CAM 20499

Genetic Testing for Hereditary Pancreatitis

Category:Laboratory   Last Reviewed:July 2019
Department(s):Medical Affairs   Next Review:July 2020
Original Date:April 2014    

Description
In chronic pancreatitis (CP), recurrent attacks of acute pancreatitis evolve into a chronic inflammatory state with exocrine insufficiency, diabetes and increased risk for pancreatic cancer. Hereditary pancreatitis (HP) is a subset of CP defined clinically as a familial pattern of CP. Variants of several genes are associated with HP. Demonstration of a pathogenic variant in one or several of these genes can potentially be used to confirm the diagnosis of HP, provide information on prognosis and management and/or determine the risk of CP in asymptomatic relatives of patients with HP.

For individuals who have CP or acute recurrent pancreatitis (ARP) who receive testing for genes associated with HP, the evidence includes cohort studies on variant detection rates. Relevant outcomes are test accuracy, symptoms, change in disease status, morbid events and hospitalizations. There are studies on the detection rate of HP-associated genes in various populations. Few studies have enrolled patients with known HP; those doing so have reported detection rates for disease-associated variants between 52% and 62%. For other studies that tested patients with CP or ARP, disease-associated variant detection rates varied widely across studies. There is a lack of direct evidence that testing for HP improves health outcomes, and insufficient chain of evidence that, in patients with CP or ARP, management would change after genetic testing in a manner likely to improve health outcomes. The evidence is insufficient to determine the effects of the technology on health outcomes.

Clinical input supported the use of genetic testing for HP in children, despite a lack of evidence for improvements in outcomes, due to the possibility of reduced diagnostic testing in the setting of a genetically determined HP diagnosis. As a result, genetic testing for HP in children (≤18 years) with ARP (>1 episode) or CP may be considered medically necessary. 

For individuals who are asymptomatic with family members with HP who receive testing for a known familial variant associated with HP, the evidence includes a very limited number of studies. Relevant outcomes are test accuracy, symptoms, change in disease status, morbid events and hospitalizations. No direct evidence was identified comparing outcomes in patients tested or not tested for a familial variant co. It is possible that at-risk relatives who are identified with a familial variant may alter lifestyle factors (e.g., diet, smoking, alcohol use), and this may delay or prevent CP onset. However, studies evaluating behavioral changes and impact on disease are lacking. The evidence is insufficient to determine the effects of the technology on health outcomes.

Background 
PANCREATITIS
Acute and chronic pancreatitis (CP) are caused by trypsin activation within the pancreas, resulting in autodigestion, inflammation, elevation of pancreatic enzymes in serum and abdominal pain. CP is defined as a state of ongoing inflammation associated with chronic or recurrent symptoms and progression to exocrine and endocrine pancreatic insufficiency.

Alcohol is the major etiologic factor in 80% of CP, which has a peak incidence in the fourth and fifth decades of life. Gall stones, hypercalcemia, inflammatory bowel disease, autoimmune pancreatitis and peptic ulcer disease can also cause CP. About 20% of CP is idiopathic.

A small percentage of CP is categorized as hereditary pancreatitis (HP), which usually begins with recurrent episodes of acute pancreatitis in childhood and evolves into CP by age 20 years. Multiple family members may be affected over several generations, and pedigree analysis often reveals an autosomal dominant pattern of inheritance. Clinical presentation and family history alone are sometimes insufficient to distinguish between idiopathic CP and HP, especially early in the course of the disease. Individuals with HP have an estimated 40% to 55% lifetime risk of developing pancreatic cancer.1 

Genetic Determinants
PRSS1 Variants
Whitcomb et al. discovered that disease-associated variants of protease, serine, 1 (trypsin 1) (PRSS1) on chromosome 7q35 cause HP. PRSS1 encodes cationic trypsinogen. Gain of function variants of the PRSS1 gene cause HP by prematurely and excessively converting trypsinogen to trypsin, which results in pancreatic autodigestion. Between 60% and 80% of people who have a disease-associated PRSS1 variant will experience pancreatitis in their lifetimes; 30% to 40% will develop CP. Most, but not all, people with a disease-associated variant of PRSS1 will have inherited it from one of their parents. The proportion of HP caused by a de novo variant of PRSS1 is unknown. In families with 2 or more affected individuals in 2 or more generations, genetic testing has shown that most have a demonstrable disease-associated PRSS1 variant. In 60% to 100%, the variant is detected by sequencing technology (Sanger or next-generation), and duplications of exons or the whole PRSS1 gene are seen in about 6%. Two PRSS1 point variants (p.Arg122His, p.Asn29Ile) are most common, accounting for 90% of disease-associated variants in affected individuals. Over 40 other PRSS1 sequence variants have been found, but their clinical significance is uncertain. Pathogenic PRSS1 variants are present in 10% or less of individuals with CP.2

