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Genetic Testing for Hereditary Pancreatitis

Policy Number: MP-590

Latest Review Date: February 2019

Category: Laboratory

Policy Grade: D

DESCRIPTION OF PROCEDURE OR SERVICE:

In chronic pancreatitis (CP), recurrent attacks of acute pancreatitis evolve into a chronic inflammatory state with exocrine insufficiency, endocrine insufficiency manifested as diabetes mellitus, 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.

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 an ongoing inflammatory state associated with chronic/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. Hereditary pancreatitis is associated with a markedly increased risk of pancreatic cancer, although hereditary pancreatitis patients account for only a small fraction of all cases of pancreatic cancer and are only a subset of the 10% of pancreatic cancers that are considered to have a genetic or familial predisposition. Individuals with HP have an estimated 40% to 55% lifetime risk of developing pancreatic cancer.

Genetic Determinants

PRSS1 Variants

Whitcomb et al (2001) 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 then 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 two or more affected individuals in two or more generations, genetic testing shows 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.

Targeted analysis of exons two and three, 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 posttest genetic counseling have remained central features of reviews and guidelines. However, several other genes have emerged as significant contributors to both HP and CP. These include 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 cystic fibrosis (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. Individuals with heterozygous variants of the CFTR gene (CF carriers) have a three- to four-fold increased risk for CP. Individuals with two CFTR pathogenic variants (homozygotes or compound heterozygotes) will benefit from CFspecific 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 recurrent acute 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 two variants (p.R254W and 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). Tropical pancreatitis is a disease almost exclusively occurring in the setting of tropical climate and malnutrition.

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.

POLICY:

Effective for dates of service on and after October 1, 2015:

Genetic testing for hereditary pancreatitis may be considered medically necessary in patients with pancreatitis when one or more of the following criteria are met:

  • Relatives known to carry variants associated with hereditary pancreatitis; OR
  • Idiopathic chronic pancreatitis or recurrent acute attacks of pancreatitis for which there is not identifiable cause when the onset of pancreatitis occurs before age 25; OR
  • An unexplained documented episode of pancreatitis as a child.

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


Effective for dates of service prior to October 1, 2015:

Genetic testing for hereditary pancreatitis using serine protease 1 gene (PRSS1) may be considered medically necessary in patients with pancreatitis when one or more of the following criteria are met:

  • Relatives known to carry mutations associated with hereditary pancreatitis; OR
  • Idiopathic chronic pancreatitis or recurrent acute attacks of pancreatitis for which there is not identifiable cause when the onset of pancreatitis occurs before age 25; OR
  • An unexplained documented episode of pancreatitis as a child.

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

KEY POINTS:

This policy was updated with literature reviews through January 7, 2019.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

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 chronic pancreatitis or acute recurrent pancreatitis.

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

Patients

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

Intervention

The test being considered is genetic testing for hereditary pancreatitis

Comparator

The following practive is currently being used: standard clinical evaluation and management without genetic testing.

Outcomes

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

Timing

The timeframe 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.

Study Selection Criteria

For the evaluation of clinical validity of genetic testing for variants associated with hereditary pancreatitis, methodologically credible studies were selected using the following principals:

For the evaluation of clinical validity of the tests, studies that meet the following eligibility criteria were considered:

  • Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculated scores)
  • Included a suitable reference standard
  • Patient/sample clinical characteristics were described
  • Patient/sample selection criteria were described
  • Included a validation cohort separate from development cohort

Simplifying Test Terms

There are 3 core characteristics for assessing a medical test. Whether imaging, laboratory, or other, all medical tests must be:

  • Technically reliable
  • Clinically valid
  • Clinically useful.

Because different specialties may use different terms for the same concept, we are highlighting the core characteristics. The core characteristics also apply to different uses of tests, such as diagnosis, prognosis, and monitoring treatment.

Diagnostic tests detect presence or absence of a condition. Surveillance and treatment monitoring are essentially diagnostic tests over a time frame. Surveillance to see whether a condition develops or progresses is a type of detection. Treatment monitoring is also a type of detection because the purpose is to see if treatment is associated with the disappearance, regression, or progression of the condition.

