Medical Policy

Policy Num:      11.001.037
Policy Name:    Intracellular Micronutrient Analysis
Policy ID:           [11.001.037]  [Ac / B / M- / P-]  [2.04.73]

Last Review:     January 08, 2025
Next Review:     January 20, 2026

Related Policies: None

Intracellular Micronutrient Analysis

summary

Description

Commercial laboratories offer panels of tests evaluating intracellular levels of micronutrients (essential vitamins and minerals). Potential uses of these tests include screening for nutritional deficiencies in healthy people or those with chronic disease and aiding in the diagnosis of disease in patients with nonspecific symptoms.

Summary of Evidence

For individuals who have chronic diseases or nonspecific generalized symptoms who receive intracellular micronutrient analysis, the evidence includes an observational study. Relevant outcomes are symptoms and change in disease status. No studies were identified that evaluated the clinical validity or clinical utility of intracellular micronutrient testing compared with standard testing for vitamin or mineral levels. Limited data from observational studies are available on correlations between serum and intracellular micronutrient levels. No randomized controlled trials or comparative studies were identified evaluating the direct health impact of intracellular micronutrient testing. Moreover, there are insufficient data to construct a chain of evidence that intracellular micronutrient testing would likely lead to identifying patients whose health outcomes would be improved compared with alternative approaches to patient management. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

OBJECTIVE

The objective of this evidence review is to determine whether intracellular micronutrient analysis to detect vitamin and mineral deficiencies improves the net health outcome in patients with chronic diseases or nonspecific generalized symptoms.

POLICY statements

Intracellular micronutrient panel testing is considered investigational.

POLICY GUIDELINES

Coding

Please see the Codes table for details.

BENEFIT APPLICATION

BlueCard/National Account Issues

This testing is currently only available through 2 reference laboratories: SpectraCell Laboratories and IntraCellular Diagnostics.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

BACKGROUND

“Micronutrients” collectively refer to essential vitamins and minerals necessary in trace amounts for health. Clinical deficiency states (states occurring after prolonged consumption of a diet lacking the nutrient that is treated by adding the nutrient to the diet) have been reported for vitamins A, B₁, B₁₂, C, and D, selenium, and other micronutrients. Classic nutritional deficiency diseases are uncommon in the U. S.; most people derive sufficient nutrition from their diets alone or in combination with over-the-counter multivitamins.

Laboratory tests are available for individual micronutrients and are generally used to confirm suspected micronutrient deficiencies. Testing is performed by serum analysis using standardized values for defining normal and deficient states. Also, some commercial laboratories offer panels of vitamin and mineral testing that also use serum analysis.

Diagnostic Testing

This evidence review evaluates laboratory tests that measure the intracellular levels of micronutrients. This testing, also known as intracellular micronutrient analysis, micronutrient testing, or functional intracellular analysis, is sometimes claimed to be superior to serum testing because intracellular levels reflect more stable micronutrient levels over longer time periods than serum levels and because intracellular levels are not influenced by recent nutrition intake. However, the relation between serum and intracellular levels of micronutrients is complex. The balance of intracellular and extracellular levels depends on a number of factors, including the physiology of cellular transport mechanisms and the individual cell type.

At least 2 commercial laboratories offer intracellular testing for micronutrients. Laboratories perform a panel of tests evaluating the intracellular level of various micronutrients (eg, minerals, vitamins, amino acids, fatty acids). The test offered by IntraCellular Diagnostics (EXA Test®) evaluates epithelial cells from buccal swabs and assesses levels of intracellular mineral electrolyte (ie, magnesium, calcium, potassium, phosphorus, sodium, chloride).^1,SpectraCell Laboratories offers a panel of tests that evaluates the intracellular status of micronutrients within lymphocytes in blood samples.^2, The micronutrients measured by the test include:

• Vitamins: A, B₁, B₂, B₃, B₆, B₁₂, C, D, K; biotin, folate, pantothenic acid

• Minerals: calcium, magnesium, manganese, zinc, copper

• Antioxidants: a-lipoic acid, coenzyme Q10, cysteine, glutathione, selenium, vitamin E

• Amino acids: asparagine, glutamine, serine

• Carbohydrate metabolism: chromium, fructose sensitivity, glucose-insulin metabolism

• Fatty acids: oleic acid

• Metabolites: choline, inositol, carnitine

The SpectraCell micronutrient panel also may include SPECTROX™ for evaluation of the total antioxidant function and IMMUNIDEX™ for immune response score.