Targeted analysis of exons 2 and 3, where the common disease-associated variants are found, or PRSS1 sequencing, are first-line tests, followed by duplication analysis. The general indications for PRSS1 testing and emphasis on pre- and post-test genetic counseling have remained central features of reviews and guidelines.3,4 However, several other genes have emerged as significant contributors to both HP and CP. They include the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene, serine peptidase inhibitor, Kazal type 1 (SPINK1) gene, chymotrypsin C (CTRC) gene and claudin-2 (CLDN-2) gene.

CFTR Variants
Autosomal recessive variants of CFTR cause CF, a chronic disease with onset in childhood that causes severe sinopulmonary disease and numerous gastrointestinal abnormalities. The signs and symptoms of CF can vary widely. On rare occasions, an affected individual may have mild pulmonary disease, pancreatic exocrine sufficiency and may present with acute, recurrent acute or CP.3 Individuals with heterozygous variants of the CFTR gene (CF carriers) have a 3- to 4-fold increased risk for CP. Individuals with 2 CFTR pathogenic variants (homozygotes or compound heterozygotes) will benefit from CF-specific evaluations, therapies and genetic counseling.

SPINK Variants
The SPINK gene encodes a protein that binds to trypsin and thereby inhibits its activity. Variants in SPINK are not associated with acute pancreatitis but are found, primarily as modifiers, in acute recurrent pancreatitis and seem to promote the development of CP, including for individuals with compound heterozygous variants of the CFTR gene. Autosomal recessive familial pancreatitis may be caused by homozygous or compound heterozygous SPINK variants. 

CTRC Variants
CTRC is important for the degradation of trypsin and trypsinogen, and 2 variants (p.R254W, p.K247_R254del) are associated with increased risk for idiopathic CP (odds ratio [OR], 4.6), alcoholic pancreatitis (OR=4.2) and tropical pancreatitis (OR=13.6).6

CLDN2 Variants
CLDN2 encodes a member of the claudin protein family, which acts as an integral membrane protein at tight junctions and has tissue-specific expression. Several single-nucleotide variants in CLDN2 have been associated with CP.

Genetic Testing for Variants
Testing for variants associated with HP is typically done by direct sequence analysis or next-generation sequencing (NGS). A number of laboratories offer testing for the relevant genes, either individually or as panels. For example, ARUP Laboratories (Salt Lake City, UT) offers a Pancreatitis Panel, which includes direct (Sanger) sequencing of CFTR, CTRC, PRSS1 and SPINK.7 Prevention Genetics (Marshfield, WI) offers a Chronic Pancreatitis Sequencing Panel, which includes NGS of 5 genes: CASR, CFTR, CTRC, PRSS1 and SPINK1.8 Ambry Genetics (Aliso Viejo, CA) offers a Pancreatitis Panel, which includes NGS of PRSS1, SPINK1, CTRC and CFTR. Ambry’s PancNext panel consists of NGS of 13 genes: APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11 and TP53. 

Regulatory Status
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Improvement Act (CLIA). Genetic testing for hereditary pancreatitis is available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by CIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of these tests.