Prognostic tests predict the risk of developing a condition in the future. Tests to predict response to therapy are also prognostic. Response to therapy is a type of condition and can be either a beneficial response or adverse response. The term predictive test is often used to refer to response to therapy. To simplify terms, we use prognostic to refer both to predicting a future condition or to predicting a response to therapy.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review, and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility.

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse). 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 percent of patients who are first identified as having clinically defined HP and then tested for genetic variants. Most studies that examine the disease-associated variant detection rate use a population of patients with idiopathic chronic pancreatitis (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.

Observational Studies

A summary of representative observational studies reporting the rate 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 Herediatary Pancreatitis Gene Testing

Study

Population

Genes Tested

Detection Rate

Clinical Specificity

Studies in Patients with CP, AP, or ARP

Weiss et al (2018)

1462 patients with AP

3999 controls

PRSS1-PRSS2,

RIPPLY,

MORC4

PRSS1-PRSS2: OR 0.88; 95%

CI 0.81-0.97; p=0.01.

RIPPLY: OR 1.27, 95% CI 1.07-

1.5, p=0.005.

MORC4: OR 1.32, 95% CI 1.12-

1.56, p=0.001.

NR

Zou et al (2018)

1061 idiopathic CP patients and

1196 controls

SPINK1,

PRSS1, CTRC,

CFTR

  • CP group: 50.42% (535/1061)
  • Control group: 5.94% (71/1196)
  • OR: 16.12; p<0.001 (CI NR)

NR

Saito et al (2016) (Japan)

128 children with CP or ARP

PRSS1, SPINK, CTRC, CPA1

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

NR

Vue et al (2016) (United States)

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

SPINK, CFTR, PRESS1,

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

NR

Koziel et al (2015) (Poland)

221 patients with AP and 345 healthy controls

SPINK, CFTR, CTRC

  • Variant 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)

NR

Poddar et al (2015) (India)

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

PRSS1, SPINK, CFTR

44% (38/68)

NR

Schwarzenberg et al (2015) (international)

170 children, 76 with CP and 94 with ARP

PRSS1, SPINK, CFTR, CTRC

67% (51/76 with CP)

NR

Masson et al (2013)

(France)

253 patients with idiopathic CP

PRSS1

SPINK

CFTR

CTRC

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

NR

Wang et al (2013)

(China)

75 children with idiopathic CP

PRSS1

SPINK

CFTR

CTRC

CLDN2

  • 66.7% (50/75) (with PRSS1 or SPINK

variants

NR

Sultan et al (2012) (U.S.)

29 children with recurrent acute or CP

PRSS1

SPINK

CFTR

79% (23/29)

NR

Gasiorowska et al (2011)

(Poland)

14 patients with idiopathic CP; 46 control

patients without pancreatitis

PRSS1

SPINK

50% (7/14)

11% (5/46)

Joergensen et al (2010)

(Denmark)

122 patients with idiopathic pancreatitis

PRSS1

SPINK

CFTR

40% (49/122)

NR

Rebours et al (2009)

(France)

200 patients with CP

PRSS1

68% (136/200)

NR

Keiles et al (2006)

(U.S.)

389 patients with recurrent or CP

referred for genetic testing

PRSS1

SPINK

CFTR

49% (185/381)

NR

Truninger et al (2001)

(Germany)

104 patients with CP

PRSS1

8% (8/104)

NR

Studies in Patients with HP

Applebaum-Shapiro et al

(2001) (U.S.)

115 patients with HP defined clinically;

PRSS1

52% (60/115)

13%

(46/349)

Ceppa et al (2013) (U.S.)

87 patients with HP, defined by known pathogenic variant or family history

PRSS1

SPINK

CFTR

62% (54/87)

NR

AP: acute pancreatitis; ARP: acute recurrent pancreatitis; CI: confidence interval; CP: chronic pancreatitis; HP: hereditary pancreatitis; NR: not reported

Only two studies were identified that included patients with known HP. Applebaum 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. 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. 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 are 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 mix adult and pediatric populations, while others report on either adults or children. Finally, genes tested for in these studies differ, with many studies not including all of the known genes that are associated with HP.

Culetto et al (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 aged 35 and younger (n=66) were more likely to have a genetic cause of pancreatitis identified than older patients (10% vs 1.5%, p=0.003).