Regulatory Status

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. Intracellular micronutrient panel testing is offered by SpectraCell Laboratories and IntraCellular Diagnostics under the auspices of the Clinical Laboratory Improvement Amendments. 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.

RATIONALE

This evidence review was created in July 2011 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through November 25, 2024.

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.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1

Intracellular Micronutrient Analysis

Clinical Context and Test Purpose

The purpose of diagnostic testing of patients who have chronic diseases or nonspecific generalized symptoms is to identify micronutrient deficiencies, not indicated by specific signs and/or symptoms, that would inform management decisions and improve health outcomes.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is patients with chronic diseases or with nonspecific generalized symptoms.

Interventions

The test being considered is intracellular micronutrient analysis.

Comparators

The following practices are currently being used to identify micronutrient deficiencies: serum testing for individual nutritional deficiencies or standard management without nutritional testing.

Outcomes

The general outcomes of interest are symptoms and change in disease status. The timeframe for short- and long-term symptom improvement and change in disease status vary by the chronic disease affecting the patient.

Study Selection Criteria

For the evaluation of the clinical validity of the intracellular micronutrient test panel, 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 calculate scores)

• Included a suitable reference standard (describe the reference standard)

• Patient/sample clinical characteristics were described

• Patient/sample selection criteria were described

Clinically Valid

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).

No studies on the sensitivity and specificity of intracellular micronutrient analysis tests compared with a reference standard (eg, serum testing) were identified.

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.

No evidence from randomized controlled trials was identified supporting the use of intracellular micronutrient analysis tests.

Chain of 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.

An observational study by Houston (2010) provided some data relevant to a chain of evidence.^3, The study described a single center's experience with micronutrient testing in the management of hypertension. A total of 3338 patients treated over 5 years received micronutrient testing. Among the 3338 patients, 671 (20%) were considered to have hypertension (defined as blood pressure >140/90 mm Hg). The author stated that there were differences in levels of many micronutrients in the hypertensive vs nonhypertensive populations but did not report the specific micronutrients for which levels differed. Hypertensive patients identified as having micronutrient deficiencies were treated with high-dose therapy of appropriate supplements, as well as with recommendations on an optimal diet, exercise, and weight management. The author reported that, after 6 months, 62% of the hypertensive population had succeeded in reaching their blood pressure goals and had tapered and discontinued the hypertensive medication. The report did not provide data on micronutrient levels before or after treatment or 6-month blood pressure data for a comparison group of hypertensive patients who did not undergo micronutrient testing.

Section Summary: Clinically Useful

There is no direct evidence that intracellular micronutrient analysis improves health outcomes in patients with chronic diseases or nonspecific generalized symptoms. Moreover, there are insufficient data to construct a chain of evidence that intracellular micronutrient testing would likely lead to identifying patients whose health outcomes would be improved compared with alternative approaches to patient management.

Summary of Evidence

For individuals who have chronic diseases or nonspecific generalized symptoms who receive intracellular micronutrient analysis, the evidence includes an observational study. Relevant outcomes are symptoms and change in disease status. No studies were identified that evaluated the clinical validity or clinical utility of intracellular micronutrient testing compared with standard testing for vitamin or mineral levels. Limited data from observational studies are available on correlations between serum and intracellular micronutrient levels. No randomized controlled trials or comparative studies were identified evaluating the direct health impact of intracellular micronutrient testing. Moreover, there are insufficient data to construct a chain of evidence that intracellular micronutrient testing would likely lead to identifying patients whose health outcomes would be improved compared with alternative approaches to patient management. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

No guidelines or statements were identified.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

A search of ClinicalTrials.gov in November 2024 did not identify any ongoing or unpublished trials that would likely influence this review.

References

1. IntraCellular Diagnostics. Mitochondria: Exploration of Intracellular Space. Accessed November 25, 2024. https://www.exatest.com/
2. SpectraCell Laboratories. Micronutrient Test. Accessed November 25, 2024. https://spectracell.sitewrench.com/search-tests
3. Houston MC. The role of cellular micronutrient analysis, nutraceuticals, vitamins, antioxidants and minerals in the prevention and treatment of hypertension and cardiovascular disease. Ther Adv Cardiovasc Dis. Jun 2010; 4(3): 165-83. PMID 20400494

Codes

Policy History