Policy

  1. Genetic testing for hereditary pancreatitis is considered MEDICALLY NECESSARY in patients <20 years old and the individual is presenting with one of the following situations:
    • Recurrent (two separate, documented episodes with hyperlipasemia) attacks of acute pancreatitis for which there is no identifiable cause 
    • Unexplained chronic pancreatitis 
    • A family history of recurrent acute pancreatitis, idiopathic chronic pancreatitis, or childhood pancreatitis without a known cause in a first- or second-degree relative 
    • Unexplained episode of pancreatitis in a child that required hospitalization.
  2. Genetic testing for hereditary pancreatitis is considered INVESTIGATIONAL in all other situations

Policy Guidelines
Coding
CPT code 81401 includes the following testing for hereditary pancreatitis:

PRSS1 (protease, serine, 1 (trypsin 1)) (e.g., hereditary pancreatitis), common variants (e.g., N29I, A16V, R122H) 

CPT code 81404 includes the following testing for hereditary pancreatitis: 

PRSS1 (protease, serine, 1 (trypsin 1)) (e.g., hereditary pancreatitis), full gene sequence
SPINK1 (serine peptidase inhibitor, Kazal type 1) (e.g., hereditary pancreatitis), full gene sequence

CPT code 81222 and/or 81223 might be reported for CFTR testing for hereditary pancreatitis:

81222: CFTR (cystic fibrosis transmembrane conductance regulator) (e.g., cystic fibrosis) gene analysis; duplication/deletion variants 
81223: full gene sequence 

Testing for duplication/deletion variants for PRSS1 and SPINK1 would be reported with the unlisted molecular pathology code 81479. 

Benefit Application
BlueCard/National Account Issues
The U.S. Food and Drug Administration (FDA) has not regulated these tests because, to date, they have been offered as laboratory-developed services, subject only to the general laboratory operational regulation under the Clinical Laboratory Improvement Amendments (CLIA) of 1988. Laboratories performing clinical tests must be certified for high-complexity testing under CLIA.

Rationale
Validation of the clinical use of any genetic test focuses on 3 main principles: (1) analytic validity, which refers to the technical accuracy of a test in detecting a variant that is present or in excluding a variant that is absent; (2) clinical validity, which refers to the diagnostic performance of the test (sensitivity, specificity, positive and negative predictive values) in detecting clinical disease; and (3) clinical utility (i.e., how the results of a diagnostic test will be used to change management of the patient and whether these changes in management lead to clinically important improvements in health outcomes). Following is a summary of the key literature.

GENETIC TESTING FOR HEREDITARY PANCREATITIS IN PATIENTS WITH CHRONIC PANCREATITIS OR RECURRENT ACUTE PANCREATITIS

Clinical Context and Test Purpose 
The purpose of genetic testing of patients who have chronic pancreatitis (CP) or acute recurrent pancreatitis (ARP) is to confirm a diagnosis and inform management decisions. 

The question addressed in this evidence review is: Does genetic testing improve health outcomes in individuals with CP or ARP? 

The following PICOTS were used to select literature to inform this review.

Patients
The relevant population of interest is patients with chronic pancreatitis or recurrent acute pancreatitis.

Interventions
Genetic testing for hereditary pancreatitis (HP).

Comparators
Standard clinical management without genetic testing.

Outcomes
The general outcomes of interest are test accuracy, symptoms, change in disease status, morbid events and hospitalizations. 

Time
The time frame for outcome measurement varies from short-term development of symptoms to long-term survival outcomes. There are no clear established frameworks to use for outcome time frames.

Setting
Patients are generally referred by a family practice physician or gastroenterologist to a medical geneticist. Referral for genetic counseling is important for explanation of genetic disease, heritability, genetic risk, test performance and possible outcomes

Analytic Validity
Testing for variants in the protease, serine, 1 (trypsin 1) (PRSS1), serine peptidase inhibitor (SPINK) and cystic fibrosis (CF) transmembrane conductance regulator (CFTR) genes is usually done by direct sequence analysis, which is the criterion standard for detecting a variant that is present and/or excluding a variant that is absent. Testing can also be done by next-generation sequencing, which has an accuracy that approaches that of direct sequencing. In patients who test negative by either of these methods, duplication/deletion analysis may be performed to detect copy number variations. These genetic testing methods are considered to have high analytic validity.  

Clinical Validity
The clinical validity of genetic testing for HP refers to the variant detection rate in patients who have known HP.

There is a lack of published evidence on the percentage of patients who are first identified as having clinically defined HP and then tested for genetic variants. Most studies that examined disease-associated variant detection rates use a population of patients with idiopathic CP and do not necessarily require that patients have a family history of CP. In other studies, cohorts of patients with HP were defined by the presence of genetic variants or family history, which therefore may include patients with genetic variants who do not have a family history of CP.

