Coverage Policy Manual
Policy #: 2013018
Category: Laboratory
Initiated: June 2013
Last Review: June 2022
  Genetic Test: Lactase Insufficiency

Description:
Genetic testing of adults with suspected lactase insufficiency is proposed as an alternative to current diagnostic practices. Studies have demonstrated a tight correlation between a single nucleotide polymorphism (SNP) -13910 C>T upstream of the gene coding for the enzyme lactase and lactase insufficiency in persons of European ancestry. Currently, two indirect tests of lactose digestion, the hydrogen breath test (HBT) and lactose tolerance blood test (LTT), are the most preferred diagnostic tests for confirmation of lactase insufficiency.
 
The predominant carbohydrate in milk is the disaccharide lactose consisting of the simple sugars glucose and galactose. The brush-border enzyme lactase hydrolyzes lactose into its monosaccharide components that are absorbable by the intestinal mucosa. Except for rare instances of congenital hypolactasia, most infants are able to produce lactase with enzyme levels highest at birth. Sometime after weaning in the majority of children there is a decrease in lactase production through a multifactorial process that is regulated at the gene transcription level (NIG, 2010).  
 
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 (Matthews, 2005). 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) (Shaukat, 2010). The ethnic groups with the highest rates of lactase insufficiency are Asian, Native American and Blacks with the lowest rates in people of northern European origin.
 
Problems with the absorption of lactose can be described in several terms:
    • 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 (Wilt, 2010). Lactase insufficiency is highly correlated with the C/C genotype at -13910 in the lactase promoter region. In adults with a homozygous lactase persistence genotype (T/T) lactase levels are approximately 10-times higher than for the lactase insufficient genotype (C/C) with heterozygous individuals (C/T) showing intermediate levels (Misselwitz, 2013). These heterozygous individuals may experience symptoms of lactose intolerance when ingesting quantities of lactose greater than their intermediate level of lactase can digest.
    • Lactose malabsorption – indicates that a sizable fraction of lactose is not able to be absorbed in the small bowel and is delivered to the colon. Malabsorption is tested by HBT or LTT (Wilt, 2010).
    • Lactose intolerance – indicates that lactose malabsorption causes gastrointestinal symptoms. There is no genetic test for lactose intolerance and demonstration of lactose intolerance requires patients to self-report symptoms after lactose ingestion. Diagnosis of lactose intolerance is highly susceptible to the placebo effect and studies should appropriately conduct a blinded lactose challenge with an indistinguishable placebo (Shaukat, 2010). A meta-analysis by Jellema and colleagues indicated that no specific patient complaint could predict lactose malabsorption with sensitivity and specificity ranging from 0-90% and 18-96% for the most common lactose intolerance symptoms (Jellema, 2010). Similarly, patient self-reported milk tolerance was also not found to be accurate in predicting lactose malabsorption with sensitivity and specificity ranging from 30-70% and 25-87% respectively (Jellema, 2010).  
 
Lactase insufficiency is a common condition which occurs in approximately (70%) of persons after weaning (Haberkorn, 2012). An insufficiency of lactase results in the malabsorption of lactose, 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 (Hogenauer, 2005). However, the demonstration of lactose malabsorption does not necessarily indicate that an individual will be symptomatic. Many variables determine if a person who malabsorbs lactose develops symptoms, including: 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 the 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 fraction of those who are lactase insufficient. In addition, lactose malabsorption may be secondary (secondary hypolactasia) to an acquired condition such as: small bowel bacterial overgrowth, infectious enteritis, mucosal damage from celiac disease, inflammatory bowel disease, antibiotics, gastrointestinal surgery, short bowel syndrome, radiation enteritis or other conditions which may lead to reduction of lactase expression in the small intestine (Misselwitz, 2013).  
 
Clinical Diagnosis of Lactase Insufficiency
Mucosal biopsy of the duodenum followed by biochemical lactase assay to directly measure lactase activity is the reference standard for diagnosis of lactase insufficiency. This approach may also exclude other causes of secondary lactose malabsorption through endoscopy. However, this approach is limited in utility 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 level are the hydrogen breath test (HBT) and lactose tolerance blood test (LTT) which measure lactose malabsorption. Because lactose malabsorption is nearly always attributable to lactase insufficiency, this can typically be imputed from measurements of lactose malabsorption (Shaukat,2010).  
 
