Medical Policy

 

Subject: Genetic Testing for Hereditary Pancreatitis
Document #: GENE.00036 Publish Date:    12/27/2017
Status: Reviewed Last Review Date:    02/02/2017

Description/Scope

This document addresses the use of genetic testing for hereditary pancreatitis.

Note: Please see the following related documents for additional information:

Position Statement

Medically Necessary:

Genetic testing for hereditary pancreatitis is considered medically necessary in children under 18 years of age with recurrent pancreatitis with elevated amylase or lipase when results of the genetic test, when positive, will render additional invasive diagnostic testing unnecessary.

Investigational and Not Medically Necessary:

Genetic testing for hereditary pancreatitis is considered investigational and not medically necessary for all other indications.

Rationale

Pancreatitis is an inflammation of the pancreas. It can be acute or chronic. Acute pancreatitis occurs suddenly and usually resolves in a few days with treatment. Chronic pancreatitis does not improve, it gets worse over time and leads to permanent damage to the pancreas. Hereditary pancreatitis is a subset of chronic pancreatitis. It is an autosomal dominant disease that is characterized by frequent attacks of epigastric pain with nausea and vomiting. Symptoms of hereditary pancreatitis can start after birth, but onset varies and some people don't show symptoms until adulthood.

The majority of hereditary pancreatitis cases are associated with sequence variants in the protease, serine, 1 (trypsin 1) gene (PRSS1). It is estimated that 65-80% of individuals with hereditary pancreatitis have mutations in the PRSS1 gene. When hereditary pancreatitis is caused by mutations in the PRSS1 gene, it is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In some cases, an affected person inherits the PRSS1 gene mutation from one affected parent. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family. It is estimated that 20% of people who have the altered PRSS1 gene never have an episode of pancreatitis (this situation is known as reduced penetrance). It is unclear why some people with a mutated gene never develop signs and symptoms of the disease. And although rare, sequence variants in three other genes may show an increased risk for developing pancreatitis. These three genes are the serine peptidase inhibitor, Kazal type 1 gene (SPINK1), the chymotrypsin C (caldecrin) gene (CTRC), and the cystic fibrosis transmembrane conductance regulator (ATP-binding cassette sub-family C, member 7) gene (CFTR), which is more commonly associated with cystic fibrosis. Some cases are caused by mutations in other genes, some of which have not been identified.

Keiles (2006) retrospectively analyzed 381 individuals who were referred for genetic testing because of a problem with chronic, hereditary, or recurrent pancreatitis. All participants underwent gene analysis for CFTR, PRSS1 and SPINK1 genetic mutations. A total of 174 participants were negative for any findings in all 3 genes. A total of 22 participants carried a variant in the CFTR gene. A total of 196/381 participants (51%) were negative for any significant findings and 185/381 (49%) participants carried at least 1 mutation in 1 or more genes.

Raty and colleagues (2007) reported on 36 individuals in a Finnish family with hereditary pancreatitis. The purpose of the study was to report on the incidence of PRSS1 and SPINK1 mutations and to correlate the findings to the clinical symptoms of hereditary pancreatitis. All of the individuals underwent abdominal ultrasound and lab tests. Blood tests were done for mutational analysis of PRSS1 and SPINK1. A total of 10 individuals were affected by mutations (8 individuals had the PRSS1 mutation and 2 individuals had the SPINK1 mutation). There were 4 participants with PRSS1 mutation who had clinical chronic pancreatitis. The 2 participants with SPINK1 mutation did not show any signs or symptoms of chronic pancreatitis.

A 2010 study by Joergensen and colleagues, looked at 122 participants with pancreatitis of unknown origin and compared the clinical and genetic aspects of those with hereditary pancreatitis and with CFTR and SPINK1 mutations with those individuals who retained the diagnosis of true idiopathic pancreatitis after genetic testing for hereditary pancreatitis, SPINK1, and CTFR mutations. Blood testing was analyzed for PRSS1, SPINK1, and CFTR mutations. Genetic mutations were found in 40% of the participants. There were 18 participants initially identified as having hereditary pancreatitis, and after their first-degree relatives were tested, a total of 38 participants were identified as having hereditary pancreatitis and 28 participants had SPINK1 and CFTR mutations. Pancreatic cancer was diagnosed in 5% of the families with hereditary pancreatitis.

And while the above studies show that genetic mutations for hereditary pancreatitis may be found in individuals with chronic hepatitis, these studies are varied in the populations of people tested and varied in which genes are tested. Clinical utility has not been demonstrated as there is no evidence in the peer-reviewed published literature that treatment is changed by testing or that health outcomes are improved as a result of testing. Testing of at-risk relatives has not been shown to improve outcomes nor does it show that results of genetic testing alters the prevalence or course of disease.

The incidence of recurrent pancreatitis in children is not very common. Consequently the literature regarding genetic testing for hereditary pancreatitis in children is sparse, including some case series (Awano, 2013; Corleto, 2010; Terlizzi, 2013). While there is a paucity of evidence and literature, there is consensus opinion that, in children with recurrent episodes of pancreatitis, a positive result of this genetic testing can render additional invasive diagnostic testing unnecessary.

