Genetic Testing for Hereditary Pancreatitis AHS – M2079

Description of Procedure or Service

Pancreatitis is defined as inflammation of the pancreas that progresses from acute (AP) (sudden onset; duration <6 months) to recurrent acute (RAP) (>1 episode of acute pancreatitis) to chronic (CP) (duration >6 months) (Jessica LaRusch, Solomon, & Whitcomb, 2014). This recurrent inflammation can lead to total destruction of the pancreas with subsequent pancreatic insufficiency, secondary diabetes, increased risk for pancreatic cancer and severe unrelenting pain (Ravi Kanth & Nageshwar Reddy, 2014).

Hereditary pancreatitis is the early onset form of chronic pancreatitis that is carried in an autosomal dominant pattern with variable penetrance (J. LaRusch, Barmada, Solomon, & Whitcomb, 2012).

***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician.

Policy

BCBSNC will provide coverage for genetic testing for hereditary pancreatitis when it is determined to be medically necessary because the medical criteria and guidelines shown below are met.

Benefits Application

This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore member benefit language should be reviewed before applying the terms of this medical policy.

When Genetic Testing for Hereditary Pancreatitis is covered

Genetic testing for hereditary pancreatitis is considered medically necessary in symptomatic patients <20 years old and the individual is presenting with one of the following situations:

1. Recurrent (two separate, documented episodes with hyperlipasemia) attacks of acute pancreatitis for which there is no identifiable cause
2. Unexplained chronic pancreatitis (define)
3. Unexplained pancreatitis with family history of recurrent acute pancreatitis, idiopathic chronic pancreatitis, or childhood pancreatitis without a known cause in a first- or second-degree relative
4. Unexplained episode of pancreatitis in a child that required hospitalization

When Genetic Testing for Hereditary Pancreatitis is not covered

Genetic testing for hereditary pancreatitis is considered investigational in all other situations.

Policy Guidelines

Background

Pancreatitis is caused by unregulated trypsin activity within the pancreatic acinar cell or pancreatic duct that leads to pancreatic autodigestion, and pancreatic inflammation (Lerch & Gorelick, 2000; D. C. Whitcomb, 1999). Under acinar cell stress (e.g., hyperstimulation, intracellular hypercalcemia), intracellular trypsinogen is likely converted to trypsin, which activates other digestive enzymes causing injury. Injury releases immune system-activating molecules that cause an initial acute inflammatory response, followed by recruitment of tissue macrophages and activated pancreatic stellate cells. Recurrent injury leads to chronic pancreatitis and fibrosis, mediated by pancreatic stellate cells (Werlin et al., 2015).

Chronic pancreatitis (CP) is a progressive inflammatory disease in which the pancreatic tissue is destroyed over time and replaced by fibrous tissue. The process of fibrosis usually leads to progressive worsening in structure of pancreas, changes in arrangement and composition of the islets and deformation of the large ducts (Brock, Nielsen, Lelic, & Drewes, 2013), eventually leading to the impairment of both exocrine and endocrine functions (Braganza, Lee, McCloy, & McMahon, 2011). The annual incidence of the disease has been estimated to 5-10 per 100,000 persons. (Molven, Njolstad, & Weiss, 2015) The main symptom of CP is pain, however it is highly variable in character, frequency, and severity (Mullady et al., 2011; D. C. Whitcomb et al., 2008). Therapeutic efforts are mostly aimed at extracting stones and decompressing pancreatic ducts to achieve ideal drainage of the pancreatic duct (Li et al., 2010; Tandan & Nageshwar Reddy, 2013).

The etiologies of chronic pancreatitis are classified by the TIGAR-O system into alcoholism, hyperlipidemia, obstructive damage caused by trauma or congenital anomalies, hereditary pancreatitis, autoimmune pancreatitis, and idiopathic(Etemad & Whitcomb, 2001; Sun et al., 2015) The most common by far being alcohol abuse, accounting for around 70% of all cases.