A summary of representative studies reporting rates of detecting disease-associated variants in patients with symptoms of pancreatitis is included in Table 1.  

Table 1. Summary of Studies Reporting the Clinical Validity of HP Gene Testing

Study   Population   Genes Tested   Detection Rate

Patients with HP

Applebaum-Shapiro (2001)
 
(U.S.)10
115 patients with HP defined clinically
 
PRSS1   52% (60/115)  
Ceppa (2013)
 
(U.S.)11  
87 patients  with HP, defined by known pathogenic variant or family history   PRSS1, SPINK, 
CTFR  
62%  (54/87)  
Patients with CP and/or ARP    

Vue (2016) (U.S.)12  

91 children with ARP (n=77) or CP (n=14)  

SPINK, CFTR, PRESS1 

33/69 (48%) tested had at least 1 disease-associated variant 

Saito (2016)  (Japan)13 

128 children with CP or ARP  

 PRSS1, SPINK, CTRC, CPA1

39.1% (50/128) had at least 1 abnormal variant  

Koziel (2015) (Poland)14  

221 patients with AP and 345 healthy controls 

 SPINK, CFTR, CTRC

  • Variants identified: SPINK (6.3% of AP, 3.2% controls)
  • CFTR (2.3% of AP, 3.8% of controls)
  • CTRC (1.8% of AP, 1.2% of controls)

Schwarzenberg (2015) (international)15  

170 children, 76 with CP and 94 with acute recurrent pancreatitis

PRSS1, SPINK, CFTR
CTRC

67% (51/76 with CP) 

Poddar (2015) (India)16 

68 children with pancreatitis (35.3% acute, 32.3% acute recurrent, 32.3% chronic); 25 healthy controls 

PRSS1, SPINK,
CFTR 

44% (38/68) 

Masson (2013)
(France)17

 

253 patients with idiopathic CP

 

PRSS1, SPINK, 
CTFR, CTRC 

  • 23.7% (60/253)  “causal”mutation
  • 24.5% (62/253)  “contributory” variant

Wang (2013)
China)18

75 children with idiopathic CP

PRSS1, SPINK, CFTR
CTRC, CLDN2
  • 66.7% (50/75) (with PRSS1 or SPINK variants)
Sultan (2012)
 
(U.S.)19  
29 children with ARP or CP PRSS1, SPINK,  
CTFR  
79% (23/29)  
Gasiorowska (2011)
 
(Poland)20  
14 patients with idiopathic CP; 
46 control patients without pancreatitis  
PRSS1, SPINK   50% (7/14)  
Joergensen (2010)
 
(Denmark)21  
122 patients with idiopathic pancreatitis   PRSS1, SPINK,  
CTFR  
40% (49/122)  
Rebours (2009)
 
(France)22  
200 patients with CP   PRSS1   68% (136/200)  
Keiles (2006)
 
(U.S.)23 
389 patients with recurrent or CP referred for genetic testing   PRSS1, SPINK,  
CTFR  
49% (185/381)  
Truninger (2001)
 
(Germany) 24 
104 patients with CP PRSS1   8% (8/104)  

 AP: acute pancreatitis; ARP: acute recurrent pancreatitis;  CP: chronic pancreatitis; HP: hereditary pancreatitis. 

Only 2 studies were identified that included patients with known HP. Applebaum-Shapiro et al. (2001) identified PRSS1 variants in 52% of patients with HP; other patients may have had different disease-associated variants not addressed in this study.10 Ceppa et al. (2013) identified PRSS1, SPINK or CFTR disease-associated variants in 62% of patients with HP. Again, other patients may have had different, rarer, variants.11  

The true clinical sensitivity and specificity for genetic testing in cases of HP are uncertain for a number of reasons. First, the populations in published studies have been defined differently, with most not consisting of patients with clinically defined HP. The populations are from different geographic regions, in which the prevalence of genetic variants may vary. Some of the studies have mixed adult and pediatric populations, while others have reported on either adults or children. Finally, genes tested for in these studies have differed, with many studies not including all of the known genes associated with HP. 

