Genetic Testing for Lactase Insufficiency

POLICY NUMBER

L.2.04.462

DESCRIPTION

Genetic testing of adults with suspected lactase insufficiency is proposed as an alternative to current diagnostic practices, which include hydrogen breath test, lactose tolerance blood test,and intestinal biopsy.

Lactase

The predominant carbohydrate in milk is the disaccharide, lactose, comprising the simple sugars, glucose and galactose. The brush-border enzyme, lactase (also called lactase-phlorizin hydrolase), hydrolyzes lactose into its monosaccharide components, which are absorbable by the intestinal mucosa. Except in rare instances of congenital hypolactasia, most infants can produce lactase, and enzyme levels are highest at birth. Sometime after weaning in most children, there is a decrease in lactase production through a multifactorial process that is regulated at the gene transcription level.

The decrease in lactase level varies significantly by ethnic group both in terms of the lowest level of lactase and time from weaning necessary to reach the nadir of lactase activity. By 2 to 12 years of age, two groups emerge: a group with insufficient levels of lactase activity (primary hypolactasia or lactase non-persistence) and a group that retains the infant level of lactase activity through adulthood (lactase persistence). Ethnic groups with the highest prevalences of lactase insufficiency are Asian, Native American, and Black, with the lowest prevalences in people of northern European origin.

Prevalence of Lactase Insufficiency by Ethnicity

ªIdentified through hydrogen breath test or lactose tolerance blood test.

Several terms are used to describe lactose malabsorption: lactase insufficiency, lactose malabsorption, and lactose intolerance.

Lactase Insufficiency

Lactase insufficiency (lactase non-persistence or primary hypolactasia) indicates that lactase activity is a fraction of the original infantile level. Direct measurement of lactase activity is tested biochemically through duodenal biopsy. Lactase insufficiency is highly correlated with the C/C genotype at -13910 in the lactase promoter region. In adults homozygous for the lactase persistence genotype (T/T), lactase levels are approximately 10 times higher than in those who are homozygous lactase insufficient (C/C); heterozygous persons (C/T) have intermediate lactase activity levels. In heterozygous people, symptoms of lactose intolerance may appear if the quantity of ingested lactose exceeds the maximum digestible by the reduced level of lactase.

Lactose Malabsorption

Lactose malabsorption indicates that a large portion of lactose cannot be absorbed in the small bowel and is delivered to the colon. Malabsorption is tested by hydrogen breath test (HBT) or lactose tolerance blood test.

Lactose Intolerance

Lactose intolerance indicates that lactose malabsorption causes gastrointestinal symptoms. There is no genetic test for lactose intolerance; demonstration of lactose intolerance requires individuals to self-report symptoms (see the table below) after lactose ingestion. Diagnosis of lactose intolerance is highly susceptible to the placebo effect, and studies should conduct a blinded lactose challenge with an indistinguishable placebo. A meta-analysis by Jellema and colleagues has indicated that no specific complaint could predict lactose malabsorption; for common lactose intolerance symptoms, sensitivity and specificity ranged from 0% to 90% and 18% to 96%, respectively. Similarly, self-reported milk intolerance was inaccurate for predicting lactose malabsorption, with sensitivity and specificity ranging from 30% to 70% and 25% to 87%, respectively.

Symptoms of Lactose Intolerance

Symptoms

Lactase insufficiency is common, occurring in approximately 70% of persons after weaning. Lactase insufficiency results in lactose malabsorption, which may lead to symptoms of lactose intolerance such as abdominal pain, bloating, diarrhea, and increased flatulence, caused by bacterial fermentation of undigested lactose in the colon. However, demonstration of lactose malabsorption does not necessarily indicate that a person will be symptomatic. Factors that determine whether a person with lactose malabsorption will develop symptoms include the dose of lactose ingested, residual intestinal lactase activity, ingestion of food along with lactose, the ability of the colonic flora to ferment lactose, and individual sensitivity to the products of lactose fermentation. Because of these factors, the number of persons reporting symptoms of lactose intolerance is likely only a portion of those who are lactase insufficient. Also, lactose malabsorption may be secondary (secondary hypolactasia) to acquired conditions, such as small bowel bacterial overgrowth, infectious enteritis, mucosal damage due to celiac disease, inflammatory bowel disease, antibiotics, gastrointestinal surgery, short bowel syndrome, radiation enteritis, or other conditions that may lead to reduced lactase expression in the small intestine.

Clinical Diagnosis

Mucosal biopsy of the duodenum followed by biochemical lactase assay to directly measure lactase activity is the criterion standard for diagnosing lactase insufficiency. Although this approach may also exclude other causes of secondary lactose malabsorption, the utilityis limited due to the invasiveness of the procedure and the patchy expression of lactase in the duodenum.

Two common alternatives to this direct method of measuring lactase activity are the hydrogen breath test (HBT) and the lactose tolerance blood test, which measure lactose malabsorption. Because lactose malabsorption is nearly always attributable to lactase insufficiency, insufficiency typically can be imputed from the assessment of lactose malabsorption.