The HBT measures the amount of hydrogen exhaled by gas chromatography for up to 3 hours after ingesting 25-50 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 0.31–2.5 mL/min is indicative of bacterial fermentation from the 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 ingestion of lactose (Shaukat, 2010). The following factors are associated with a rise in breath hydrogen and may cause false-positive results if present at time of testing:  Diabetes, Small bowel disease (e.g., celiac, giardiasis), Bacterial overgrowth, Altered colon pH, Antibiotic usage, Probiotic usage, Smoking, Exercise, Aspirin usage and Colonic bacterial adaptation.
 
The LTT measures blood glucose increase over time with blood drawn at 15, 30, 60, and 90 minutes after ingesting a 25-50 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 a rise in 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),  and Bacterial overgrowth.
 
Molecular Diagnosis of Lactase Insufficiency
Enattah and colleagues identified the first DNA variant to control transcription of lactase in 2002 (Enattah, 2010). This polymorphism, -13910 C>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 polymorphism is thought to be related to the domestication of animals during the last 10,000-12,000 years, and persons with the C/C genotype have been shown to be strongly associated with lactase insufficiency phenotype in Caucasians. Other polymorphisms have been identified in the same MCM6 regulatory region which are associated with additional ethnic groups (such as Africans and Arabs), but these have not been as commonly observed but prevalences of these vary geographically (Misselwitz, 2013; Raz, 2013) have not been as commonly observed and to date no commercially available testing kits have incorporated these polymorphisms.
 
Prometheus’s LactoType® is a commercially available polymerase chain reaction􀯅based test that assesses the most common lactase nonpersistence variant, MCM6 –13910 C>T, in patients with suspected lactose intolerance. Fulgent Clinical Diagnostics Lab also offers MCM6 sequencing and deletion/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 of Lactase Insufficiency
The goal of treatment should be to ensure adequate nutrients important for skeletal health (NIH, 2010). Dietary adjustment to restrict the consumption of foods containing lactose is the principal form of therapy for patients with lactase insufficiency. 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 patients.
 
Regulatory Status
No U.S. Food and Drug Administration (FDA)-cleared genotyping tests were found. Thus, genotyping is offered as a laboratory-developed test. Clinical laboratories may develop and validate tests in-house (“home-brew”) and market them as a laboratory service; such tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA).The laboratory offering the service must be licensed by CLIA for high-complexity testing.
 
Coding
Effective July 1, 2013, the following test will be included under CPT code 81400:
 
LCT (lactase-phlorizin hydrolase) (e.g., lactose intolerance), 13910 C>T variant
 

Policy/
Coverage:
EFFECTIVE JUNE 2021
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of targeted MCM6 -13910C>T variant analysis for the prediction of lactase insufficiency does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, the use of targeted MCM6 -13910C>T variant analysis for the prediction of lactase insufficiency is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
EFFECTIVE PRIOR TO JUNE 2021
 
The use of targeted MCM6 -13910C>T variant analysis for the prediction of lactase insufficiency does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, the use of targeted MCM6 -13910C>T variant analysis for the prediction of lactase insufficiency is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
EFFECTIVE PRIOR TO JUNE 2018
 
The use of targeted mutation analysis of -13910 C>T for the prediction of lactase insufficiency does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, the use of targeted mutation analysis of -13910 C>T for the prediction of lactase insufficiency is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 

Rationale:
This policy was created in 2013 and is based on a search of the MEDLINE database through April 2013. Literature that describes the analytic validity, clinical validity, and clinical utility of genetic testing for lactase insufficiency was sought.
 
Analytic validity (the technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent)
 
According to the LactoTYPE® manufacturer the analytical sensitivity and specificity for polymerase chain reaction (PCR) sequencing of LCT -13910 C>T polymorphism is approximately 99%.
 
