Idiopathic and Hereditary Pancreatitis Testing

Pancreatitis, Panel (CFTR, CTRC, PRSS1, SPINK1) Sequencing 2010876
Method: Polymerase Chain Reaction/Sequencing

Preferred test for individuals with history of idiopathic pancreatitis

Pancreatitis (CTRC) Sequencing 2010703
Method: Polymerase Chain Reaction/Sequencing

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

Pancreatitis (PRSS1) Sequencing and Deletion/Duplication 3001768
Method: Polymerase Chain Reaction/Sequencing and Multiplex Ligation Dependent Probe Amplification

Preferred test for individuals with idiopathic pancreatitis who

  • Are <20 years of age OR
  • Have two affected first-degree relatives
Pancreatitis (SPINK1) Sequencing 2002012
Method: Polymerase Chain Reaction/Sequencing

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

Cystic Fibrosis (CFTR) Sequencing 0051110
Method: Polymerase Chain Reaction/Sequencing

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

Related Tests
Familial Mutation, Targeted Sequencing 2001961
Method: Polymerase Chain Reaction/Sequencing

Useful when a pathogenic familial variant identifiable by sequencing is known

Pancreatitis (PRSS1) Deletion/Duplication 3001760
Method: Multiplex Ligation-dependent Probe Amplification

Second-tier test when previous full gene sequencing of PRSS1 has been performed and is negative in individuals with idiopathic pancreatitis <20 years of age and/or two affected first-degree relatives.

Appropriate test to order with PRSS1 full gene sequencing for most comprehensive coverage of PRSS1 gene.

Pancreatitis (SPINK1) Deletion/Duplication 3001764
Method: Multiplex Ligation-dependent Probe Amplification

Appropriate test for adults with idiopathic pancreatitis:

  • When previous full gene sequencing of SPINK1 has been performed and is negative or detects one variant
  • If other components of the pancreatitis panel (CTRC, CFTR, and PRSS1 genes) have been sequenced without providing a complete explanation for the pancreatitis

Pancreatitis is a relatively common disorder with many etiologies that causes inflammation in the pancreas. Acute pancreatitis (AP) is a result of acute inflammation, and patients 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 uncover 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 

Idiopathic

  • More common than previously thought 

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
  • CFTR, CTRC, SPINK1 are autosomal recessive/digenic

Penetrance

80% in the U.S. for PRSS1 variants R122H (p.Arg122His) and N29I (p.Asn29Ile) 

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%
    • Pancreatitis (SPINK1) deletion/duplication analysis: unknown
  • Analytical sensitivity/specificity: 99%

Results

Positive Negative Inconclusive

Single gain-of-function PRSS1 gene variant detected, OR copy number variant in PRSS1 detected

2 pathogenic CFTR, SPINK1, or CTRC gene variants detected, OR 1 pathogenic variant detected in 2 different genes (digenic inheritance) is causative for pancreatitis

Single pathogenic CFTR, SPINK1, or CTRC gene variant detected (increases risk for pancreatitis, but  is not causative)

No pathogenic variants detected in CFTR, CTRC, PRSS1, or SPINK1 genes

  • No genetic etiology for pancreatitis determined, but genetic etiology is not excluded

Consider additional testing if suspicions remain

Gene variant detected, but whether variant is pathogenic or benign is unknown

Limitations

  • Large deletions/duplications, regulatory region variants, and deep intronic variants will not be detected
  • Diagnostic errors can occur due to rare sequence variations
  • Variants in currently unknown genes may be associated with pancreatitis
References 
  1. Conwell DL, Lee LS, Yadav D, Longnecker DS, Miller FH, Mortele KJ, Levy MJ, Kwon R, Lieb JG, Stevens T, Toskes PP, Gardner TB, Gelrud A, Wu BU, Forsmark CE, Vege SS. American Pancreatic Association Practice Guidelines in Chronic Pancreatitis: evidence-based report on diagnostic guidelines. Pancreas. 2014; 43(8): 1143-62. PubMed
  2. Gupte A, Goede D, Tuite R, Forsmark CE. Chronic pancreatitis. BMJ. 2018; 361: k2126. PubMed
  3. Shelton C, Solomon S, LaRusch J, Whitcomb DC. PRSS1-Related Hereditary Pancreatitis. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, editors. GeneReviews, University of Washington, 1993-2019. Seattle, WA [Last Update: Apr 2019; Accessed: Jul 2019]
  4. Sossenheimer MJ, Aston CE, Preston RA, Gates LK, Ulrich CD, Martin SP, Zhang Y, Gorry MC, Ehrlich GD, Whitcomb DC. Clinical characteristics of hereditary pancreatitis in a large family, based on high-risk haplotype. The Midwest Multicenter Pancreatic Study Group (MMPSG) Am J Gastroenterol. 1997; 92(7): 1113-6. PubMed
  5. Masson E, Chen J, Audrézet M, Cooper DN, Férec C. A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients. PLoS One. 2013; 8(8): e73522. PubMed
  6. LaRusch J, Whitcomb DC. Genetics of pancreatitis. Curr Opin Gastroenterol. 2011; 27(5): 467-74. PubMed
  7. Yadav D, Lowenfels AB. The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology. 2013; 144(6): 1252-61. PubMed

Last Update: August 2019