The HBT measures by gas chromatography the amount of hydrogen exhaled for up to 3 hours after ingesting 25 to 50 g of lactose. Persons undergoing HBT are required to fast overnight and refrain from activities that may elevate breath hydrogen during testing. A rise in breath hydrogen of 0.31 to 2.5 mL/min is indicative of bacterial fermentation from malabsorbed lactose. A negative HBT can exclude lactose malabsorption as the cause of symptoms, and a positive result indicates that the symptoms may be attributable to lactose ingestion. The following factors are associated with increased breath hydrogen and may cause false-positive results if present at the time of testing:

• Diabetes

• Small bowel disease (e.g., celiac, giardiasis)

• Bacterial overgrowth

• Altered colon pH

• Antibiotic usage

• Probiotic usage

• Smoking

• Exercise

• Aspirin usage

• Colonic bacterial adaptation.

The lactose tolerance blood test measures blood glucose increase over time with blood drawn at 15, 30, 60, and 90 minutes after ingesting a 25- to 50-g dose of lactose. A glucose increase of less than 20 mg/dL above an 8-hour fasting level indicates an abnormal test. The following factors are associated with increased blood sugar when undergoing a lactose tolerance test and may cause false-positive results:

• Diabetes

• Small-bowel disease (e.g., celiac, giardiasis)

• Thyroid disorders

• Motility disorders (stomach, small bowel)

• Bacterial overgrowth

Molecular Diagnosis

In 2002, Enattah and colleagues identified the first DNA variant to control transcription of lactase. This variant (MCM6 - 13910C>T) is located in a noncoding region of the MCM6 gene that is upstream of the lactase gene (LCT). The less common T allele has been associated with lactase persistence and has demonstrated an autosomal dominant pattern of inheritance. This variant is thought to be related to the domestication of animals during the last 10,000 to 12,000 years, and persons with the C/C genotype have been shown to be strongly associated with a lactase insufficiency phenotype in whites. Other variants in the same MCM6 regulatory region are associated with other ethnic groups (such as Africans and Arabs), but prevalence varies geographically, and to date, no commercially available testing kits have incorporated these variants.

Prometheus’s LactoTYPE® is a commercially available polymerase chain reaction-based test that assesses the most common lactase non-persistence variant, MCM6 -13910 C>T, in individuals with suspected lactose intolerance. Fulgent Clinical Diagnostics Lab also offers MCM6 sequencing as well as deletion and duplication analysis using next-generation sequencing. Demonstration of the C/C genotype can be used as indirect evidence of lactase insufficiency and lactose malabsorption.

Treatment

The goal of treatment should be to ensure adequate nutrition for skeletal health. For individuals with lactase insufficiency, dietary adjustment to restrict the consumption of foods containing lactose is the principal form of therapy. However, even lactose maldigesters can usually tolerate small amounts of lactose (12 g/day) with no or minimal symptoms. Lactase enzyme preparations are available for symptom relief but may not be effective in all individuals.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test. 

POLICY

The use of targeted MCM6 -13910C>T variant analysis for the prediction of lactase insufficiency is considered investigational.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Genetics Nomenclature Update

The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It was implemented for genetic testing medical evidence review updates in 2017 (see Table 1). The Society's nomenclature is recommended by the Human Variome Project, the HUman Genome Organization, and by the Human Genome Variation Society itself.

The American College of Medical Genetics (ACMG) and Genomics and the Association for Molecular Pathology (AMP) standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table 2 shows the recommended standard terminology—"pathogenic," "likely pathogenic," "uncertain significance," "likely benign," and "benign"—to describe variants identified that cause Mendelian disorders.

Table 1. Nomenclature to Report on Variants Found in DNA

Table 2. ACMG-AMP Standards and Guidelines for Variant Classification

Genetic Counseling

Experts recommend formal genetic counseling for individuals who are at risk for inherited disorders and who wish to undergo genetic testing. Interpreting the results of genetic tests and understanding risk factors can be difficult for some individuals; genetic counseling helps individuals understand the impact of genetic testing, including the possible effects the test results could have on the individual or their family members. It should be noted that genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing; further, genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

07/18/2013: New policy added. Approved by Medical Policy Advisory Committee.

07/11/2014: Policy reviewed; description updated. Policy statement unchanged.

07/30/2015: Code Reference section updated for ICD-10.

09/14/2015: Policy description updated regarding tests. Policy statement unchanged. Investigative definition updated in the Policy Guidelines section.

06/07/2016: Policy number A.2.04.94 added.

06/26/2017: Code Reference section updated to revise code description for CPT code 81400.

10/12/2017: Policy description updated regarding symptoms of lactose intolerance. Policy statement updated to change "mutation analysis" to "variant analysis." Policy Guidelines updated to add genetics nomenclature update and genetic counseling information.

12/22/2017: Code Reference section updated to revise description for CPT code 81400 effective 01/01/2018.

06/12/2018: Policy description updated regarding lactase insufficiency by ethnicity. Policy statement updated to add "MCM6."

06/06/2019: Policy reviewed; no changes.

06/18/2020: Policy reviewed; no changes.

08/02/2021: Policy reviewed; no changes.

06/20/2022: Policy description updated. Policy statement unchanged. Policy Guidelines updated with minor changes.

07/13/2023: Policy updated to change "patients" to "individuals." Policy statement unchanged.

06/17/2024: Policy description updated to change "patients" to "individuals." Policy statement unchanged.

08/27/2024: Policy updated to change the medical policy number from “A.2.04.94” to “L.2.04.462.”

SOURCE(S)

Blue Cross and Blue Shield Association Policy # 2.04.94

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

Investigational Codes

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