Weiss et al (2018) used genetic testing to analyze associations between common variants and acute pancreatitis (AP); 1462 patients with AP and 3999 healthy controls were evaluated. For all AP patients, significant associations were found for PRSS1-PRSS2 variant (rs10273639) (OR 0.88, 95% CI: 0.81- 0.97, p=0.01), RIPPLY variant (rs7057398) (OR 1.27, 95% CI: 1.07-1.5, p=0.005), and MORC4 (rs12688220) (OR 1.32, 95% CI: 1.12-1.56, p=0.001). Patients were included with AP of all etiologies and did not specifically have a history of recurrent episodes. The population was drawn from four European countries and the variant identification varied in the different populations. The results confirmed that PRSS1-PRSS2 is protective. The other two variants are being investigated for a pathogenic phenotype.

Zou et al (2018) analyzed 1196 controls and 1061 Han Chinese patients with idiopathic chronic pancreatitis (CP) tested with targeted next-generation sequencing of four CP-associated genes (SPINK1, PRSS1, CTRC, CFTR). The objective of the study was to focus on rare variants defined as <1% frequency in the control population. Variants were identified in 535 (50.42%; OR=16.12; p<0.001) patients with CP compared to 71 (5.94%) controls. There was also an interest in assessing the influence of a variant on clinical presentation and disease onset. Median age at disease onset differed between mutation-positive (29.7±14.84 years) and mutation negative patients (43.01±15.97; p<0.001). When patients were divided into idiopathic (n=715), alcoholic (n=206), and smoking-associated (n=140) CP subgroups, the rates of pathogenic genotypes were 57.1%, 39.8%, and 32.1%, respectively. The study did not assess the variants more commonly encountered which are associated with a more defined phenotype.

Section Summary: Clinically Valid

A number of studies have reported variant detection rates in various populations of patients with CP, but there is limited frequency information on populations of patients with known HP. Studies that tested patients with known HP reported variant detection rates between 52% and 62%. Genotype-phenotype studies have attempted to characterize rarer variants as well as determine the influence of variant status on clinical presentation and disease onset. Multiple observational studies that tested patients with AP or ARP with variant detection rates varying widely. These studies have added information to the variant frequency differences in populations and subgroups.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials.

There are no direct outcome data regarding the clinical usefulness of testing for confirmation of HP; (i.e., there are no studies that report outcome data in patients who have been tested for HP compared with patients who have not been tested).

Indirect Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

A chain of evidence would demonstrate 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 Clinically Valid 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 include 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.

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 recurrent acute pancreatitis, 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. Chinnakotla et al (2014) conducted a retrospective study that 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. Genetic testing was not available for all patients with suspected HP. Multiple causes of HP or familial pancreatitis were included: 38 with PRSS1 variants; nine 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. A 2008 review article reported that patients with HP have an earlier age of onset compared with patients with other etiologies of CP. Other studies have reported data from an observational cohort and a registry that disease progression is slower in patients with HP and that surgical intervention is required less often for patients with HP. The registry 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. A small case series 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.

A 2017 systematic review and meta-analysis by Hu et al investigated the association between the p.R122H variant in the PRSS1 gene and the risk of CP. Eight case-control studies in which patients had CP, whether hereditary or of another cause, were included. Analysis of all 8 reviewed studies (n=1733 patients with CP of all etiologies combined; n=2415 controls) showed an overall pooled odds ratio (OR) of 4.78 (95% confidence interval [CI], 1.13 to 20.20); heterogeneity was low (I2=32.2%). A subgroup analysis compared hereditary CP with nonhereditary CP in 4 studies (n=225 patients, n=2214 controls). There was low heterogeneity between the studies (p=0.235, I2=29.5%), with a pooled OR for an association between the p.R122H variant and the risk of hereditary CP of 65.52 (95% CI, 9.09 to 472.48). By comparison, the pooled OR for an association between the p.R122H variant, and an increased risk of nonhereditary CP was 2.79 (95% CI, 0.68 to 1.55).

There is an increased risk for pancreatic cancer in individuals with chronic pancreatitis caused by hereditary pancreatitis. Individuals with HP have an estimated 40% to 55% lifetime risk of developing pancreatic cancer. The risk estimates are primarily derived from study of populations diagnosed with clinical evaluation and family history and antedate characterizations based on genetic variant status. These risk estimates may also represent populations with higher smoking prevalence rates. Smoking increases the likelihood developing pancreatic cancer in all populations. In general, pancreatic cancer is diagnosed at late stages and has very low five-year survival rates. The lack of specificity of premalignant signs and symptoms and uncertainties about the most appropriate imaging or diagnostic studies to assess pancreatic lesions limit the opportunity to make an earlier diagnosis. However, evidence informed consensus guidelines and opinions have recently appeared to screen for pancreatic cancer in individuals at high risk.