Hereditary pancreatitis (HP) presents as an autosomal dominant chronic pancreatitis with variable penetrance. This variability has been attributed to a genetic predisposition to chronic pancreatitis, with the additive effects of environmental and inherited factors. Most pancreatitis genes either directly encode components of the trypsin system of the exocrine pancreas or are likely to perturb this system indirectly.

The phenotype of HP is increased susceptibility to acute pancreatitis, resulting in chronic pancreatitis (including pancreatic fibrosis, chronic pain, maldigestion and diabetes mellitus) occurring in at least 50%. The risk of pancreatic cancer is also increased.

Genes associated with Hereditary Pancreatitis from: (Ooi, Gonska, Durie, & Freedman, 2010; Vue, McFann, & Narkewicz, 2016)

PRSS1 encodes trypsin-1 (cationic trypsinogen) a major pancreatic digestive enzyme. Mutations in PRSS1 typically result in a trypsin protein that is either prematurely activated or resistant to degradation(J. LaRusch et al., 2012; Masson, Le Marechal, Delcenserie, Chen, & Ferec, 2008)causing autosomal dominant pancreatitis in 60%-100% of families with hereditary pancreatitis (J. LaRusch & Whitcomb, 2011).

SPINK1 encodes serine protease inhibitor, Kazel-type 1, a trypsin inhibitor that is upregulated by inflammation(Grendell, 2003). It is not a typical susceptibility gene for acute pancreatitis, but rather a susceptibility gene for the chronic pancreatitis that follows acute pancreatitis

CTRC encodes chymotrypsin C, Prematurely activated trypsin is destroyed by CTRC by acting on the molecule within the calcium-binding loop in the absence of calcium and therefore is a crucial candidate gene in the pathogenesis of pancreatitis (Szmola & Sahin-Toth, 2007).

CASR encodes calcium sensing receptor, mutations of which can cause increased calcium ion levels increasing trypsin activation and failed trypsin degradation (D. C. Whitcomb, 2004a).

CFTR encodes the cystic fibrosis transmembrane conductance protein. Mutations are associated with recurrent acute and chronic pancreatitis as dysfunctional CFTR results in retention of zymogens which can become active and result in pancreatitis (J. LaRusch & Whitcomb, 2011).

CLDN2 encodes claudin-2, a tight-junction protein that seals the space between epithelial cells, normally expressed in the proximal pancreatic duct, and is thought to facilitate the transport of water and sodium into the duct to match the chloride and bicarbonate that are actively secreted by pancreatic duct cells through CFTR. It is strongly associated with alcohol-related chronic pancreatitis rather than recurrent acute pancreatitis(Ravi Kanth & Nageshwar Reddy, 2014).

CPA1 encodes carboxypeptidase A1, mutation is associated with nonalcoholic chronic pancreatitis, especially with an early age of onset (Witt et al., 2013). Risk for chronic pancreatitis (which is unrelated to trypsin activation) appears to be related to endoplasmic reticulum stress from pathogenic variants that alter protein folding, triggering the unfolded protein response.
MYO9B gene and the two tight-junction adaptor genes, PARD3 and MAGI2, have been linked to gastrointestinal permeability. Impairment of the mucosal barrier plays an important role in the pathophysiology of acute pancreatitis. (Nijmeijer et al., 2013).

CEL encodes carboxyl-ester lipase, mutations can cause an autosomal dominant syndrome of maturity-onset diabetes of the young (MODY) and exocrine pancreatic dysfunction (Molven et al., 2015).

As the number of genes and mutations involved in the onset and progression of pancreatitis becomes higher (Ooi et al., 2010; Walker, Warren, Gawn, & Jiao, 2013), the time and cost of screening and sequencing specific genes continues to increase. However, massive parallel sequencing or next generation sequencing (NGS) is becoming standardized(Ballard et al., 2015), and the cost per patient is rapidly dropping(Palermo et al., 2016). NGS includes whole genome sequencing, whole exome sequencing (WES) and other methods. Because the cost of WES is now less than the cost of sequencing CFTR use of this technology is becoming an attractive alternative to classic targeted gene sequencing or mutation specific genotyping for a genetic counseling workup (J. LaRusch et al., 2012).

