown factors.

For families in which a known pathogenic variant is not identified, additional risk information cannot be provided.

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.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for hereditary pancreatitis are possible.

Note: The reduced penetrance and inability to predict the natural disease course or severity of disease based on a genetic test result generally makes interpretation of prenatal testing indeterminate.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Pancreas Foundation (NPF)
    101 Federal Street
    Suite 1900
    Boston MA 02210
    Phone: 866-726-2737 (toll-free); 617-342-7019
    Fax: 617-342-7080
    Email: info@pancreasfoundation.org
  • Pancreatica.org
    149 Bonifacio Place
    Monterey CA 93940
    Phone: 831-658-0600
    Email: webmaster@pancreatica.org
  • Pancreatic Cancer Action Network
    2221 Rosecrans Avenue
    Suite 7000
    El Segundo CA 90245
    Phone: 877-272-6226 (toll-free); 310-725-0025
    Fax: 310-725-0029
    Email: info@pancan.org
  • European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer
    NIHR Pancreas Biomedical Research Unit, Royal Liverpool University Hospital
    5th Floor UCD Building
    Daulby Street
    Liverpool L69 3GA
    United Kingdom
    Phone: +44 (0) 151 706 4168
    Fax: +44 (0) 151 706 5826
    Email: europac@liverpool.ac.uk

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with hereditary pancreatitis, the following evaluations are recommended:

  • Evaluation of pancreatic exocrine function (see Chronic Pancreatitis, Maldigestion)
  • Evaluation of pancreatic endocrine function (i.e., assessment of glucose tolerance)
  • Consideration of pancreatic cancer surveillance in persons with chronic pancreatitis

Treatment of Manifestations

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

Acute Pancreatitis

Treatment of acute pancreatitis usually focuses on pain management and discontinuation of smoking and alcohol use to slow the rate of progression and to decrease the likelihood of complications, including pancreatic cancer.

Pancreatic pain can result from pancreatic duct obstruction, parenchyma hypertension, pancreatic ischemia, inflammation, neuropathy, and central pain [Fasanella et al 2007, Mullady et al 2011]. Genetic factors, many of which remain unknown or not convincingly accountable, are thought to play a role in pain perception, tolerance, and response to medication.

  • Analgesics are offered when pancreatic enzyme replacement therapy is not sufficient to control pain.
  • Antioxidants have been reported to improve pain control in a few individuals with hereditary pancreatitis [Perrault 1994, Uomo et al 2001] and non-alcoholic chronic pancreatitis [Bhardwaj et al 2009, Burton et al 2011].
  • Endoscopic or surgical interventions may be useful for treating obstructive pain [Clarke et al 2012].
  • Total pancreatectomy with islet autotransplantation is sometimes considered in patients with severe pain and/or inflammation that cannot be controlled by other approaches [Bellin et al 2011].

Endoscopic and surgical interventions are also useful for complications such as pseudocysts, bile-duct or duodenal obstruction, infected pancreatic necrosis, and malignancy.

Obstructions or calcifications in the pancreatic ducts may be relieved by procedures such as endoscopic retrograde cholangiopancreatography (ERCP), in which endoscopic cannulation of the common bile duct and pancreatic duct is followed by injection of radiographic dye. Decompressing/clearing of blockage decreases pain as well as the number of hospitalizations required and recurrent attacks in many persons with HP [Dever et al 2010]. Of note, patients with obstruction of a shorter duration have better outcomes than patients in whom treatment is delayed [Clarke et al 2012]. Note: Because of the risk for acute pancreatitis following ERCP, it is only recommended for obtaining brushings (for evaluation of strictures) and for therapeutic intervention, not for diagnosis.

Although a variety of surgical approaches are used for non-cancerous pancreatic disorders that cause pain or obstruction from multiple strictures, pancreatic surgery in those with hereditary pancreatitis is unlikely to stop the underlying inflammatory process. Furthermore, pancreatic surgery often reduces the number of islet cells which are essential in pancreatic endocrine function [Sutton et al 2010, Kobayashi et al 2011]. Because total pancreatectomy with islet cell auto-transplantation (TPIAT) may be a future option for persons with HP, retaining as many islet cells as possible is an important consideration before proceeding with any pancreatic surgery [Sutton et al 2010, Bellin et al 2011].