Section Summary: Clinical Utility for Testing for Variants Associated With HP

The published 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 indirect evidence does not indicate that treatment would be different 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 severity of disease in patients with HP versus other types of CP. A systematic review and meta-analysis identified eight studies that included patients with CP of several etiologies and found an increased association between the presence of the PRSSI gene p.R122H variant in both hereditary and nonhereditary 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.

Intervention

The test being considered is genetic testing for hereditary pancreatitis.

Comparators

The following practice is currently being used: standard clinical management without genetic testing.

Outcomes

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

Timing

There are no clinical guidelines with recommendations for testing asymptomatic relatives of patients with HP or for monitoring asymptomatic individuals if 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, genetic risk.

Technical Reliability

See the previous section for patients with CP or ARP.

Clinically Valid

See the previous section for patients with CP or ARP.

Clinically Useful

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 underwent genetic testing with patients who did not undergo genetic testing. It is possible that at-risk relatives who are identified with disease-associated variants may alter lifestyle factors such as diet, smoking and alcohol use, and this may delay the onset or prevent CP. 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 the onset of pancreatitis. It is possible that patients may alter lifestyle factors that increase risk of pancreatitis, but studies are lacking.

Summary of Evidence

For individuals who have chronic pancreatitis or recurrent acute pancreatitis who receive testing for genes associated with hereditary pancreatitis, the evidence includes cohort studies on variant detection rates and a systematic review. 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 enroll patients with known HP; those doing so had reported detection rates for disease-associated variants of 52% and 62%, respectively. Other studies that tested patients with CP or ARP; the disease-associated variant detection rate varied widely across studies. There is a lack of direct 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 hereditary pancreatitis who receive testing for a known familial variant associated with hereditary pancreatitis, 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 that compared outcomes in patients tested for a familial variant compared with patients not tested for a familial variant. It is possible that at-risk relatives who are identified with a familial variant may alter lifestyle factors such as diet, smoking, and alcohol use, and this may delay the onset or prevent CP. 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.

Practice Guidelines and Position Statements

American College of Gastroenterology

The American College of Gastroenterology’s 2013 guidelines on management of acute pancreatitis (AP) includes the following statement on genetic testing:

“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).”

The American College of Gastroenterology 2015 Clinical Guideline: Genetic Testing and Management of Hereditary Gastrointestinal Cancer Syndromes recommended genetic testing of patients with suspected familial pancreatic cancer to include analysis of BRCA1/2,CDKN2A, PALB2, and ATM. Evaluation for Peutz-Jeghers Syndrome, Lynch Syndrome, and hereditary pancreatitis-associated genes should be considered if personal and/or family history criteria are met for the syndrome.

American Pancreatic Association

In 2014, the American Pancreatic Association published Practice Guidelines in Chronic Pancreatitis: Evidence-Based Report on Diagnostic Guidelines. A classification guideline for the etiology of chronic pancreatitis includes genetic mutations in PRSS1, CFTR, SPINK1, and others.

American College of Medical Genetics and Genomics

The American College of Medical Genetics issued a policy statement on laboratory standards and guidelines for population-based cystic fibrosis (CF) carrier screening in 2001, which were updated in 2004 and reaffirmed in 2013. These guidelines provide recommendations about specific variant testing in CF, but do not specifically address genetic testing for suspected 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. The indications recommended for symptomatic patients included:

  • Recurrent (two 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 that has required 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 understand the (autosomal dominant) mode of inheritance and incomplete penetrance…….. of HP mutations….”