Clinical validity (the diagnostic performance of the test [sensitivity, specificity, positive and negative predictive values] in detecting clinical disease)
 
Many reports on the diagnosis of lactase insufficiency by PCR mutation analysis of -13910 C>T have been published. Eighteen studies were identified which compared genotyping of SNP -13910 C>T to HBT and found a sensitivities and specificities ranging from 71-100% and 46-100%, respectively (Gugatschka, 2005; Buning, 2005; Hogenauer, 2005; Bulhoes, 2007; Schirru, 2007; Bernardes, 2007; Szilagyi, 2007; Mattar, 2008;Kerber, 2007; Mattar, 2008; Krawcyk, 2008; Mottes, 2008; Waud, 2008; DiStefano, 2008; Nagy, 2009; Szilagyi, 2009; Babu, 2010; Pohl, 2010; Mendoza-Torres, 2011).  . Five studies compared genotyping to LTT with sensitivity and specificity ranging from 85-100% and 87-95%, respectively (Nilsson, 2004; Gugatschka, 2005; Ridefelt, 2005; Szilagvi, 2007; Babu, 2010). Heterogeneity in study population, dose of lactose given in HBT/LTT, and age of participants contributed to the wide range of observed sensitivities and specificities. A direct comparison of these tests is prohibited because no studies were identified that compared genotyping and HBT/LTT to the gold standard of biopsy. Indirect comparison is not possible due to the small number of studies comparing genotyping, HBT, or LTT to biopsy.
 
It is to be expected that there is not complete agreement between genotyping for lactase insufficiency and indirect tests of lactose malabsorption as these tests do not measure the same parameters. LTT and HBT are intended to diagnosis lactose malabsorption that can be caused by reasons other than lactase insufficiency. Additionally, because lactase activity persists for years after weaning, the inclusion of children can affect the concordance between HBT/LTT and genotyping. DiStefano and colleagues found that the overall kappa value for the agreement of HBT and genotyping was .74, but for those younger than and older than 30 years of age, the kappa values were .56 and 1, respectively (p<0.005).
 
In addition, the SNP -13910 C>T is not the only MCM6 polymorphism implicated in regulating transcription of the LCT gene. A study by Eadala and colleagues recruited patients with irritable bowel disease along with healthy control patients and found that while the C/C genotype was strongly associated with experiencing symptoms of lactose intolerance following HBT, there was a high proportion of lactose sensitivity in C/T and T/T genotype patients as well (Eadala, 2011). A Colombian study by Mendoza-Torres and colleagues found a low (46%) specificity when comparing HBT to genotyping. The authors attributed this finding to the genetic heterogeneity of the Colombian and Caribbean population studied and recommend against using genotyping to assess lactase insufficiency in this population (Mendoza, 2012). These results suggest that unmeasured genetic variation may help explain more fully explain lactase insufficiency.
 
A meta-analysis by Marton et al. assessed the diagnostic accuracy of the LTT and HBT tests compared to genotyping for the polymorphism -13910 C>T for prediction of lactase insufficiency phenotype (Marton, 2012). Seventeen studies evaluated HBT and 5 evaluated LTT. The overall sensitivity and specificity of the HBT was 88% (95% confidence interval [CI]: 85-90%) and 85% (95% CI: 82-87%), respectively. Both sensitivity and specificity showed high heterogeneity (I2 78% and 87%) and the authors detected a potential for publication bias within their included studies. LTT overall sensitivity was 94% (95% CI: 90-97%) with a specificity of 90% (95% CI: 84 – 95%). No significant heterogeneity was observed for the sensitivity and specificity of the LTT. Three studies also assessed the sensitivity of the -2018 G>A genotype, which has also been described in Europeans, and found a less accurate overall sensitivity and specificity of 87% (95% CI: 79-93%) and 76% (95% CI: 67-83%) than the -13910 C>T polymorphism.
 
Clinical utility (how the results of the 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)
 
No studies were identified that attempted to demonstrate improved patient outcomes or changes to patient management because of genetic testing for lactase insufficiency.
 