Clinical Validity and Utility

Testing for mutations in the PRSS1, SPINK, and CFTR genes is usually done by either direct sequence analysis or next generation sequencing, both of which have high analytic validity. Several studies have evaluated the clinical validity of genetic testing (Applebaum-Shapiro et al., 2001; Ceppa et al., 2013; Poddar, Yachha, Mathias, & Choudhuri, 2015; Sultan, Werlin, & Venkatasubramani, 2012). One limitation with some studies was lack of inclusion of patients with clinically defined hereditary pancreatitis. Hence, the true clinical sensitivity and specificity of genetic testing in hereditary pancreatitis cannot be accurately determined and needs to be further researched. Similarly, there is a lack of published literature on the clinical utility of testing. Further research is required to evaluate how genetic testing will impact patient management decision and clinical outcomes.

Kumar et al (2016) sought to characterize and identify risk factors associates with ARP and CP in childhood in a multinational cross sectional study (INSPPIRE). They found that “At least 1 gene mutation in pancreatitis-related genes was found in 48% of patients with ARP vs 73% of patients with CP (P < .001). Children with PRSS1 or SPINK1 mutations were more likely to present with CP compared with ARP (PRSS1: OR = 4.20; 95% CI, 2.14-8.22; P < .001; and SPINK1: OR = 2.30; 95% CI, 1.03-5.13; P = .04). Obstructive risk factors did not differ between children with ARP or CP (33% in both the ARP and CP groups), but toxic/metabolic risk factors were more common in children with ARP (21% overall; 26% in the ARP group and 15% in the CP group; OR = 0.55; 95% CI, 0.31-0.99; P = .046).” They conclude that “Genetic mutations are common in both ARP and CP. Ethnicity and mutations in PRSS1 or SPINK1 may influence the development of CP. The high disease burden in pediatric CP underscores the importance of identifying predisposing factors for progression of ARP to CP in children.”

Gabarczyk (2017) et al also found that CTRC variants are strong CP risk factors in pediatric patients. They showed that p.Arg254Trp (4.6%) and p.Lys247_Arg254del (5.3%) heterozygous mutations are frequent and significantly associated with CP risk in pediatric patients (odds ratio [OR] = 19.1; 95% CI 2.8-160; P = 0.001 and OR = 5.5; 95% CI 1.6-19.4; P = 0.001, respectively) and that the c.180TT genotype of common p.Gly60Gly variant is strong, an independent CP risk factor (OR = 23; 95% CI 7.7-70; P < 0.001) with effect size comparable to p.Arg254Trp mutation.

According to Whitcomb (2017), genetic testing for pancreatitis susceptibility genes (PRSS1, CFTR, SPINK1, and CTRC) in symptomatic patients should be considered in patients who meet any of the following criteria:

• An unexplained documented episode of pancreatitis as a child
• Idiopathic chronic pancreatitis, particularly when the onset of pancreatitis occurs before age 25 
• A family history of recurrent acute pancreatitis, idiopathic chronic pancreatitis, or childhood pancreatitis without a known cause 
• Relatives known to carry mutations associated with hereditary pancreatitis (ie, PRSS1 mutations) 
• Recurrent acute attacks of pancreatitis for which there is no identifiable cause 
• Patients eligible for approved research protocols 

For asymptomatic patients, predictive testing can be considered for individuals who have a firstdegree relative with a known PRSS1 mutation, but is generally not recommended for individuals under 16 years of age (D. Whitcomb, 2017). Additionally, predictive testing of SPINK1 or CFTR mutations in asymptomatic individuals is of minimal value, because mutations are common and most patients with these mutations do not develop disease (D. Whitcomb, 2017). 