International Consensus Guidelines for Chronic Pancreatitis

In 2018, the working group for the International Consensus Guidelines for Chronic Pancreatitis in collaboration with The International Association of Pancreatology, American Pancreatic Association, Japan Pancreas Society, PancreasFest Working Group, and the European Pancreatic Club, published consensus statements on the diagnosis ad management of early chronic pancreatitis. 38 It included the following recommendation:

“Genetic variants are important risk factors for Early CP and can add specificity to the likely etiology, but they are neither necessary nor sufficient to make a diagnosis. (Quality assessment: moderate; Recommendation: strong; Agreement: strong)”

International Study Group of Pediatric Pancreatitis

The International Study Group of Pediatric Pancreatitis INSPPIRE (The International Study Group of Pediatric Pancreatitis: In search for a cuRE) consortium developed an expert consensus opinion on evaluation of children with acute recurrent and chronic pancreatitis.39 There was strong consensus that search for a genetic cause of ARP or CP should include PRSS1, SPINK1, CFTR and CTRC gene mutation testing.

American Society of Clinical Oncology

In 2018, the American Society of Clinical Oncology (ASCO) published “Evaluating Susceptibility to Pancreatic Cancer: ASCO Provisional Clinical Opinion”.  ASCO reported that cancer-unaffected individuals should be offered genetic risk evaluation if they are: members of families with an identified pathogenic cancer susceptibility gene variant, from families that meet criteria for genetic evaluation for known hereditary syndromes that are linked to pancreatic cancer and, from families that meet criteria for familial pancreatic cancer. ASCO further considered what surveillance strategies should be used for individuals with predisposition to pancreatic ductal adenocarcinoma to screen for pancreatic and other cancers. Surveillance can be considered for individuals who are first-degree relatives of individuals with familial pancreatic cancer and/or individuals with a family history of pancreatic cancer who carry a pathogenic germline variant in genes associated with predisposition to pancreatic cancer.

U.S. Preventive Services Task Force Recommendations

Not applicable.

KEY WORDS:

Hereditary Pancreatitis, PRSS1, SPINK1, CFTR, trypsin 1, CTRC, serine protease 1 gene, CLDN2, HP, Chronic Pancreatitis, Acute Recurrent Pancreatitis, ARP, Pancreatitis

 

APPROVED BY GOVERNING BODIES:

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.

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 Laboratory Improvement Amendments (CLIA). Genetic testing for hereditary pancreatitis is available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits. Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply.

FEP: Special benefit consideration may apply. Refer to member’s benefit plan. FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.

CURRENT CODING:

CPT Codes:

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

81404

Molecular pathology procedure, Level 5 (e.g., 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) - PRSS1 (protease, serine, 1 [trypsin 1]) (eg, hereditary pancreatitis), full gene sequence , SPINK1 (serine peptidase inhibitor, Kazal type 1) (e.g., hereditary pancreatitis), full gene sequence

81405

Molecular pathology procedure, Level 6 (e.g. analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11-25 exons, regionally targeted cytogenomic array analysis - CTRC (chymotrypsin C) (e.g. hereditary pancreatitis), full gene sequence (Effective 01/01/2018)

81222

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

81223

CFTR (cystic fibrosis transmembrane conductance regulator) (e.g., cystic fibrosis) gene analysis; CFTR full gene sequence

Testing for duplication/deletion variants for PRSS1 and SPINK1 would be reported with the unlisted molecular pathology code. There is no mention of CLDN2 testing in CPT, so the unlisted molecular pathology code would be reported for that testing.

Prior to 1/1/18, there was no mention of CTRC in CPT, so the unlisted molecular pathology code would be reported. After 1/1/18, use the applicable CPT code.

81479

Unlisted molecular pathology procedure

REFERENCES:

  1. AmbryGenetics. PancNext. n.d.; www.ambrygen.com/clinician/genetic-testing/34/oncology/pancnext. Accessed January 9, 2018.
  2. Ambry Genetics. Pancreatitis Testing. www.ambrygen.com/tests/pancreatitis-testing. Accessed January, 2018.
  3. Applebaum-Shapiro SE, Finch R, Pfutzer RH, et al. Hereditary pancreatitis in North America: the Pittsburgh- Midwest Multi-Center Pancreatic Study Group Study. Pancreatology. 2001; 1(5):439-44
  4. Arup Laboratories LTD. Pancreatitis, Panel (CFTR, CTRC, PRSS1, SPINK1) Sequencing. ltd.aruplab.com/tests/pub/2010876.
  5. Ballard DD, Flueckiger JR, Fogel EL, et al. Evaluating Adults With Idiopathic Pancreatitis for Genetic Predisposition: Higher Prevalence of Abnormal Results With Use of Complete Gene Sequencing. Pancreas. Jan 2015; 44(1):116-121.
  6. Behrman SW, Fowler ES. Pathophysiology of Chronic Pancreatitis. Surg Clin N Am 87 (2007) 1309-1324.
  7. 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.
  8. Canto MI. Screening and surveillance approaches in familial pancreatic cancer. Gastrointest Endosc Clin N Am. Jul 2008; 18(3):535-553, x.
  9. 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.
  10. 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.
  11. 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.
  12. Ellis I, Lerch MM, Whitcomb DC, et al. Genetic testing for hereditary pancreatitis: guidelines for indications, counselling, consent and privacy issues. Pancreatology. 2001; 1(5):405-415.
  13. Fink EN, Kant JA, Whitcomb DC. Genetic counseling for nonsyndromic pancreatitis. Gastroenterol Clin North Am. Jun 2007; 36(2):325-333, ix.
  14. Gariepy CE, Heyman MB, Lowe ME, et al. Causal Evaluation of Acute Recurrent and Chronic Pancreatitis in Children: Consensus From the INSPPIRE Group. J Pediatr Gastroenterol Nutr. Jan 2017;64(1):95-103.
  15. 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.
  16. Gemmel C, Eickhoff A, Helmstadter L, et al. Pancreatic cancer screening: state of the art. Expert Rev Gastroenterol Hepatol. Feb 2009; 3(1):89-96.
  17. Grody WW, Cutting GR, Klinger KW, et al. Laboratory standards and guidelines for population-based cystic fibrosis carrier screening. Genet Med. Mar-Apr 2001; 3(2):149-154.
  18. 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.
  19. 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. Oct 8 2017; 2017:9505460.
  20. 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.
  21. Keiles S, Kammesheidt A. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. Oct 2006; 33(3):221-227.
  22. Koziel D, Gluszek S, Kowalik A, et al. Genetic mutations in SPINK1, CFTR, CTRC genes in acute pancreatitis. BMC Gastroenterol. Jun 23 2015; 15:70.
  23. Lowenfels AB, Maisonneuve P, DiMagno EP, et al. Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group. J Natl Cancer Inst. Mar 19 1997; 89(6):442-446.
  24. 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.
  25. Morinville VD, Lowe ME, Elinoff BD, et al. Hereditary pancreatitis amlodipine trial: a pilot study of a calciumchannel blocker in hereditary pancreatitis. Pancreas. Nov 2007; 35(4):308-312.
  26. 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.
  27. Oruc N, et al. Angiotensin-converting enzyme gene DD genotype neither increases susceptibility to acute pancreatitis nor influences disease severity. HBP (Oxford) 2009; 11(1): 45-49.
  28. 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.
  29. Poddar U, Yachha SK, Mathias A, et al. Genetic predisposition and its impact on natural history of idiopathic acute and acute recurrent pancreatitis in children. Dig Liver Dis. Apr 25 2015.
  30. Prevention Genetics. Chronic Pancreatitis NextGen Sequencing (NGS) Panel. 2014. www.preventiongenetics.com/clinical-dna-testing/test/chronic-pancreatitis-nextgen-sequencing-ngs-panel/2452/.
  31. Rai P, Sharma A, Gupta A, et al. Frequency of SPINK1 N34S mutation in acute and recurrent acute pancreatitis. J Hepatobiliary Pancreat Sci. May 21 2014.
  32. Rai P, Sharma A, Gupta A, et al. Frequency of SPINK1 N34S mutation in acute and recurrent acute pancreatitis. J Hepatobiliary Pancreat Sci. May 21 2014.
  33. 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.
  34. 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.
  35. Saito N, Suzuki M, Sakurai Y, et al. Genetic analysis of Japanese children with acute recurrent and chronic pancreatitis. J Pediatr Gastroenterol Nutr. Oct 2016; 63(4):431-436.
  36. Schwarzenberg SJ, Bellin M, Husain SZ, et al. Pediatric chronic pancreatitis is associated with genetic risk factors and substantial disease burden. J Pediatr. Apr 2015; 166(4):890-896 e891.
  37. Solomon S, Whitcomb, D.C., LaRusch, J, et al. PRSS1-Related Hereditary Pancreatitis. GeneReviews 2012.
  38. Stoffel EM, McKernin SE, Brand R, et al. Evaluating Susceptibility to Pancreatic Cancer: ASCO Provisional Clinical Opinion. J Clin Oncol. Jan 10 2019;37(2):153-164.
  39. 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.
  40. Syngal S, Brand RE, Church JM, et al. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. Feb 2015;110(2):223-262; quiz 263.
  41. Teich N, Mossner J. Hereditary chronic pancreatitis. Best Pract Res Clin Gastroenterol. 2008; 22(1):115-130.
  42. Tenner S, Baillie J, DeWitt J, et al. American College of Gastroenterology guideline: management of acute pancreatitis. Am J Gastroenterol. Sep 2013; 108(9):1400-1415; 1416.
  43. 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.
  44. Vue PM, McFann K, Narkewicz MR. Genetic mutations in pediatric pancreatitis. Pancreas. Aug 2016; 45(7):992-996.
  45. 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.
  46. Watson MS, Cutting GR, Desnick RJ, et al. Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel. Genet Med. Sep-Oct 2004; 6(5):387-391.
  47. Weiss FU, Hesselbarth N, Parniczky A, et al. Common variants in the CLDN2-MORC4 and PRSS1-PRSS2 loci confer susceptibility to acute pancreatitis. Pancreatology. Jun 1 2018.
  48. Werlin S, Konikoff FM, Halpern Z, et al. Genetic and electrophysiological characteristics of recurrent acute pancreatitis. J Pediatr Gastroenterol Nutr. May 2015; 60(5):675-679.
  49. Whitcomb DC. Framework for interpretation of genetic variations in pancreatitis patients. Front Physiol. 2012; 3:440.
  50. Whitcomb DC. Value of genetic testing in the management of pancreatitis. Gut. Nov 2004; 53(11):1710-1717.
  51. Whitcomb DC, Shimosegawa T, Chari ST, et al. International consensus statements on early chronic Pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with The International Association of Pancreatology, American Pancreatic Association, Japan Pancreas Society, PancreasFest Working Group and European Pancreatic Club. Pancreatology. May 21 2018.
  52. Yadav D, Lowenfels AB. The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology. Jun 2013; 144(6):1252-1261.
  53. Zou WB, Tang XY, Zhou DZ, et al. SPINK1, PRSS1, CTRC, and CFTR Genotypes Influence Disease Onset and Clinical Outcomes in Chronic Pancreatitis. Clin Transl Gastroenterol. Nov 12 2018;9(11):204.

