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PRSS1-Related Hereditary Pancreatitis

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

Author Information
, MS, CGC
Division of Gastroenterology, Hepatology & Nutrition
Department of Medicine
University of Pittsburgh
Hillman Cancer Center
Pittsburgh, Pennsylvania
, MD, PhD
Medicine, Cell Biology & Physiology, and Human Genetics
Division of Gastroenterology, Hepatology and Nutrition
University of Pittsburgh & UPMC
Pittsburgh, Pennsylvania
, PhD
Medicine, Cell Biology & Physiology, and Human Genetics
Division of Gastroenterology, Hepatology and Nutrition
University of Pittsburgh
Pittsburgh, Pennsylvania

Initial Posting: .

Summary

Disease characteristics. PRSS1-related hereditary pancreatitis (HP) 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. On average, acute pancreatitis occurs by age ten years and chronic pancreatitis by age 20 years. 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. Chronic pancreatitis typically manifests as episodic or continuous mild to severe abdominal pain, exocrine pancreatic insufficiency leading to maldigestion, and pancreatic endocrine insufficiency (glucose intolerance progressing to type I diabetes mellitus). The risk for pancreatic cancer increases after age 50 years.

Diagnosis/testing. Acute pancreatitis is the presence of two of the following three findings:

  • Sudden onset of typical epigastric abdominal pain
  • Serum amylase or lipase greater than three times normal
  • Characteristic findings on abdominal imaging

In chronic pancreatitis irreversible pancreatic changes are documented by histology, abdominal imaging, and/or functional studies. Presence of a PRSS1 disease-causing mutation establishes the diagnosis of PRSS1-related HP.

Management. Treatment of manifestations: Acute pancreatitis: prevention focuses on abstaining from smoking, drinking alcohol, exercising, and eating large fatty meals and on use of antioxidants; standard treatment of symptoms is fluid hydration, pain medication, and management of complications. Chronic pancreatitis: continue strategies to prevent acute attacks. Pancreatic enzyme replacement therapy to improve digestion in those with pancreatic insufficiency and pain with eating, steatorrhea, and/or diarrhea; treatment of diabetes mellitus type I in the usual manner with metformin being the drug of choice to address glucose intolerance and possibly reduce the rate of pancreatic cancer.

Prevention of primary manifestations: Low-fat diet, multiple small meals, good hydration during exercise, antioxidants.

Surveillance: Referral to a surveillance program that includes biomarker research and other new techniques.

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 mutation to allow early diagnosis and prevention and/or management of symptoms

Genetic counseling. PRSS1-related HP is inherited in an autosomal dominant manner. The proportion of PRSS1-related HP caused by a de novo mutation is unknown. Each child of an individual with PRSS1-related HP has a 50% chance of inheriting the mutation. Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation of an affected family member has been identified. Requests for prenatal testing for conditions such as PRSS1-related HP that do not affect intellect and have some treatment available are not common.

Diagnosis

Clinical Diagnosis

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 disease-causing germline mutation [Whitcomb & Lowe 2010]. The diagnosis of PRSS1-related hereditary pancreatitis requires the identification of a disease-causing PRSS1 mutation.

Hereditary pancreatitis usually has an acute phase and a chronic phase.

Acute pancreatitis is defined as the presence of two of the following three findings [Banks & Freeman 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 on abdominal imaging [O’Connor et al 2011]

Chronic pancreatitis is a syndrome of pancreatic inflammation lasting more than six months with irreversible pancreatic changes documented by one of the following:

  • Histology (atrophy; fibrosis and/or sclerosis)
  • 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)

Molecular Genetic Testing

Gene. PRSS1, encoding cationic trypsinogen, is the only gene in which mutations are known to cause PRSS1-related hereditary pancreatitis.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in PRSS1-Related Hereditary Pancreatitis

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
PRSS1Sequence analysis 2 / mutation scanning 3Sequence variants 460%-100%
Deletion / duplication analysis 5Exonic or whole-gene deletions≤6%
Targeted mutation analysisMutation panels vary by laboratorySee footnote 6

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Some laboratories offer sequence analysis of select exons (e.g., exons 2 and 3) because of the high prevalence of mutations in these exons, namely p.Asn29Ile in exon 2 and p.Arg122His in exon 3.

3. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably among laboratories depending on the specific protocol used.

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment.

6. 90% of PRSS1 mutations include p.Asn29Ile and p.Arg122His.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband. Molecular genetic testing of PRSS1 is indicated in persons with 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 family history of recurrent acute pancreatitis, chronic pancreatitis of unknown cause, and/or childhood pancreatitis of unknown cause consistent with autosomal dominant inheritance

Approach to molecular genetic testing:

1.

Targeted mutation analysis (of exons 2 and 3, in which 90% of mutations have been identified to date) or sequence analysis of the complete coding region of PRSS1

2.