At least 1 study (2015) found that the proportion of patients with acute pancreatitis attributable to genetic causes is higher among younger patients. In a group of 309 subjects with acute pancreatitis, patients ages 35 and younger (n=66) were more likely to have a genetic cause of pancreatitis identified (10%) than older patients (1.5%; p=0.003).25  

Section Summary: Clinical Validity for Testing for Variants Associated With HP
A number of studies have reported variant detection rates in various populations of patients with CP, but few studies have enrolled a population of patients with known HP. Studies that tested patients with known HP reported detection rates between 52% and 62%; studies may not have tested for all relevant genetic variants. For other studies that tested patients with CP or ARP, disease-associated variant detection rates varied widely across studies. 

Clinical Utility
Direct Evidence
There are no direct outcome data on the clinical utility of testing for confirmation of HP (i.e., no studies have reported outcomes data for patients tested and not tested for HP). 

Chain of Evidence
A chain of evidence would evidence that genetic testing can identify individuals with HP who would not otherwise be identified, that treatments are available for these patients that would not otherwise be given to patients with CP or ARP, and that these treatments improve health outcomes. 

There is some evidence that testing patients with HP, or patients with CP or ARP, can identify individuals with disease-associated variants (see Clinical Validity section). However, it is unclear whether patient management would differ for patients with CP depending on whether or not a variant associated with HP is found. Conservative therapy for CP includes a low-fat diet with multiple small meals, maintenance of good hydration, use of antioxidants and avoidance of smoking and alcohol use. While all of these interventions may alter the natural history of the disease, there is no evidence that the impact differs for HP compared with other etiologies of CP. 

Moreover, there is a lack of evidence that treatments (e.g., for CP-related pain) would differ depending on whether or not patients had HP. Total pancreatectomy with islet cell transplantation (or total pancreatectomy with islet autotransplantation [TP-IAT]) has been investigated in CP or ARP, particularly as a treatment for intractable pain in patients with impaired quality of life in whom medical, endoscopic or prior surgical treatment have failed. However, questions remain about the best timing of surgery, selection of candidates, evaluation of outcomes and follow-up.26 Chinnakotla et al. (2014) retrospectively compared outcomes after TP-IAT for patients with HP or familial pancreatitis compared with other causes of CP among 484 patients treated at a single institution from 1977 to 2012, 80 of whom had HP.27 Genetic testing was not available for all patients with suspected HP. Multiple causes of HP or familial pancreatitis were included: 38 with PRSS1 variants; 9 with SPINK1 variants; 14 with CFTR variants; and 19 with familial pancreatitis without a variant specified. Patients with HP were younger at the time of TP-IAT (mean age, 21.9 years vs. 37.9 years in nonhereditary CP, p<0.001), but had a longer history of pancreatitis (mean, 10.1 years vs. 6.4 years in nonhereditary CP, p<0.001). Pain scores significantly improved after TP-IAT (p<0.001), with no significant differences between HP and nonhereditary CP. 

Several studies were identified that examined whether the severity and/or natural history of CP differs in patients with and without disease-associated variants. Some have reported that patients with HP have an earlier age of onset compared with patients with other etiologies of CP.28 Other studies have examined whether the severity and natural history differ for patients with HP, but findings have been inconsistent. Some studies have reported that disease progression is slower in patients with HP28-30 and that surgical intervention is required less often for patients with HP.29 However, 1 study also reported that the cumulative risk for exocrine failure was more than twice as high for patients with disease-associated variants compared with patients without disease-associated variants.30 In another small study (1998) that compared the clinical course of patients with HP to those with alcoholic CP, most clinical manifestations were similar, but patients with HP had a higher rate of pseudocysts.31  

Section Summary: Clinical Utility for Testing for Variants Associated With HP
The evidence on clinical utility does not support an improvement in health outcomes associated with genetic testing. For diagnostic testing, there is a lack of direct evidence that genetic testing leads to management changes. A chain of evidence does not indicate that treatment would differ for patients with HP compared to other patients with CP. In addition, the evidence to date is insufficient to determine whether patients with HP respond differently to treatments such as TP-IAT than other patients with CP. However, there is a suggestion that patients with HP have earlier onset of disease and inconsistent evidence on disease severity in patients with HP versus other types of CP. 