Lactase insufficiency is the normal phenotype for most adults, and a confirmatory diagnosis with HBT, LTT, or genotyping is generally not necessary. Empiric diagnosis by dietary restriction is adequate in most circumstances as this is the primary treatment for lactase insufficient patients. Patients who achieve satisfactory symptom control following dietary modifications do not require further diagnostic testing. For the majority of patients who do not achieve symptom control following dietary modifications, testing is indicated for the presence of other conditions that can cause symptoms similar to lactase deficiency. The proposed clinical utility of genotyping for lactase insufficiency is that the test offers a more comfortable assessment for patients when compared to the HBT, LTT or biopsy. Traditional testing methods may be associated with discomfort caused by the ingestion of a large volume of lactose and there is dietary preparation and fasting before testing. Additionally, factors that influence the interpretation of the indirect HBT and LTT will not lead to false-positive test results from genotyping. Arroyo and colleagues suggest that genetic testing, when used in conjunction with HBT, can help in the diagnosis of secondary hypolactasia when there is a positive HBT and the patient is not C/C genotype (Arroyo, 2012).
 
Ongoing Clinical Trials
A search of online site ClinicalTrials.gov identified no ongoing studies evaluating molecular diagnostic tests for lactase deficiency.
 
Summary
Genetic testing of adults with suspected lactase insufficiency is proposed as an alternative to current diagnostic practices, which include hydrogen breath test (HBT), lactose tolerance blood test (LTT) and intestinal biopsy. Studies have demonstrated a tight correlation between a single nucleotide polymorphism (SNP) -13910 C>T upstream of the gene coding for the enzyme lactase and lactase insufficiency in persons of European ancestry, and studies in Caucasian populations report a high degree of agreement for the diagnosis of lactase insufficiency between genotyping and both the HBT and LTT. Genetic testing has the potential advantage of sparing patients the discomfort of fasting and experiencing symptoms of lactose intolerance during the administration of HBT or LTT. Genotyping may also have additional utility in the diagnosis of secondary hypolactasia.
 
However, because there is no current treatment for lactase insufficiency, and management involves dietary restriction and palliation of lactose intolerance symptoms alone, an empiric diagnosis of lactose intolerance in the absence of confirmation with HBT, LTT or genotyping followed by treatment with dietary restriction of lactose is suitable. There is currently insufficient evidence that the assessment of the genetic etiology of lactose intolerance would affect patient management or improve clinical outcomes.
 
Practice Guidelines and Position Statements
No guidelines or position statements were identified with recommendations on testing for lactase deficiency.
 
2014 Update
A literature search conducted through April 2014 did not reveal any new information that would prompt a change in the coverage statement.
 
2015 Update
A literature search conducted through April 2015 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
According to the Genetic Testing Registry, analytical sensitivity of next-generation sequencing and deletion/duplication analysis of MCM6 exceeds 98%. Analytical specificity and accuracy are 96% and 97%, respectively (NCBI, 2014).
 
A study by Enko and colleagues compared genotyping to a hydrogen/methane breath test, which may be more sensitive than HBT, and reported Cohens kappa statistic (К) of 0.44, indicating moderate agreement (Enko, 2014).
 
Santonocito and colleagues found a similar proportion (~80%) of homozygous genotypes for lactase nonpersistence among 1426 patients with gastrointestinal symptoms and 1000 healthy volunteers in south central Italy (Santonocito, 2015).
 
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2018. No new literature was identified that would prompt a change in the coverage statement.  
 
2019 Update
A literature search was conducted through May 2019.  There was no new information identified that would prompt a change in the coverage statement.  
 
2020 Update
A literature search was conducted through May 2020.  There was no new information identified that would prompt a change in the coverage statement.  
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2022. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:
81400Molecular pathology procedure, Level 1 (eg, identification of single germline variant [eg, SNP] by techniques such as restriction enzyme digestion or melt curve analysis)

References: Kerber M, Oberkanins C, Kriegshauser G et al.(2007) Hydrogen breath testing versus LCT genotyping for the diagnosis of lactose intolerance: a matter of age? Clin Chim Acta 2007; 383(1-2):91-6.

Arroyo MA, Lopes A, Piatto V et al.(2010) Perspectives for Early Genetic Screening of Lactose Intolerance: - 13910C/T Polymorphism Tracking in the MCM6 Gene. Open Biol J 2010; 3:66-71.

Babu J, Kumar S, Babu P et al.(2010) Frequency of lactose malabsorption among healthy southern and northern Indian populations by genetic analysis and lactose hydrogen breath and tolerance tests. Am J Clin Nutr 2010; 91(1):140-6.