If no mutation is identified, consideration of deletion/duplication analysis

For guidelines related to testing strategy, see:

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Pancreatitis refers to inflammation of the pancreas that can be acute (sudden onset; duration <6 months), recurrent acute (>1 episode of acute pancreatitis), or chronic (duration >6 months).

The range of symptoms and disease course vary in persons with hereditary pancreatitis. On average, onset of the disease (as acute pancreatitis) occurs by age ten years, chronic pancreatitis develops by age 20 years, and the incidence of pancreatic cancer dramatically rises at age 50 years.

Acute pancreatitis. Findings can range from vague abdominal pain lasting for one to three days to episodes of severe acute pancreatitis requiring hospitalization that may last for days to weeks.

Recurrent acute pancreatitis (RAP). Signs and symptoms of RAP secondary to hereditary pancreatitis are identical to those of pancreatitis of any other cause except they usually occur earlier in life and in the absence of an identifiable precipitating event. Persons with a PRSS1 mutation may also have other risk factors for pancreatitis, such as gallstones, alcohol consumption, and/or smoking, especially when the onset is later in life. Of note, persons with hereditary pancreatitis report that even small amounts of alcohol may sometimes trigger episodes of pain or acute pancreatitis.

In hereditary pancreatitis, RAP can lead to chronic pancreatitis [Yadav & Whitcomb 2010] and is thus regarded as a transition state to chronic pancreatitis.

Chronic pancreatitis. Long-standing inflammation results in complications that can include the following [Etemad & Whitcomb 2001]:

  • 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 chronic pain, regardless of intensity.
  • 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 and protein-vitamin deficiency detected on blood testing.
  • Pancreatic endocrine insufficiency manifesting initially as inappropriately elevated levels of blood glucose (glucose intolerance). Up to 48% of persons with HP develop diabetes mellitus type I [Howes et al 2004, Rebours et al 2009].
  • High risk for pancreatic cancer in some families and not in others [Rebours et al 2012]

Pathophysiology

The pathophysiology of hereditary pancreatitis syndrome is indistinguishable from that of other causes (e.g., idiopathic chronic pancreatitis) of RAP and CP.

The key factors are:

  • Pancreatic injury which occurs when a stressor overwhelms pancreatic defenses. With PRSS1 gain-of-function mutations, mutant cationic trypsinogen either becomes activated to trypsin too easily or is resistant to inactivation by autolysis (the hydrolysis of trypsin at arginine 122). Excess trypsin activity within the pancreas causes injury by direct hydrolysis of other proteins, activation of other pancreatic digestive enzymes, and cross-activation of the immune system.
  • Inflammatory response in which the release of the products of digestion and death of acinar cells lead to intense inflammation, manifest clinically as acute pancreatitis. Although inflammatory cells cause further damage, the acute-phase proteins (including the pancreatic secretory trypsin inhibitor coded by SPINK1 and other protease inhibitors) control the inflammation, usually within one to three days. Of note, persons who also have SPINK1 mutations have more damage and a worse clinical course than those who do not.
  • Healing/regeneration which occurs after mild acute pancreatitis without residual damage
  • Complications. Severe damage or recurrent acute pancreatitis tends to be associated with scarring (fibrosis and sclerosis). In some, but not all, individuals inflammation causes sensory nerve hypertrophy and severe pain. Chronic inflammation also increases the risk of pancreatic cancer [Whitcomb & Ulrich 1999, Yadav & Whitcomb 2010].

Genotype-Phenotype Correlations

Genotype-phenotype correlations found in persons with a p.Arg122His mutation included earlier age of onset and a more severe phenotype [Creighton et al 2000, Howes et al 2004].

Penetrance

The reported penetrance of HP varies:

This variability suggests that penetrance is determined by genetic, epigenetic, and/or environmental factors, but the mechanism is unknown

Most individuals who develop recurrent acute and/or chronic pancreatitis are symptomatic by age 20 years [Sossenheimer et al 1997, Howes et al 2004].

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.

‘Familial pancreatitis’ refers to more cases of pancreatitis in a family than expected by chance alone (i.e., >1), regardless of etiology.

‘Hereditary pancreatitis’ is a subtype of familial pancreatitis in which an autosomal inheritance pattern suggests a single gene disorder such as PRSS1-related hereditary pancreatitis.

Prevalence

The initial estimate for the total number of persons with hereditary pancreatitis in the United States was approximately 1000 based on the number of known families with hereditary pancreatitis [Lowenfels & Whitcomb 1997].

Genotyping of cohorts with pancreatitis suggests that the prevalence may be higher than previously suspected:

  • PRSS1 germline mutations associated with hereditary pancreatitis were seen in 2% to 4% of unselected individuals with chronic pancreatitis.
  • A report from France estimated a population prevalence of 0.3:100,000 persons with PRSS1-related hereditary pancreatitis [Rebours et al 2009].
  • In Denmark 12.4% of persons with pancreatitis were initially classified as having idiopathic acute and chronic pancreatitis, and 9% of these had PRSS1 mutations (1% of all patients with pancreatitis) [Joergensen et al 2010].