TARGETED TESTING ASYMPTOMATIC RELATIVES OF PATIENTS WITH HP 

Clinical Context and Test Purpose
The purpose of genetic testing of asymptomatic relatives of patients with HP is to determine the likelihood that the individual will develop CP. 

The question addressed in this evidence review is: Does genetic testing improve health outcomes in asymptomatic relatives of patients with HP? 

The following PICOTS were used to select literature to inform this review. 

Patients 
The relevant population of interest is patients who are asymptomatic with a relative or relatives who have been diagnosed with HP. 

Interventions
Genetic testing for HP. 

Comparators
Standard clinical management without genetic testing. 

Outcomes
The general outcomes of interest are test accuracy, symptoms, change in disease status, morbid events and hospitalizations. 

Time
There are no clinical guidelines with recommendations for monitoring asymptomatic individuals found to have variants associated with HP. The time frame for outcome measurement varies from short-term development of symptoms to long-term survival outcomes. There are no clear established frameworks to use for outcome time frames. 

Setting
Asymptomatic patients might be referred by a family practice physician to a medical geneticist. Referral for genetic counseling is important for explanation of genetic disease, heritability and genetic risk. 

Analytic Validity
Same as previous section for patients with CP or ARP. 

Clinical Validity
Same as previous section for patients with CP or ARP. 

Clinical Utility
Predictive testing can be performed in asymptomatic relatives of patients with known HP to determine the likelihood of CP. For this population, no direct evidence was identified that compared outcomes in patients who did and did not undergo genetic testing. It is possible that at-risk relatives who are identified with disease-associated variants might alter lifestyle factors (e.g., diet, smoking, alcohol use), and this might delay or prevent CP onset. However, evidence on this question is lacking, so that conclusions cannot be made on whether genetic testing of asymptomatic family members of patients with HP improves outcomes. 

Section Summary: Targeted Testing Asymptomatic Relatives of Patients With HP
There is a lack of evidence that genetic testing of asymptomatic relatives of patients with HP leads to interventions that delay or prevent pancreatitis onset. It is possible that patients might alter lifestyle factors that increase risk of pancreatitis, but studies are lacking. 

SUMMARY OF EVIDENCE
For individuals who have chronic pancreatitis (CP) or acute recurrent pancreatitis (ARP) who receive testing for genes associated with hereditary pancreatitis (HP), the evidence includes cohort studies on variant detection rates. Relevant outcomes are test accuracy, symptoms, change in disease status, morbid events and hospitalizations. There are studies on the detection rate of HP-associated genes in various populations. Few studies have enrolled patients with known HP; those doing so have reported detection rates for disease-associated variants between 52% and 62%. For other studies that tested patients with CP or ARP, disease-associated variant detection rates varied widely across studies. There is a lack of direct evidence that testing for HP improves health outcomes, and insufficient chain of evidence that, in patients with CP or ARP, management would change after genetic testing in a manner likely to improve health outcomes. The evidence is insufficient to determine the effects of the technology on health outcomes. 

For individuals who are asymptomatic with family members with HP who receive testing for a known familial variant associated with HP, the evidence includes a very limited number of studies. Relevant outcomes are test accuracy, symptoms, change in disease status, morbid events and hospitalizations. No direct evidence was identified comparing outcomes in patients tested or not tested for a familial variant co. It is possible that at-risk relatives who are identified with a familial variant may alter lifestyle factors (e.g., diet, smoking, alcohol use), and this may delay or prevent CP onset. However, studies evaluating behavioral changes and impact on disease are lacking. The evidence is insufficient to determine the effects of the technology on health outcomes. 

CLINICAL INPUT FROM PHYSICIAN SPECIALTY SOCIETIES AND ACADEMIC MEDICAL CENTERS
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received from 2 specialty medical societies (one of which provided 2 responses) and 4 academic medical centers (one of which provided 2 responses) when this policy was under review in 2014, with specific focus on testing in children. There was consensus among reviewers that genetic testing for hereditary pancreatitis is medically necessary in children. 