Applicable Federal Regulations

This test is considered a laboratory developed test (LDT); developed, validated and performed by individual laboratories.

LDTs are regulated by the Centers for Medicare and Medicaid (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA’88).

As an LDT, the U. S. Food and Drug Administration has not approved or cleared this test; however, FDA clearance or approval is not currently required for clinical use.

Guidelines and Recommendations

Practice Guidelines and Position Statements

A Consensus Committees of the European Registry of Hereditary Pancreatic Diseases, the Midwest Multi-Center Pancreatic Study Group and the International Association of Pancreatology developed guidelines for genetic testing of the PRSS1 gene and genetic counseling for HP (Ellis, Lerch, & Whitcomb, 2001). The recommended indications for symptomatic patients included:

• Recurrent (two separate, documented episodes with hyperlipasemia) attacks of acute pancreatitis for which there is no explanation (anatomical anomalies, ampullary or main pancreatic strictures, trauma, viral infection, gallstones, alcohol, drugs, hyperlipidaemia, etc.)
• Unexplained chronic pancreatitis 
• A family history of pancreatitis in a first- or second-degree relative
• Unexplained episode of pancreatitis in a child that required hospitalization 

Predictive (presymptomatic) genetic testing of unaffected relatives is considered more complex. Predictive testing is recommended only for individuals with a first-degree relative with a defined HP gene mutation, and who are over 16 years of age and capable of making an independent a fully informed decision (Ellis et al., 2001).

The American Society of Clinical Oncology (ASCO) states that “genetic testing is sometimes considered for patients who develop recurrent pancreatitis at young ages. Genetic testing is available for mutations in the PRSS1, SPINK1, and CFTR genes”("American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility," 2003).

In 2013, the American College of Gastroenterology issued guidelines for the management of acute pancreatitis. They include the following recommendation: “genetic testing may be considered in young patients (< 30 years old) if no cause is evident and a family history of pancreatic disease is present (conditional recommendation, low quality of evidence)”(Tenner, Baillie, DeWitt, & Vege, 2013). ACG also states that “the role of genetic testing in AP has yet to be determined, but may be useful in patients with more than one family member with pancreatic disease. Individuals with IAP and a family history of pancreatic diseases should be referred for formal genetic counseling” (Tenner et al., 2013).

United European Gastroenterology

The United European Gastroenterology published evidence based guidelines (Lohr et al., 2017) for the diagnosis and therapy of chronic pancreatitis which recommend:

All patients with a family history or early onset disease (<20 years) should be offered genetic testing for associated variants.

Genetic screening for every CP patient cannot be recommended since alcohol abuse is the predominant cause of the disease in up to 60% of adult cases. In patients with early onset CP, genetic screening can be offered after informed consent (see Statement 1-2). Note, the genetic test results will neither change the medical treatment offered to the patient nor alter the disease course. However, it might enable some patients to understand their disease better and might even impact family planning. In patients with alcoholic CP, routine genetic testing cannot be recommended. Variants in SPINK1 and CTRC, and to a lesser extent, common single-nucleotide polymorphisms (SNPs) in the PRSS1 and CLDN2-MORC4 loci, are associated with alcoholic CP.

European Pancreatic Club/ Hungarian Pancreatic Study Group

The European Pancreatic Club, in collaboration with the Hungarian Pancreatic Study Group organized a consensus guideline meeting on the diagnosis and management of pancreatitis in the pediatric population which recommend:

Pediatric AP and RAP often develop in the background of genetic susceptibility and genetic testing is warranted in patients with a second episode of idiopathic AP or first episode of idiopathic AP and a family history of AP or CP, full sequence analysis of PRSS1, SPINK1, CTRC, CPA1 and CFTR gene exons and exon-intron boundaries and testing for the pathogenic CEL hybrid allele are recommended. Variants in the PRSS1 and CPA1 genes may be associated with a family history of pancreatitis or even autosomal dominant hereditary pancreatitis. Children with a single episode of AP are at risk for developing a second episode. However, genetic testing is cumbersome and expensive. There is usually no therapeutic consequence, but it may assist in long term prognosis.

