Idiopathic and Hereditary Pancreatitis Testing

Preferred test for individuals with history of idiopathic pancreatitis

For adults with idiopathic pancreatitis if other components of panel (CFTR, PRSS1, SPINK1) have been sequenced without providing a complete explanation for the pancreatitis

Preferred test for individuals with idiopathic pancreatitis who:

  • Are <20 years of age OR
  • Have two affected first-degree relatives

For adults with idiopathic pancreatitis if other components of panel (CFTR, CTRC, PRSS1) have been sequenced without providing a complete explanation for the pancreatitis

May be used to test for variants causative for mild cystic fibrosis in individuals with idiopathic pancreatitis

Related Tests

Useful when a pathogenic familial variant identifiable by sequencing is known

Use to asses for large deletion/duplication in CFTR, PRSS1, or SPINK1 previously identified in a family member

Pancreatitis is a relatively common disorder with multiple etiologies that causes inflammation in the pancreas. Acute pancreatitis (AP) is a result of sudden inflammation, and patients may present with increased pancreatic enzyme concentrations. Chronic pancreatitis (CP) is a syndrome of progressive inflammation that may lead to permanent damage to pancreatic structure and function. Genetic testing can be utilized to determine a genetic cause of idiopathic or hereditary AP or CP and/or to assess risk of disease in family members.

Disease Overview

Incidence/Prevalence

  • Chronic pancreatitis
    • Incidence: ~4-12/100,000 per year 
    • Prevalence: ~37-42/100,000 
  • Idiopathic chronic pancreatitis is more common than previously thought 
  Symptoms/Presentation Etiologies
Acute pancreatitis

Sudden onset of pain in the upper abdomen, fever, nausea and vomiting, rapid pulse

Increased concentrations of pancreatic enzymes: lipase, amylase

Common

  • Gallstone passage or obstruction; chronic, heavy alcohol use

Other

  • Abdominal trauma, medications, infections, tumors, genetic abnormalities, vascular abnormalities
Chronic pancreatitis

Abdominal pain, nausea, vomiting, weight loss, diarrhea, oily stools

At advanced stages, pain often decreases, and malabsorption and diabetes may occur

Patients with CP have up to a 40% lifetime risk for pancreatic cancer 

Alcohol related

  • 44-65% of cases 
  • Alcohol use and smoking are independent risk factors but together have a multiplicative effect on risk 

Other

  • Autoimmune response, hereditary disorders of the pancreas, cystic fibrosis, hypercalcemia, hyperlipidemia, hyperparathyroidism, medications

Genetics

Genes

  • CFTR, CTRC, PRSS1, SPINK1
  • Other genes have been reported to be associated with CP but are not currently included in the ARUP test menu

Inheritance

  • PRSS1 is autosomal dominant with gain-of-function variants
    • 80% in the U.S. for PRSS1 variants R122H (p.Arg122His) and N29I (p.Asn29Ile) 
  • CFTR, CTRC, SPINK1 are autosomal recessive/digenic

Test Interpretation

Sensitivity/Specificity in Idiopathic Pancreatitis

  • Clinical sensitivity for contributory or causative variants
    • Pancreatitis panel (CFTR, CTRC, PRSS1, SPINK1) sequencing: ~48% 
    • Pancreatitis (CFTR) sequencing: ~28%
    • Pancreatitis (SPINK1) sequencing: ~16%
    • Pancreatitis (PRSS1) sequencing: ~ 9%
    • Pancreatitis (CTRC) sequencing: ~4%
    • Pancreatitis (PRSS1) deletion/duplication analysis: ~6%
  • Analytical sensitivity/specificity: 99%

Results

Result Interpretation
Positive

One of the following:

  • One PRSS1 pathogenic variant or copy number variant detected
  • Two pathogenic CFTR, SPINK1, or CTRC gene variants detected
  • One pathogenic variant detected in two different genes (digenic inheritance)
  • One pathogenic variant detected in CFTR, CTRC, or SPINK1 genes (may increase the risk for pancreatitis but is not causative)
Negative No pathogenic variants detected in any of the genes; reduces the risk for hereditary pancreatitis but genetic etiology is not excluded
Uncertain Variant(s) of uncertain clinical significance detected; may be disease-causing or benign

Limitations

  • Regulatory region variants, deep intronic variants, and some large deletions/duplications will not be detected.
  • Diagnostic errors can occur due to rare sequence variations.
  • Variants in currently unknown genes may be associated with pancreatitis.

References

Additional Resources