Medical Policy

 


Subject: Genetic Testing for Hereditary Pancreatitis
Document #: GENE.00036 Publish Date:    02/28/2018
Status: Reviewed Last Review Date:    01/25/2018
 
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 typically resolves in a few days. Chronic pancreatitis worsens over time and may lead to permanent pancreatic damage. Hereditary pancreatitis is a type 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 won’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. 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. Of the 381 participants tested, 174 were negative for any findings in all three genes, 22 carried a variant in the CFTR gene, 196 (51%) were negative for any significant findings, and 185 (49%) carried at least one mutation in one 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.

In a 2017 meta-analysis by Hu and colleagues, eight studies were reviewed to look at the association between the p.R122H mutation in the PRSS1 gene and the risk of chronic pancreatitis. While the studies showed that a PRSS1 mutation was associated with an increased risk of hereditary chronic pancreatitis, there was no mention of clinical utility. 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 common. Consequently the literature regarding genetic testing for hereditary pancreatitis in children is sparse, including small case series (Awano, 2013; Corleto, 2010; Dai, 2016; 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 other, 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. Pancreatitis may also have a genetic cause or be idiopathic. Hereditary pancreatitis is estimated to account for approximately 3% to 6% of all pancreatitis cases. Treatment of pancreatitis is focused on management of symptoms, especially of pain, and of any associated 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 may take 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. Dai LN, Chen YW, Yan WH, et al. Hereditary pancreatitis of 3 Chinese children: case report and literature review. Medicine (Baltimore). 2016; 95(36):e4604.
  5. 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.
  6. Hu C, Wen L, Deng L, et al. The differential role of human cationic trypsinogen (PRSS1) p.R122H mutation in hereditary and nonhereditary chronic pancreatitis: a systematic review and meta-analysis. Gastroenterol Res Pract. 2017; 2017:9505460.
  7. 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.
  8. Keiles S, Kammesheidt A. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006; 33(3):221-227.
  9. 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.
  10. 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.
  11. Rebours V, Lévy P, Ruszniewski P. An overview of hereditary pancreatitis. Dig Liver Dis. 2012; 44(1):8-15.
  12. 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.
  13. 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.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Tenner S, Baillie J, DeWitt J, et al. American College of Gastroenterology guideline: management of acute pancreatitis. Am J Gastroenterol. 2013; 108(9):1400-1415.
Websites for Additional Information
  1. American Gastroenterological Association. Understanding pancreatitis. Available at: www.gastro.org. Accessed on December 7, 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 December 7, 2017.
Index

Genetic testing
Pancreatitis

Document History

Status

Date

Action

Reviewed

01/25/2018

Medical Policy & Technology Assessment Committee (MPTAC) review. Updated Rationale, Background/Overview, Definitions, and References sections.

 

01/01/2018

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

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.