POLICY HISTORY:

Medical Policy Group, April 2011 (1): update to Policy, Key Points, Key Words and References for PRSS1

Medical Policy Group, December 2012 (3): Coding Updates – added code 81404 and 81479

Medical Policy Panel, August 2013

Medical Policy Panel, November 2014

Medical Policy Group, January 2015 (3): Updated description for CPT code 81404

Medical Policy Group, February 2015 (3): Creation of individual policy with all references related to genetic testing for hereditary pancreatitis removed from medical policy #136; update to Description, Key Points, Governing Bodies, Key Words, Coding & References; no change to intent of policy statement; added “Genetic testing for hereditary pancreatitis in all other situations is considered not medically necessary investigational”

Medical Policy Panel, August 2015

Medical Policy Group, September 2015 (3): 2015 Updates to Description, Key Points, Key Words, Coding & References; Policy section updated to remove “using serine protease 1 gene (PRSS1)” from the coverage statement as testing for multiple mutations is allowed based on criteria

Medical Policy Group, October 2015

Available for comment October 2 through November 16, 2015

Medical Policy Group, November 2015: 2016 Annual Coding Update. Verified coding.

Medical Policy Panel, February 2017

Medical Policy Group, February 2017 (3): 2017 Updates to Description, Key Points & References; Removed strikethrough policy information from last update; No change to policy statement intent.

Medical Policy Panel, February 2018

Medical Policy Group, March 2018 (4): Updates to Description, Key Points, Coding and References. No change to policy statement.

Medical Policy Panel, February 2019

Medical Policy Group, February 2019 (9): Updates to Description, Key Points, and References. Added key words: HP, Chronic Pancreatitis, Acute Recurrent Pancreatitis, ARP, Pancreatitis. No change to policy statement.


This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.