Differential Diagnosis

The morphologic features and laboratory findings of hereditary pancreatitis are the same as those of other etiologies including alcohol-related chronic pancreatitis, tropical pancreatitis, and idiopathic chronic pancreatitis [Shrikhande et al 2003]. Of note, alcoholic pancreatitis refers to pancreatitis resulting from increased alcohol exposure. A minimum of five drinks (>60 oz of ethanol) per day is usually required for alcohol to be a risk factor [Yadav et al 2009]. The effect of alcohol is potentiated by cigarette smoking [Yadav et al 2009].

Smoking is a dose-dependent, independent risk factor for development of chronic pancreatitis [Yadav et al 2009, Andriulli et al 2010].

The differential diagnosis of PRSS1-related hereditary pancreatitis includes familial pancreatitis, idiopathic chronic pancreatitis, CFTR-related hereditary pancreatitis, CTRC-related hereditary pancreatitis, and SPINK1-related hereditary pancreatitis.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with PRSS1-related hereditary pancreatitis, the following evaluations are recommended:

  • Evaluation of pancreatic exocrine function (see Treatment of Manifestations, 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 PRSS1-related hereditary pancreatitis are similar to those 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.

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 and surgical interventions are reserved 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 and recurrent attacks in many persons with HP [Dever et al 2010]. Note: Because of the risk of acute pancreatitis following ERCP, it is only recommended for obtaining brushings (for evaluation of strictures) and for therapeutic intervention, not 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 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].

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]. It is recommended that persons in whom pancreatectomy is being considered be referred to expert 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: Islet autotransplantation should not be offered to older adults with long-standing chronic pancreatitis and diabetes mellitus because the implanted cells may be malignant.

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 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 is improved with pancreatic digestive enzymes [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.
  • Several expert groups (e.g., University of Minnesota, University of Pittsburgh) are offering pancreatic islet autotransplantation in an effort 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 the process is irreversible.

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

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 vitamins, 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):

  • Fecal elastase-1 analysis (ScheBo® Biotech AG; Giessen, Germany). This simple and relatively inexpensive test 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). This test 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 analogues (e.g., CCK-8) or receptor agonists (e.g., cerulean) have also been used to assess acinar cell function.
  • 13C-mixed triglyceride breath test. 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. This test 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. This test, 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);
    • 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. Diabetes mellitus is a common disorder and both type 1 and type 2 can overlap with HP. 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]. Type 3c 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 of hypoglycemia.

Chronic pancreatitis is associated with a gradual loss of 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 antidiabetic 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 antidiabetic agent [Decensi et al 2010]

Prevention of Primary Manifestations

Prevention of primary manifestations in hereditary pancreatitis 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.
  • Multiple small meals. No evidence-based guidelines exist; however, small meals are recommended to 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].

Surveillance

Long-standing chronic inflammation of the pancreas is associated with an increased risk for pancreatic cancer. 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.

Because surveillance for early evidence of colon cancer is effective, it is hypothesized that such surveillance may benefit individuals with hereditary pancreatitis age 40 years and older who have long-standing chronic pancreatitis and a strong family history of pancreatic cancer. Because long-standing chronic pancreatitis results in pancreatic scarring and fibrosis that make assessment of abnormalities difficult [Brand et al 2007, Ulrich 2001], 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 use exacerbate all pancreatitis regardless of cause [Lowenfels et al 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]

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 mutation 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].

A pilot study evaluated the use of the calcium channel blocker amlodipine [Morinville et al 2007]; however, this treatment cannot yet be recommended.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

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.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

  • Many individuals diagnosed with PRSS1-related hereditary pancreatitis have an affected parent.
  • A proband with PRSS1-related hereditary pancreatitis may have the disorder as the result of a new mutation. Because simplex cases (i.e., a single occurrence in a family) have not been evaluated sufficiently to determine if the mutation was de novo, the proportion of PRSS1-related hereditary pancreatitis caused by de novo mutations is unknown.
  • If the disease-causing mutation found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include molecular genetic testing for the PRSS1 mutation identified in the proband. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: (1) Although most individuals diagnosed with PRSS1-related hereditary pancreatitis 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. (2) If the parent is the individual in whom the mutation first occurred s/he may have somatic mosaicism for the mutation and may be mildly/minimally affected.

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 mutation, the risk to the sibs of inheriting the mutation is 50%.
  • The sibs of a proband with clinically unaffected parents are still at increased risk for PRSS1-related hereditary pancreatitis because of the possibility of reduced penetrance in a parent.
  • If the disease-causing mutation found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

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

Other family members

  • The risk to other family members depends on the status of the proband's parents.
  • If a parent is affected, his or her 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 mutation. When neither parent of a proband with an autosomal dominant condition has disease-causing mutation or clinical evidence of the disorder it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal 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.