Pancreatectomy. Although controversial, pancreatectomy has been performed as a last resort to improve the quality of life in those with uncontrolled pain, particularly young adults and children [Sutton et al 2010, Bellin et al 2014]. It is recommended that persons in whom pancreatectomy is being considered be referred to specialized centers. In persons with adequate endocrine pancreatic function, islet cell isolation and autotransplantation may be considered at the time of total pancreatectomy [Bellin et al 2008]. Note: Caution is needed for islet autotransplantation in older adults with longstanding chronic pancreatitis and diabetes mellitus because the number of islet cells is limited and because of the potential for transplanting malignant cells.

Total pancreatectomy with islet auto-transplantation (TPIAT) is increasingly used to manage severe manifestations of pancreatitis; however, in most cases pancreatitis can be managed without TPIAT. Thus, TPIAT should only be used as a last resort [Bellin et al 2014].

Issues to consider prior to referral for TPIAT:

  • The operation is irreversible.
  • Serious and life-threatening complications are associated with the operation (as with other major surgeries).
  • Pain relief is not universal.
  • Protection from diabetes mellitus is often incomplete and of variable duration.
  • Life-long, full-dose pancreatic digestive enzyme replacement therapy will be necessary.

Chronic Pancreatitis

Treatment of chronic pancreatitis focuses on improving quality of life by managing pancreatic pain, maldigestion, and diabetes mellitus.

Pain is a variable complication of recurrent and chronic inflammation and ranges from minimal to severe and disabling. Pain can result from inflammation, ischemia, obstructed pancreatic ducts, pseudocysts, and/or maldigestion [Fasanella et al 2007].

  • One small study from Italy suggested that vitamins and antioxidants reduced pain in hereditary pancreatitis [Uomo et al 2001]; two larger studies found that antioxidants helped relieve pain in idiopathic pancreatitis [Bhardwaj et al 2009, Burton et al 2011].
  • Pain from maldigestion can be improved with pancreatic digestive enzymes [Dhanasekaran & Toskes 2010, Whitcomb et al 2010, Burton et al 2011].
  • If the main pancreatic duct is obstructed, a trial of endoscopic treatment is often used for diagnostic, therapeutic, and prognostic reasons in determining longer-term therapy.
  • Surgery has been reported to be helpful by many patients; however, surgical approaches should be postponed if islet autotransplantation is being considered.
  • Pancreatic islet autotransplantation, available in several major centers expert in the treatment of pancreatitis, is used in an attempt to both control severe pain and delay the development of diabetes mellitus [Sutton et al 2010, Kobayashi et al 2011]. It is recommended that physicians and patients work closely with expert centers since pancreatic islet autotransplantation is irreversible.

Maldigestion results from pancreatic exocrine insufficiency, which is the failure of the pancreas to produce enough digestive enzymes to digest a meal.

Clinical measures of pancreatic exocrine insufficiency include observation of steatorrhea (fat and oil in the stool), symptoms of maldigestion (bloating, gas, cramps, and diarrhea), and nutritional deficiencies (e.g., fat-soluble vitamin deficiency and protein malnutrition with low albumin, prealbumin, or retinal binding protein).

Pancreatic enzyme deficiency can be identified using invasive or noninvasive testing (see review by Lieb & Draganov [2008]). The first two are most commonly used by expert centers in the United States:

  • Fecal elastase-1 analysis (ScheBo® Biotech AG; Giessen, Germany) is a simple and relatively inexpensive test that evaluates the amount of human elastase-1 present in the stool. 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 [Amann et al 1996].
  • Secretin-stimulated pancreatic bicarbonate secretion testing (ChiRhoStim®, ChiRhoClin, Inc; Burtonsville, MD) requires intubation of the duodenum and careful measurement of pancreatic bicarbonate secretion over about an hour (depending on the method). It is considered very sensitive, but only assesses pancreatic 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.
  • 13C-mixed triglyceride breath test is of limited availability in the US. This test measures the ability of pancreatic lipase to digest a special substrate in the intestine after a test meal [Domínguez-Muñoz et al 2007].
  • 72-hour fecal fat is used to demonstrate that pancreatic digestive enzyme supplements are effective in digesting fat in the intestine of persons with severe pancreatic exocrine insufficiency. It is usually performed in a clinical research unit over four to five days during which time the patient eats a special high-fat meal (>100 grams of fat per day) and all stool samples are collected and analyzed. It is not used for diagnosis because of the complexity and inconvenience of the test.
  • Sudan stain, which identifies fat in the stool, is not sensitive or specific for pancreatic insufficiency since undigested oils or fats can be present as a result of:
    • Their nature (e.g., mineral oil, olestra), or
    • Blocking of pancreatic lipase (e.g., orlistat), or
    • Diseases of the intestinal mucosa.
  • 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.

