CPT 81223, 81401, 81404 - Genetic Testing for Hereditary Pancreatitis

Code Description CPT

81223 CFTR (cystic fibrosis transmembrane conductance regulator) (eg, cystic fibrosis) gene analysis; full gene sequence

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)

Includes the following tests: PRSS1 (protease, serine, 1 [trypsin 1]) (eg, hereditary pancreatitis), common variants (eg, N29I, A16V,R122H)

81404 Molecular pathology procedure, Level 5 (eg, analysis of 2-5 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 6-10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis)

Includes the following tests: PRSS1 (protease, serine, 1 [trypsin 1]) (eg, hereditary pancreatitis), full gene sequence, SPINK1 (serine peptidase inhibitor, Kazal type 1) (eg, hereditary pancreatitis), full gene sequence

81479 Unlisted molecular pathology


Genetic Testing for Hereditary Pancreatitis

Introduction

The pancreas is an important organ behind and below the stomach. It releases enzymes to help us digest our food and also releases hormones (insulin and glucagon) to help the body control how it uses the food for energy. If the pancreas becomes inflamed, it is called pancreatitis. In some people, pancreatitis may have come on suddenly and only lasts for a short time (acute pancreatitis). Other people may have been sick with pancreatitis for a long time (chronic pancreatitis). Chronic pancreatitis may seem to run in some families, and as a result these cases may be caused by genetic problems. Genetic testing has sometimes been done to see if a person has hereditary pancreatitis. This policy discusses when genetic testing for hereditary pancreatitis may be medically necessary.


Testing Medical Necessity

Genetic testing for hereditary pancreatitis

Genetic testing for hereditary pancreatitis may be considered medically necessary for patients aged 18 years and younger with unexplained recurrent (greater than 1 episode) acute or chronic pancreatitis with documented elevated amylase or lipase levels.

Related Information 

Genetic Counseling
Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual’s family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Consideration of Age

The age described in this policy for medical necessity of genetic testing for hereditary pancreatitis is age 18 and younger.  Having recurrent pancreatitis in children is not very common. The literature regarding genetic testing for hereditary pancreatitis in children is sparse. Although there is a lot of evidence, there is consensus opinion from physician medical societies that, in children with more than one episode of pancreatitis, a positive result of this genetic testing may make additional invasive testing unnecessary. See the Evidence Review section below for more detail.

Evidence Review 

Description
In chronic pancreatitis (CP), recurrent attacks of acute pancreatitis evolve into a chronic inflammatory state with exocrine insufficiency, 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 genetic 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.

Background  Pancreatitis

Acute and chronic pancreatitis (CP) is caused by the premature activation of trypsinogen into trypsin within the pancreas, resulting in autodigestion, inflammation, increased levels of pancreatic enzymes in the 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. Individuals with HP have an estimated 40% to 55% lifetime risk of developing pancreatic cancer.


Genetic Determinants of Hereditary Pancreatitis (HP)

PRSS1 Variant
Whitcomb (2001) discovered that disease-associated variants of protease, serine, 1 (trypsin 1) (PRSS1) on chromosome 7q35 cause HP. PRSS1 encodes cationic trypsinogen.
The 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.

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.

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.

Individuals with heterozygous variants of the CFTR gene (CF carriers) have a 3- to 4-fold increased risk for CP. Individuals with 2 CFTR 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 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 2 variants (p.R254W and p.K247_R254del) are associated with an increased risk for idiopathic CP (odds ratio [OR], 4.6), alcoholic pancreatitis (OR =4.2), and tropical pancreatitis (OR =13.6).

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 polymorphisms 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 nextgeneration 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.

Prevention Genetics (Marshfield, WI) offers a Chronic Pancreatitis Sequencing Panel, which includes NGS of 5 genes: CASR, CFTR, CTRC, PRSS1, and SPINK1.
Ambry Genetics (Aliso Viejo, CA) offers a Pancreatitis Panel, which includes NGS of PRSS1, SPINK1, CTRC, and CFTR.
Ambry’s PancNext™ panel for variants associated with increased risk of pancreatic cancer consists of NGS of 13 genes: APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, and TP53.


Clinical Policy: Carrier Screening in Pregnancy

Description

This policy outlines medical necessity criteria for cystic fibrosis (CF) and spinal muscular atrophy (SMA) carrier testing.

Policy/Criteria
I. It is the policy of health plans affiliated with Centene Corporation® that CF carrier screening (CPT® code 81220) or SMA carrier screening (81401) is medically necessary for women who are pregnant and meet the following criteria:

A. No prior CF or SMA screening results are available, and
B. Pregnancy ≤ 22 weeks gestation, and
C. Underwent pretest counseling.

II. It is the policy of Centene Corporation that CF or SMA carrier screening anytime other than during pregnancy and for requests for CF screening CPT® codes 81221 – 81224 during pregnancy is medically necessary when meeting the most current version of the relevant nationally recognized decision support tools

Authorization Protocols

Requests for prior authorization will be accepted up to 5 business days after specimen collection and reviewed for medical necessity based on the above stated criteria.


CLINICAL POLICY Carrier Screening in Pregnancy


If both parents are carriers, chorionic villus sampling or amniocentesis can be performed to see whether the fetus has the disease. Since these are both invasive procedures that carry a slight risk to the fetus, further testing should only be performed if and when the course of the pregnancy will be altered based on results of the testing.

CPT Codes Description


81220 CFTR (cystic fibrosis transmembrane conductance regulator (eg. Cystic fibrosis) gene analysis; common variants (eg. ACMG/ACOG guidelines)
81221 known family variants
81222 Duplication/deletion variants
81223 Full gene sequence
81224 Intron 8 poly-T analysis (eg, male infertility)
81401 Molecular pathology procedure level 2 (used for SMA carrier testing)

Documentation Guidelines


Documentation must be adequate to verify that coverage guidelines listed above have been met. Thus, the medical record must contain documentation that the testing is expected to influence treatment of the condition toward which the testing is directed. The laboratory or billing provider must have on file the physician requisition which sets forth the diagnosis or condition that warrants the test(s).

Examples of documentation requirements of the ordering physician/nonphysician practitioner (NPP) include, but are not limited to, history and physical or exam findings that support the decision making, problems/diagnoses, relevant data (e.g., lab testing, imaging results).

Documentation requirements of the performing laboratory (when requested) include, but are not limited to, lab accreditation, test requisition, test record/procedures, reports (preliminary and final), and quality control record.

Documentation requirements for lab developed tests/protocols (when requested) include diagnostic test/assay, lab/manufacturer, names of comparable assays/services (if relevant), description of assay, analytical validity evidence, clinical validity evidence, and clinical utility.

Providers are required to code to specificity however, if an unlisted CPT code is used the documentation must clearly identify the unique procedure performed. When multiple procedure codes are submitted on a claim (unique and/or unlisted) the documentation supporting each code should be easily identifiable. If on review the contractor cannot link a billed code to the documentation, these services will be denied based on Title XVIII of the Social Security Act,
§1833(e).

When the documentation does not meet the criteria for the service rendered or the documentation does not establish the medical necessity for the services, such services will be denied as not reasonable and necessary under Section 1862(a)(1)(A) of the Social Security Act.