The presence of mutations in the above mentioned genes increases the risk of ARP and CP. Hereditary pancreatitis associated with mutations in PRSS1, especially p.R122H that could considerably increase the risk of pancreatic adenocarcinoma. Knowing the genetic risk factors may not alter the therapy, but it helps to understand the disease's etiological background for the disease and may lead to future targeted investigation.

Billing/Coding/Physician Documentation Information

This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page.

Scientific Background and Reference Sources

American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. (2003). J Clin Oncol, 21(12), 2397-2406. doi:10.1200/jco.2003.03.189

Applebaum-Shapiro, S. E., Finch, R., Pfutzer, R. H., Hepp, L. A., Gates, L., Amann, S., . . . Whitcomb, D. C. (2001). Hereditary pancreatitis in North America: the Pittsburgh-Midwest Multi-Center Pancreatic Study Group Study. Pancreatology, 1(5), 439-443.

Ballard, D. D., Flueckiger, J. R., Fogel, E. L., McHenry, L., Lehman, G. A., Watkins, J. L., . . . Cote, G. A. (2015). Evaluating Adults With Idiopathic Pancreatitis for Genetic Predisposition: Higher Prevalence of Abnormal Results With Use of Complete Gene Sequencing. Pancreas, 44(1), 116-121. doi:10.1097/mpa.0000000000000225

Braganza, J. M., Lee, S. H., McCloy, R. F., & McMahon, M. J. (2011). Chronic pancreatitis. Lancet, 377(9772), 1184-1197. doi:10.1016/s0140-6736(10)61852-1

Brock, C., Nielsen, L. M., Lelic, D., & Drewes, A. M. (2013). Pathophysiology of chronic pancreatitis. World J Gastroenterol, 19(42), 7231-7240. doi:10.3748/wjg.v19.i42.7231

Ceppa, E. P., Pitt, H. A., Hunter, J. L., Leys, C. M., Zyromski, N. J., Rescorla, F. J., . . . Lehman, G. A. (2013). Hereditary pancreatitis: endoscopic and surgical management. J Gastrointest Surg, 17(5), 847-856; discussion 856-847. doi:10.1007/s11605-013-2167-8

Durie, P. R. (1996). Inherited and congenital disorders of the exocrine pancreas. Gastroenterologist, 4(3), 169-187.

Ellis, I., Lerch, M. M., & Whitcomb, D. C. (2001). Genetic testing for hereditary pancreatitis: guidelines for indications, counselling, consent and privacy issues. Pancreatology, 1(5), 405-415.

Etemad, B., & Whitcomb, D. C. (2001). Chronic pancreatitis: diagnosis, classification, and new genetic developments. Gastroenterology, 120(3), 682-707.

Grabarczyk, A. M., Oracz, G., Wertheim-Tysarowska, K., Kujko, A. A., Wejnarska, K., Kolodziejczyk, E., Rygiel, A. M. (2017). Chymotrypsinogen C Genetic Variants, Including c.180TT, Are Strongly Associated With Chronic Pancreatitis in Pediatric Patients. J Pediatr Gastroenterol Nutr, 65(6), 652-657. doi:10.1097/mpg.0000000000001767

Grendell, J. H. (2003). Genetic factors in pancreatitis. Curr Gastroenterol Rep, 5(2), 105-109.

Kumar, S., Ooi, C. Y., Werlin, S., Abu-El-Haija, M., Barth, B., Bellin, M. D., . . . Uc, A. (2016). Risk Factors Associated With Pediatric Acute Recurrent and Chronic Pancreatitis: Lessons From INSPPIRE. JAMA Pediatr, 170(6), 562-569. doi:10.1001/jamapediatrics.2015.4955

LaRusch, J., Barmada, M. M., Solomon, S., & Whitcomb, D. C. (2012). Whole exome sequencing identifies multiple, complex etiologies in an idiopathic hereditary pancreatitis kindred. Jop, 13(3), 258-262.