PRACTICE GUIDELINES AND POSITION STATEMENTS

American College of Gastroenterology
The American College of Gastroenterology’s 2013 guidelines on management of acute pancreatitis (AP) included the following statement: "genetic testing may be considered in young patients (<30 years old) if no cause [of AP] is evident and a family history of pancreatic disease is present (conditional recommendation, low quality of evidence)."32  

American College of Medical Genetics and Genomics
The American College of Medical Genetics and Genomics issued a policy statement on laboratory standards and guidelines for population-based cystic fibrosis (CF) carrier screening in 2001,33 which were updated in 200434 and reaffirmed in 2013.35 These guidelines have provided recommendations on specific variant testing in CF, but have not specifically addressed genetic testing for suspected hereditary pancreatitis (HP).  

European Consensus Conference
A 2001 European Consensus Conference developed guidelines for genetic testing of the PRSS1 gene, genetic counseling and consent for genetic testing for HP.36 The indications recommended for symptomatic patients included:

  • Recurrent (2 or more separate, documented episodes with hyperamylasemia) attacks of acute pancreatitis for which there is no explanation
  • Unexplained chronic pancreatitis
  • A family history of pancreatitis in a first- or second-degree relative
  • Unexplained pancreatitis in a child – if recurrent or requiring hospitalization
  • Predictive genetic testing, defined as genetic testing in an asymptomatic "at-risk" relative of an individual proven to have HP, was considered more complex. Candidates for predictive testing should be a first-degree relative of an individual with a well-defined HP gene mutation [pathogenic variant], capable of informed consent and able to demonstrate an understanding of autosomal dominant inheritance, incomplete penetrance, variable expressivity and the natural history of HP. Written informed consent must be documented before the genetic test is performed. 

U.S. PREVENTIVE SERVICES TASK FORCE RECOMMENDATIONS
Not applicable. 

ONGOING AND UNPUBLISHED CLINICAL TRIALS
A search of ClinicalTrials.gov in January 2017 did not identify any ongoing or unpublished trials that would likely influence this review.

