Prss1-Related Hereditary Pancreatitis

Clinical characteristics.

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

Diagnosis/testing.

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

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

Management.

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

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

Surveillance: Referral to a surveillance program.

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

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

Genetic counseling.

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

Suggestive Findings

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

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

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

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

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

Establishing the Diagnosis

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

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

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

Clinical Description

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

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

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

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

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

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

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

Genotype-Phenotype Correlations

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

Penetrance

The reported penetrance of PRSS1-related HP varies:

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

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

Nomenclature

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

Prevalence

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

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

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

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

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

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

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

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

Evaluations Following Initial Diagnosis

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

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

Treatment of Manifestations

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

Prevention of Primary Manifestations

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

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

Surveillance

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

Agents/Circumstances to Avoid

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

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

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

Evaluation of Relatives at Risk

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

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

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

Therapies Under Investigation

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

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