Background/Overview

Pancreatitis is characterized by pain associated with inflammation and damage to the pancreas. Pancreatitis can be caused by alcohol use, cholelithiasis, drug toxicity, and infections. But there also may be a genetic cause and many cases of pancreatitis are idiopathic. Hereditary pancreatitis is estimated to account for about 3% to 6% of all pancreatitis cases. Treatment of pancreatitis is mainly focused on management of symptoms, especially of pain, and of endocrine and exocrine insufficiency.

Definitions

Acute pancreatitis: This form of pancreatitis occurs suddenly, soon after the pancreas becomes damaged or irritated.

Chronic pancreatitis: This form of pancreatitis occurs when an individual has a permanently damaged or scarred pancreas. It is a slowly progressive form of pancreatitis which takes years to develop.

Pancreatitis: An inflammation of the pancreas.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

CPT

 

81222

CFTR (cystic fibrosis transmembrane conductance regulator) (eg, cystic fibrosis) gene analysis; duplication/deletion variants

81223

CFTR (cystic fibrosis transmembrane conductance regulator) (eg, cystic fibrosis) gene analysis; full gene sequence

81224

CFTR (cystic fibrosis transmembrane conductance regulator) (eg, cystic fibrosis) gene analysis; intron 8 poly-T analysis (eg, male infertility)

81401

Molecular pathology procedure, Level 2 (eg, 2-10 SNPs, 1 methylated variant, or 1 somatic variant [typically using nonsequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat) [when specified as the following]:

  • PRSS1 (protease, serine, 1 [trypsin 1]) (eg, hereditary pancreatitis), common variants (eg, N29I, A16V, R122H)

81404

Molecular pathology procedure, Level 5 (eg, analysis of 2-5 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 6-10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis) [when specified as the following]:

  • PRSS1 (protease, serine, 1 [trypsin 1]) (eg, hereditary pancreatitis), full gene sequence
  • SPINK1 (serine peptidase inhibitor, Kazal type 1) (eg, hereditary pancreatitis), full gene sequence

81405

Molecular pathology procedure, Level 6 (eg, analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11-25 exons, regionally targeted cytogenomic array analysis [when specified as the following]:

  • CTRC (chymotrypsin C) (eg, hereditary pancreatitis), full gene sequence

ICD-10 Diagnosis

 

K85.00-K85.02

Idiopathic acute pancreatitis

K85.80-K85.92

Other acute pancreatitis, unspecified

K86.1

Other chronic pancreatitis

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

References

Peer Reviewed Publications:

  1. Awano H, Lee T, Yagi M, et al. Childhood-onset hereditary pancreatitis with mutations in the CT gene and SPINK1 gene. Pediatr Int. 2013; 55(5):646-649.
  2. Axilbund JE, Wiley EA. Genetic testing by cancer site: pancreas. Cancer J. 2012; 18(4):350-354.
  3. Corleto VD, Gambardella S, Gullotta F, et al. New PRSS1 and common CFTR mutations in a child with acute recurrent pancreatitis, could be considered an "Hereditary" form of pancreatitis ? BMC Gastroenterol. 2010; 10:119.
  4. Grocock CJ, Rebours V, Delhaye MN, et al. The variable phenotype of the p.A16V mutation of cationic trypsinogen (PRSS1) in pancreatitis families. Gut. 2010; 59(3):357-363.
  5. Joergensen MT, Brusgaard K, Crüger DG, et al. Genetic, epidemiological, and clinical aspects of hereditary pancreatitis: a population-based cohort study in Denmark. Am J Gastroenterol. 2010; 105(8):1876-1883.
  6. Keiles S, Kammesheidt A. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006; 33(3):221-227.
  7. LaRusch J, Barmada MM, Solomon S, Whitcomb DC. Whole exome sequencing identifies multiple, complex etiologies in an idiopathic hereditary pancreatitis kindred. JOP. 2012; 13(3):258-262.
  8. Räty S, Piironen A, Babu M, et al. Screening for human cationic trypsinogen (PRSS1) and trypsinogen inhibitor gene (SPINK1) mutations in a Finnish family with hereditary pancreatitis. Scand J Gastroenterol. 2007; 42(8):1000-1005.
  9. Rebours V, Lévy P, Ruszniewski P. An overview of hereditary pancreatitis. Dig Liver Dis. 2012;44(1):8-15.
  10. Terlizzi V, De Gregorio F, Sepe A, et al. Brand new SPINK1 and CFTR mutations in a child with acute recurrent pancreatitis: a case report. Minerva Pediatr. 2013; 65(6):669-672.
  11. Whitcomb DC, Gorry MC, Preston RA, et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet. 1996; 14(2):141-145.
Websites for Additional Information
  1. American Gastroenterological Association. Understanding pancreatitis. Available at: www.gastro.org. Accessed on January 9, 2017.
  2. National Institutes of Health. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Available at: http://www.niddk.nih.gov/Pages/default.aspx. Accessed on January 9, 2017.
Index

Genetic testing
Pancreatitis

Document History
Status Date Action
  12/27/2017 The document header wording updated from “Current Effective Date” to “Publish Date.” Updated Coding section with 01/01/2018 CPT changes; added Tier 2 code 81405, gene CTRC.
Reviewed 02/02/2017 Medical Policy & Technology Assessment Committee (MPTAC) review. 
Reviewed 02/04/2016 MPTAC review. Removed ICD-9 codes from Coding section.
Revised 02/05/2015 MPTAC review. Added Medically Necessary statement regarding children. Updated Coding, Definitions, Rationale and References sections.
New 05/15/2014 MPTAC review. Initial document development.