Pancreatic enzyme replacement therapy improves digestion in those with pancreatic insufficiency who have pain with eating, steatorrhea (fat in the stool), and/or diarrhea [Perrault 1994, Whitcomb et al 2010, Burton et al 2011]. Pancreatic enzymes most effectively relieve symptoms in persons with steatorrhea and in a subset of persons without steatorrhea [Bhardwaj et al 2009, Burton et al 2011].

The amount of pancreatic enzyme replacement necessary depends on the diet and on the amount of residual pancreatic function (which diminishes over time). The normal amount of lipase secreted is about 750,000-1,000,000 units (USP) per meal. (Note that earlier papers used IU, and 1 IU = 3 USP units [Pongprasobchai & DiMagno 2005].) Since a minimum of 10% of normal pancreatic enzyme output is needed to digest a meal, about 70,000-80,000 USP units of lipase are required for an average-sized adult (70 kg) with total pancreatic insufficiency. The amount can be reduced for smaller persons and those with residual pancreatic exocrine function – while monitoring symptoms and nutritional parameters.

Diabetes mellitus is a common disorder and both type 1 and type 2 can occur in patients with pancreatitis by random chance.

Type 3c diabetes mellitus is caused by loss of pancreatic tissue as a result of surgery, chronic pancreatitis, or other rare pancreatic diseases [Rossi et al 2004, Cui & Andersen 2011, Andersen et al 2013]. Type 3c diabetes mellitus is important because loss of both the insulin-producing beta cells and the glucagon-producing alpha cells results in loss of counter-regulatory hormones and risk for hypoglycemia. Furthermore, it appears to be associated with increased risk for pancreatic cancer, and use of some anti-diabetic agents (e.g., the incretins) may be of concern [Andersen et al 2013].

Chronic pancreatitis is associated with a gradual loss of islet cell function. The following may be of benefit [Cui & Andersen 2011].

  • Monitoring for glucose intolerance
  • Optimizing pancreatic insulin secretion with pancreatic enzyme replacement therapy via amino acid and fatty acid-stimulated release of endogenous incretins from the foregut, with the addition of anti-diabetic agents as needed
  • Synchronizing the entry of nutrients into the circulation with exogenous insulin therapy delivery through diet and promoting predictable early nutrient digestion and absorption with pancreatic enzyme replacement therapy
  • Use of metformin as an oral anti-diabetic agent [Decensi et al 2010]
  • Routine screening of patients with chronic pancreatitis for glucose intolerance; recommendations for management and referral have recently been published [Rickels et al 2013b].

See also Rickels et al [2013a] for new consensus guidelines on management of diabetes in pancreatitis.

Prevention of Primary Manifestations

The ability to prevent the primary manifestations of hereditary pancreatitis (regardless of genetic cause) is limited.

The following recommendations are for individuals with (or at risk for) hereditary pancreatitis; beginning in early childhood can 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. Poor hydration (for example during exercise) can lead to episodes of pancreatitis [Authors, unpublished].
  • 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]. Anti-oxidant therapy is very low risk and low cost, and thus, an appropriate first course of action [Bhardwaj et al 2009, Burton et al 2011].
  • Cessation/abstinence from smoking and alcohol, the strongest recommendation for all persons with pancreatitis. Substantial evidence shows that oxidative stress from alcohol and tobacco smoke is inherently linked to progression and pain in pancreatitis [Schoenberg et al 1995, Petrov 2010, Tandon & Garg 2011]. This observation provides a pathophysiologic link for alcohol and tobacco smoking as risk factors, and also suggests that nutrition control may be an important preventive measure. Smoking is also a major risk for pancreatic cancer [Lowenfels et al 2001]. Note: Men with one high-risk CLDN2 variant and women with two high-risk CLDN2 variants should be strongly urged to stop drinking immediately and directed to effective treatment programs.