Bernardes-Silva CF, Pereira AC, de Fatima Alves da Mota G et al.(2007) Lactase persistence/non-persistence variants, C/T_13910 and G/A_22018, as a diagnostic tool for lactose intolerance in IBS patients. Clin Chim Acta 2007; 386(1-2):7-11.

Bulhoes AC, Goldani HA, Oliveira FS et al.(2007) Correlation between lactose absorption and the C/T-13910 and G/A-22018 mutations of the lactase-phlorizin hydrolase (LCT) gene in adult-type hypolactasia. Braz J Med Biol Res 2007; 40(11):1441-6.

Buning C, Genschel J, Jurga J et al.(2005) Introducing genetic testing for adult-type hypolactasia. Digestion 2005; 71(4):245-50.

Di Stefano M, Terulla V, Tana P et al.(2009) Genetic test for lactase non-persistence and hydrogen breath test: is genotype better than phenotype to diagnose lactose malabsorption? Dig Liver Dis 2009; 41(7):474-9.

Eadala P, Matthews SB, Waud JP et al.(2011) Association of lactose sensitivity with inflammatory bowel disease--demonstrated by analysis of genetic polymorphism, breath gases and symptoms. Aliment Pharmacol Ther 2011; 34(7):735-46.

Enattah NS, Sahi T, Savilahti E et al.(2002) Identification of a variant associated with adult-type hypolactasia. Nat Genet 2002; 30(2):233-7.

Enko D, Rezanka E, Stolba R, et al.(2014) Lactose malabsorption testing in daily clinical practice: a critical retrospective analysis and comparison of the hydrogen/methane breath test and genetic test (c/t-13910 polymorphism) results. Gastroenterol Res Pract. 2014;2014:464382. PMID 24829570

Gugatschka M, Dobnig H, Fahrleitner-Pammer A et al.(2005) Molecularly-defined lactose malabsorption, milk consumption and anthropometric differences in adult males. QJM 2005; 98(12):857-63.

Haberkorn BC, Ermens AA, Koeken A et al.(2012) Improving diagnosis of adult-type hypolactasia in patients with abdominal complaints. Clin Chem Lab Med 2012; 50(1):119-23.

Hogenauer C, Hammer HF, Mellitzer K et al.(2005) Evaluation of a new DNA test compared with the lactose hydrogen breath test for the diagnosis of lactase non-persistence. Eur J Gastroenterol Hepatol 2005; 17(3):371-6.

Jellema P, Schellevis FG, van der Windt DA et al.(2010) Lactose malabsorption and intolerance: a systematic review on the diagnostic value of gastrointestinal symptoms and self-reported milk intolerance. QJM 2010; 103(8):555-72.

Krawczyk M, Wolska M, Schwartz S et al.(2008) Concordance of genetic and breath tests for lactose intolerance in a tertiary referral centre. J Gastrointest Liver Dis 2008; 17(2):135-9.

Kuchay RA, Thapa BR, Mahmood A et al.(2011) Effect of C/T -13910 cis-acting regulatory variant on expression and activity of lactase in Indian children and its implication for early genetic screening of adult-type hypolactasia. Clin Chim Acta 2011; 412(21-22):1924-30.

Marton A, Xue X, Szilagyi A.(2012) Meta-analysis: the diagnostic accuracy of lactose breath hydrogen or lactose tolerance tests for predicting the North European lactase polymorphism C/T-13910. Aliment Pharmacol Ther 2012; 35(4):429-40.

Mattar R, Monteiro Mdo S, Villares CA et al.(2008) Single nucleotide polymorphism C/T(-13910), located upstream of the lactase gene, associated with adult-type hypolactasia: validation for clinical practice. Clin Biochem 2008; 41(7-8):628-30.

Matthews SB, Waud JP, Roberts AG et al.(2005) Systemic lactose intolerance: a new perspective on an old problem. Postgrad Med J 2005; 81(953):167-73.