LaRusch, J., Solomon, S., & Whitcomb, D. C. (2014). Pancreatitis Overview. GEneReviews. 

LaRusch, J., & Whitcomb, D. C. (2011). Genetics of pancreatitis. Curr Opin Gastroenterol, 27(5), 467-474. doi:10.1097/MOG.0b013e328349e2f8

Lerch, M. M., & Gorelick, F. S. (2000). Early trypsinogen activation in acute pancreatitis. Med Clin North Am, 84(3), 549-563, viii.

Lerch, M. M., Zenker, M., Turi, S., & Mayerle, J. (2006). Developmental and metabolic disorders of the pancreas. Endocrinol Metab Clin North Am, 35(2), 219-241, vii. doi:10.1016/j.ecl.2006.02.004

Li, Z. S., Wang, W., Liao, Z., Zou, D. W., Jin, Z. D., Chen, J., . . . Wang, L. (2010). A long-term follow-up study on endoscopic management of children and adolescents with chronic pancreatitis. Am J Gastroenterol, 105(8), 1884-1892. doi:10.1038/ajg.2010.85

Lohr, J. M., Dominguez-Munoz, E., Rosendahl, J., Besselink, M., Mayerle, J., Lerch, M. M., Bruno, M. (2017). United European Gastroenterology evidence-based guidelines for the diagnosis and therapy of chronic pancreatitis (HaPanEU). United European Gastroenterol J, 5(2), 153-199. doi:10.1177/2050640616684695

Masson, E., Le Marechal, C., Delcenserie, R., Chen, J. M., & Ferec, C. (2008). Hereditary pancreatitis caused by a double gain-of-function trypsinogen mutation. Hum Genet, 123(5), 521- 529. doi:10.1007/s00439-008-0508-6

Molven, A., Njolstad, P. R., & Weiss, F. U. (2015). Lipase gene fusion: a new route to chronic pancreatitis. In Oncotarget (Vol. 6, pp. 30443-30444). United States.

Mullady, D. K., Yadav, D., Amann, S. T., O'Connell, M. R., Barmada, M. M., Elta, G. H., Anderson, M. A. (2011). Type of pain, pain-associated complications, quality of life, disability and resource utilisation in chronic pancreatitis: a prospective cohort study. Gut, 60(1), 77-84. doi:10.1136/gut.2010.213835

Nijmeijer, R. M., van Santvoort, H. C., Zhernakova, A., Teller, S., Scheiber, J. A., de Kovel, C. G.,Wijmenga, C. (2013). Association analysis of genetic variants in the myosin IXB gene in acute pancreatitis. PLoS One, 8(12), e85870. doi:10.1371/journal.pone.0085870

Ooi, C. Y., Gonska, T., Durie, P. R., & Freedman, S. D. (2010). Genetic testing in pancreatitis. Gastroenterology, 138(7), 2202-2206, 2206.e2201. doi:10.1053/j.gastro.2010.04.022

Palermo, J. J., Lin, T. K., Hornung, L., Valencia, C. A., Mathur, A., Jackson, K.,Abu-El-Haija, M. (2016). Genophenotypic Analysis of Pediatric Patients With Acute Recurrent and Chronic Pancreatitis. Pancreas, 45(9), 1347-1352. doi:10.1097/mpa.0000000000000655

Poddar, U., Yachha, S. K., Mathias, A., & Choudhuri, G. (2015). Genetic predisposition and its impact on natural history of idiopathic acute and acute recurrent pancreatitis in children. Dig Liver Dis, 47(8), 709-714. doi:10.1016/j.dld.2015.04.012

Ravi Kanth, V., & Nageshwar Reddy, D. (2014). Genetics of acute and chronic pancreatitis: An update. World J Gastrointest Pathophysiol, 5(4), 427-437. doi:10.4291/wjgp.v5.i4.427