Circumstances to Avoid

Alcohol and tobacco use exacerbate all pancreatitis regardless of cause [Lowenfels & Whitcomb 1997]. In combination, smoking and alcohol use increases the risk of developing pancreatitis eightfold [Yadav et al 2009]. Smoking doubles the risk for all forms of pancreatitis, including hereditary pancreatitis [Maisonneuve et al 2005, Yadav et al 2009]. Tobacco use is also linked with early onset of pancreatic cancer [Lowenfels et al 2001].

Dehydration worsens episodes of acute pancreatitis. Maintaining good hydration may be helpful in minimizing attacks, especially since nausea, vomiting, and loss of appetite limit oral intake during an attack.

Physical and emotional stresses aggravate pancreatitis [Applebaum et al 2000]. Avoiding these stressors in families with HP may prevent or delay worsening of symptoms and progression of disease. Yoga and other relaxation techniques may increase quality of life in persons with pancreatitis [Sareen et al 2007]. Some patients report that regular exercise, such as running, helps reduce the frequency of episodes of pancreatitis [Authors, unpublished].

Surveillance

Surveillance for pancreatic cancer in high-risk groups with pancreatitis has been considered (see Definitions, Chronic pancreatitis for discussion of pancreatic cancer risk). However, 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.

Evaluation of Relatives at Risk

It is recommended that relatives at risk for PRSS1-related hereditary pancreatitis be offered molecular genetic testing for the family-specific germline PRSS1 pathogenic variant (see Establishing the Diagnosis, Molecular Genetic Testing) to allow early diagnosis and prevention and/or management of symptoms [Applebaum et al 2000, Ellis et al 2001, Fink et al 2007]. Testing of children is appropriate in families with early onset symptoms. Presymptomatic testing is best performed in the context of genetic counseling [Fink et al 2007].

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

Therapies Under Investigation

Currently, chemopreventive agents such as calcium-channel blockers are being investigated for treatment of manifestations of hereditary pancreatitis [Morinville et al 2007].

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions.

References

Published Guidelines / Consensus Statements

  • Bellin MD, Freeman ML, Gelrud A, Slivka A, Clavel A, Humar A, Schwarzenberg SJ, Lowe ME, Rickels MR, Whitcomb DC, Matthews JB. Total pancreatectomy and islet autotransplantation in chronic pancreatitis: Recommendations from PancreasFest. Pancreatology. 2014;14:27–35. [PMC free article: PMC4058640] [PubMed: 24555976]
  • 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, counselling, consent and privacy issues. Pancreatology. 2001;1:405–15. [PubMed: 12120217]
  • Rickels MR, Bellin M, Toledo FG, Robertson RP, Andersen DK, Chari ST, Brand R, Frulloni L, Anderson MA, Whitcomb DC. PancreasFest Recommendation Conference Participants. Detection, evaluation and treatment of diabetes mellitus in chronic pancreatitis: recommendations from PancreasFest. Pancreatology. 2013;13:336–42. [PMC free article: PMC3830751] [PubMed: 23890130]

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Chapter Notes

Author Notes

Dr Whitcomb is a physician-scientist who has dedicated his career to understanding the complexity of pancreatic physiology, pathophysiology and pancreatic diseases in humans. He is the principal investigator of the Hereditary Pancreatitis Study, and the North American Pancreatitis Study II (NAPS2), which includes more than 25 major pancreas centers in the United States. He also serves as Chief, Division of Gastroenterology, Hepatology and Nutrition at the University of Pittsburgh and UPMC. He is also the editor and webmaster of pancreas.org, and co-editor of Pancreas Education and Research Letter (PEaRL), which is patient-directed update, with Sheila Solomon MS, CGC. (available through pancreas.org). Dr Whitcomb’s work is focused on personalized medicine, with emphasis on early detection and prevention of a variety of pancreatic disorders using next generation DNA sequencing, biomarkers, and comparative effectiveness research.

A specialized Pancreas Center of Excellence incorporating genetic testing and counseling early in the evaluation of pancreatic disease has been established [Whitcomb 2012].

Revision History

  • 13 March 2014 (me) Review posted live
  • 20 December 2010 (dcw) Original Submission
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