References  

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  2. Whitcomb DC. Value of genetic testing in the management of pancreatitis. Gut. Nov 2004;53(11):1710-1717. PMID 15479696
  3. Solomon S, Whitcomb, D.C., LaRusch, J, et al. PRSS1-Related Hereditary Pancreatitis. GeneReviews 2012. Accessed June 10,2015.
  4. 4. Fink EN, Kant JA, Whitcomb DC. Genetic counseling for nonsyndromic pancreatitis. Gastroenterol Clin North Am. Jun 2007;36(2):325-333, ix. PMID 17533082
  5. Whitcomb DC. Framework for interpretation of genetic variations in pancreatitis patients. Front Physiol. 2012;3:440. PMID 23230421
  6. Rosendahl J, Witt H, Szmola R, et al. Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis. Nat Genet. Jan 2008;40(1):78-82. PMID 18059268 
  7. ARUP Laboratories, Laboratory Test Directory. Pancreatitis, Panel (CFTR, CTRC, PRSS1, SPINK1) Sequencing (2010876). n.d.; http://ltd.aruplab.com/tests/pub/2010876. Accessed January 30, 2017.
  8. Prevention Genetics. Chronic Pancreatitis Sequencing Panel. n.d.; https://www.preventiongenetics.com/testInfo.php?sel=test&val=Chronic+Pancreatitis+Sequencing+Panel. Accessed January 30, 2017.
  9. Ambry Genetics. Pancreatitis Testing. n.d.; http://www.ambrygen.com/tests/pancreatitis-testing. Accessed January 30, 2017.
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  11. Ceppa EP, Pitt HA, Hunter JL, et al. Hereditary pancreatitis: endoscopic and surgical management. J Gastrointest Surg. May 2013;17(5):847-856; discussion 856-847. PMID 23435738
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  17. Masson E, Chen JM, Audrezet MP, et al. 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. PMID 23951356
  18. Wang W, Sun XT, Weng XL, et al. Comprehensive screening for PRSS1, SPINK1, CFTR, CTRC and CLDN2 gene mutations in Chinese paediatric patients with idiopathic chronic pancreatitis: a cohort study. BMJ Open. 2013;3(9):e003150. PMID 24002981
  19. Sultan M, Werlin S, Venkatasubramani N. Genetic prevalence and characteristics in children with recurrent pancreatitis. J Pediatr Gastroenterol Nutr. May 2012;54(5):645-650. PMID 22094894
  20. Gasiorowska A, Talar-Wojnarowska R, Czupryniak L, et al. The prevalence of cationic trypsinogen (PRSS1) and serine protease inhibitor, Kazal type 1 (SPINK1) gene mutations in Polish patients with alcoholic and idiopathic chronic pancreatitis. Dig Dis Sci. Mar 2011;56(3):894-901. PMID 20676769
  21. Joergensen MT, Brusgaard K, Cruger DG, et al. Genetic, epidemiological, and clinical aspects of hereditary pancreatitis: a population-based cohort study in Denmark. Am J Gastroenterol. Aug 2010;105(8):1876-1883. PMID 20502448
  22. Rebours V, Boutron-Ruault MC, Schnee M, et al. The natural history of hereditary pancreatitis: a national series. Gut. Jan 2009;58(1):97-103. PMID 18755888
  23. Keiles S, Kammesheidt A. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. Oct 2006;33(3):221-227. PMID 17003641
  24. Truninger K, Kock J, Wirth HP, et al. Trypsinogen gene mutations in patients with chronic or recurrent acute pancreatitis. Pancreas. Jan 2001;22(1):18-23. PMID 11138965
  25. Culetto A, Bournet B, Haennig A, et al. Prospective evaluation of the aetiological profile of acute pancreatitis in young adult patients. Dig Liver Dis. Jul 2015;47(7):584-589. PMID 25861839
  26. Bellin MD, Freeman ML, Gelrud A, et al. Total pancreatectomy and islet autotransplantation in chronic pancreatitis: recommendations from PancreasFest. Pancreatology. Jan-Feb 2014;14(1):27-35. PMID 24555976
  27. Chinnakotla S, Radosevich DM, Dunn TB, et al. Long-term outcomes of total pancreatectomy and islet auto transplantation for hereditary/genetic pancreatitis. J Am Coll Surg. Apr 2014;218(4):530-543. PMID 24655839
  28. Teich N, Mossner J. Hereditary chronic pancreatitis. Best Pract Res Clin Gastroenterol. 2008;22(1):115-130. PMID 18206817
  29. Mullhaupt B, Truninger K, Ammann R. Impact of etiology on the painful early stage of chronic pancreatitis: a long-term prospective study. Z Gastroenterol. Dec 2005;43(12):1293-1301. PMID 16315124
  30. Howes N, Lerch MM, Greenhalf W, et al. Clinical and genetic characteristics of hereditary pancreatitis in Europe. Clin Gastroenterol Hepatol. Mar 2004;2(3):252-261. PMID 15017610
  31. Paolini O, Hastier P, Buckley M, et al. The natural history of hereditary chronic pancreatitis: a study of 12 cases compared to chronic alcoholic pancreatitis. Pancreas. Oct 1998;17(3):266-271. PMID 9788540
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Coding Section

Codes Number Description
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)
  81405  Molecular pathology procedure, Level 6 (eg , hereditary pancreatitis), full gene sequence  
ICD-9-CM Diagnosis 577.0 Acute pancreatitis
  577.1 Chronic pancreatitis
ICD-10-CM (effective 10/01/15) K85.0-K85.9 Acute pancreatitis code range
  K86.1 Other chronic pancreatitis
ICD-10-PCS (effective 10/01/15)  

Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests.

Type of Service    
Place of Service    

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology© American Medical Association.  All Rights Reserved" 

History From 2014 Forward     

07/12/2019 

Annual review, no change to policy intent. 

07/23/2018 

Annual review, updating medical necessity criteria changing age from 18 or less to 20 or less. Updating coding. 

07/20/2017 

Annual review, no change to policy intent. Updating background, description, rationale and references. 

04/25/2017 

Updated category to Laboratory. No other changes. 

04/03/2017 

Annual review, no change to policy intent. Updating background, description, rationale and references. 

04/13/2016 

Annual review, no change to policy intent. Updating background, description ,rationale , references and regulatory status.

01/04/2016 

Updated CPT codes. No change to intent of policy. 

04/20/2015 

Annual review, added policy verbiage to allow testing as medically necessary for children who meet specific criteria. Updated background, description, rationale and references. Added guidelines and coding.

04/09/2014

New Policy.


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