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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions which (like PRSS1-related hereditary pancreatitis) do not affect intellect, have less than 100% penetrance, and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. Although decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

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
  • 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

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. PRSS1-Related Hereditary Pancreatitis: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for PRSS1-Related Hereditary Pancreatitis (View All in OMIM)

167800PANCREATITIS, HEREDITARY; PCTT
276000PROTEASE, SERINE, 1; PRSS1

Molecular Genetic Pathogenesis

Autosomal dominant hereditary pancreatitis has been conclusively linked with gain-of-function mutations in PRSS1, the gene encoding cationic trypsinogen. Gain-of-function mutations 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 mutations are seen as part of a complex genotype more often than would be expected by chance alone.

Normal allelic variants. PRSS1 comprises five exons.

Pathologic allelic variants. The mutations p.Arg122His and p.Asn29Ile are found in approximately 90% of mutation-positive individuals [Rebours et al 2009].

Affected individuals in families with hereditary pancreatitis have been found to have copy number variants in segments containing PRSS1 and PRSS2; the same finding was reported in individuals with idiopathic chronic pancreatitis in France [Masson et al 2008a].

To date, approximately 40 additional rare or private PRSS1 variants have been identified in individuals with hereditary chronic pancreatitis or simplex (i.e., a single occurrence in a family) idiopathic chronic pancreatitis of previously unknown cause. Many of these variations have not been observed in more than one affected individual. Their clinical significance is uncertain. Copy number variants of PRSS1 should also be assessed.

Table 2. Selected PRSS1 Pathologic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.47C>Tp.Ala16ValNM_002769​.4
NP_002760​.1
c.63_71dupp.K23I_I24insIDK
c.65A>Gp.Asp22Gly
c.68A>Gp.Lys23Arg
c.86A>Tp.Asn29Ile
c.86A>Cp.Asn29Thr
c.116T>Cp.Val39Ala
c.346C>Tp.Arg116Cys
c.364C>Tp.Arg122Cys
c.365G>Ap.Arg122His
c.415T>Ap.Cys139Ser

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. PRSS1 encodes the cationic trypsinogen, one of three trypsinogens synthesized by the pancreas as digestive enzymes. Cationic trypsinogen (or trypsinogen-1) makes up about two thirds of the trypsinogens; anionic trypsinogen or trypsinogen-2 (PRSS2) makes up one third; and mesotrypsinogen makes up less than 5% [Whitcomb & Lowe 2007].

Cationic trypsin is expressed as a pre-propeptide of 247 amino acid residues that is processed to trypsinogen by cleavage of a 15-residue 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. Trypsinogen has a second calcium-binding site that persists in trypsin which when occupied by calcium prevents trypsin degradation by the action of trypsin on the autolysis site (Arg-122), and by chymotrypsin C (CTRC) at Leu-81 within the calcium binding site [Szmola & Sahin-Toth 2007]. The mature trypsin molecule is an endopeptidase that cleaves peptide chains following an Arg or Lys amino acid residue. It also serves as the master activator of pancreatic zymogens by cleaving the activation peptide of most of the other major digestive enzymes made by the pancreas.

Abnormal gene product. PRSS1 mutations associated with disease are gain of function mutations. Gain of function variants have altered regulation leading to enhanced activation or delayed or impaired inactivation.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Published Guidelines/Consensus Statements

  1. 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. 2001. Available online. Accessed 2-23-12. [PubMed: 12120217]
  2. Fink EN, Kant JA, Whitcomb DC. Genetic counseling for nonsyndromic pancreatitis. 2007. Available online (registration or institutional access required). Accessed 2-23-12.

Literature Cited

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Chapter Notes

Author Notes

Hereditary Pancreatitis Study
Hereditary pancreatitis is a form of acute and chronic pancreatitis that runs in families, usually in two or more affected people in two or more generations. In some cases the family history is unclear. Pancreatitis usually develops before age 20 years. Dr Whitcomb’s group at the University of Pittsburgh is currently recruiting participants and family members for a genetic and environment research study. The primary aim of the study is to investigate the genetic factors that increase risk for pancreatitis and factors that are linked with complications. Individuals with pancreatitis beginning before age 20 years, patients with a suspected or unknown history of pancreatitis, and their related family members may be eligible to participate. As a participant in this study you will have blood drawn or provide a saliva sample and you will fill out a questionnaire. Call the Pancreas Study Office at1-888-PITT-DNA for more information.

See www.pancreas.org for more information.

Revision History

  • 1 March 2012 (me) Review posted live
  • 5 August 2011 (ss) Initial submission
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