Sultan, M., Werlin, S., & Venkatasubramani, N. (2012). Genetic prevalence and characteristics in children with recurrent pancreatitis. J Pediatr Gastroenterol Nutr, 54(5), 645-650. doi:10.1097/MPG.0b013e31823f0269

Sun, C., Liu, M. Y., Liu, X. G., Hu, L. H., Xia, T., Liao, Z., & Li, Z. S. (2015). Serine Protease Inhibitor Kazal Type 1 (SPINK1) c.194+2T > C Mutation May Predict Long-term Outcome of Endoscopic Treatments in Idiopathic Chronic Pancreatitis. Medicine (Baltimore), 94(47), e2046. doi:10.1097/md.0000000000002046

Szmola, R., & Sahin-Toth, M. (2007). Chymotrypsin C (caldecrin) promotes degradation of human cationic trypsin: identity with Rinderknecht's enzyme Y. Proc Natl Acad Sci U S A, 104(27), 11227-11232. doi:10.1073/pnas.0703714104

Tandan, M., & Nageshwar Reddy, D. (2013). Endotherapy in chronic pancreatitis. World J Gastroenterol, 19(37), 6156-6164. doi:10.3748/wjg.v19.i37.6156

Tenner, S., Baillie, J., DeWitt, J., & Vege, S. S. (2013). American College of Gastroenterology guideline: management of acute pancreatitis. Am J Gastroenterol, 108(9), 1400-1415; 1416. doi:10.1038/ajg.2013.218

Vue, P. M., McFann, K., & Narkewicz, M. R. (2016). Genetic Mutations in Pediatric Pancreatitis. Pancreas, 45(7), 992-996. doi:10.1097/mpa.0000000000000589

Walker, N. F., Warren, O. J., Gawn, L., & Jiao, L. R. (2013). The role of genetic testing in management of hereditary chronic pancreatitis. JRSM Short Rep, 4(1), 6. doi:10.1258/shorts.2012.012071

Werlin, S., Konikoff, F. M., Halpern, Z., Barkay, O., Yerushalmi, B., Broide, E., . . . Wilschanski, M. (2015). Genetic and electrophysiological characteristics of recurrent acute pancreatitis. J Pediatr Gastroenterol Nutr, 60(5), 675-679. doi:10.1097/mpg.0000000000000623

Whitcomb, D. (2017). Hereditary pancreatitis. In M. Heyman (Ed.), UpToDate. Waltham. MA. 

Whitcomb, D. C. (1999). Early trypsinogen activation in acute pancreatitis. Gastroenterology, 116(3), 770-772.

Whitcomb, D. C. (2004a). Mechanisms of disease: Advances in understanding the mechanisms leading to chronic pancreatitis. Nat Clin Pract Gastroenterol Hepatol, 1(1), 46-52. doi:10.1038/ncpgasthep0025

Whitcomb, D. C. (2004b). Value of genetic testing in the management of pancreatitis. Gut, 53(11), 1710-1717. doi:10.1136/gut.2003.015511

Whitcomb, D. C., Yadav, D., Adam, S., Hawes, R. H., Brand, R. E., Anderson, M. A., . . Barmada, M. M. (2008). Multicenter approach to recurrent acute and chronic pancreatitis in the United States: the North American Pancreatitis Study 2 (NAPS2). Pancreatology, 8(4-5), 520- 531. doi:10.1159/000152001

Witt, H., Beer, S., Rosendahl, J., Chen, J. M., Chandak, G. R., Masamune, A.,Sahin-Toth, M. (2013). Variants in CPA1 are strongly associated with early onset chronic pancreatitis. Nat Genet, 45(10), 1216-1220. doi:10.1038/ng.2730

Policy Implementation/Update Information

1/1/2019 BCBSNC will provide coverage for genetic testing for hereditary pancreatitis when it is determined to be medically necessary because the medical criteria and guidelines are met. Medical Director review 1/1/2019. Policy noticed 1/1/2019 for effective date 4/1/2019. (jd)