Mendoza Torres E, Varela Prieto LL, Villarreal Camacho JL et al.(2012) Diagnosis of adult-type hypolactasia/lactase persistence: genotyping of single nucleotide polymorphism (SNP C/T-13910) is not consistent with breath test in Colombian Caribbean population. Arq Gastroenterol 2012; 49(1):5-8.

Misselwitz B, Pohl D, Frühauf H et al.(2013) Lactose malabsorption and intolerance: pathogenesis, diagnosis and treatment. United Eur Gastroenterol J 2013 [Epub ahead of print]. Available online at http://ueg.sagepub.com/content/early/2013/03/27/2050640613484463.full.pdf+html. Last accessed May 2013.

Morales E, Azocar L, Maul X et al.(2011) The European lactase persistence genotype determines the lactase persistence state and correlates with gastrointestinal symptoms in the Hispanic and Amerindian Chilean population: a case-control and population-based study. BMJ 2011; 1(1):e000125.

Mottes M, Belpinati F, Milani M et al.(2008) Genetic testing for adult-type hypolactasia in Italian families. Ann Clin Biochem 2008; 45(Pt 1):50-8.

Nagy D, Bogacsi-Szabo E, Varkonyi A et al.(2009) Prevalence of adult-type hypolactasia as diagnosed with genetic and lactose hydrogen breath tests in Hungarians. Eur J Clin Nutr 2009; 63(7):909-12.

National Center for Biotechnology Information.(2014) Testing Registry (GTR). MCM6: performance characteristics, last updated: 2014-09-24. http://www.ncbi.nlm.nih.gov/gtr/tests/518150/performance-characteristics/. Accessed March 11, 2015.

National Institutes of Health. Lactose Intolerance and Health. Paper presented at: NIH Consensus Development Conference:2010.

Nilsson TK, Johansson CA.(2004) A novel method for diagnosis of adult hypolactasia by genotyping of the -13910 C/T polymorphism with Pyrosequencing technology. Scand J Gastroenterol 2004; 39(3):287-90.

Pohl D, Savarino E, Hersberger M et al.(2010) Excellent agreement between genetic and hydrogen breath tests for lactase deficiency and the role of extended symptom assessment. Br J Nutr 2010; 104(6):900-7.

Rasinpera H, Savilahti E, Enattah NS et al.(2004) A genetic test which can be used to diagnose adult-type hypolactasia in children. Gut 2004; 53(11):1571-6.

Raz M, Sharon Y, Yerushalmi B et al.(2013) Frequency of LCT-13910C/T and LCT-22018G/A single nucleotide polymorphisms associated with adult-type hypolactasia/lactase persistence among Israelis of different ethnic groups. Gene 2013; 519(1):67-70.

Ridefelt P, Hakansson LD.(2005) Lactose intolerance: lactose tolerance test versus genotyping. Scand J Gastroenterol 2005; 40(7):822-6.

Sahi T.(1994) Genetics and epidemiology of adult-type hypolactasia. Scand J Gastroenterol Suppl 1994; 202:7-20.

Santonocito C, Scapaticci M, Guarino D, et al.(2015) Lactose intolerance genetic testing: is it useful as routine screening? Results on 1426 south-central Italy patients. Clin Chim Acta. Jan 15 2015;439:14-17. PMID 25281930

Schirru E, Corona V, Usai-Satta P et al.(2007) Genetic testing improves the diagnosis of adult type hypolactasia in the Mediterranean population of Sardinia. Eur J Clin Nutr 2007; 61(10):1220-5.

Shaukat A, Levitt MD, Taylor BC et al.(2010) Systematic review: effective management strategies for lactose intolerance. Ann Intern Med 2010; 152(12):797-803.

Szilagyi A, Malolepszy P, Hamard E et al.(2007) Comparison of a real-time polymerase chain reaction assay for lactase genetic polymorphism with standard indirect tests for lactose maldigestion. Clin Gastroenterol Hepatol 2007; 5(2):192-6.

Szilagyi A, Shrier I, Chong G et al.(2009) Lack of effect of lactose digestion status on baseline fecal micoflora. Can J Gastroenterol 2009; 23(11):753-9.

Wilt TJ, Shaukat A, Shamliyan T et al.(2010) Lactose intolerance and health. Evid Rep Technol Assess 2010; (192):1-410.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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