This policy 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 two commercial laboratories offer intracellular testing for micronutrients. Laboratories perform a panel of tests evaluating the intracellular level of various micronutrients (e.g., minerals, vitamins, amino acids, fatty acids). The test offered by IntraCellular Diagnostics evaluates epithelial cells from buccal swabs and assesses levels of intracellular mineral electrolyte (i.e., magnesium, calcium, potassium, phosphorus, sodium, chloride). SpectraCell Laboratories offers a panel of tests that evaluates the intracellular status of micronutrients within lymphocytes in blood samples. The micronutrients measured by the test include:

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

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. 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.

Related Policies

• None

For members enrolled in Medicaid and NJ FamilyCare plans, Horizon BCBSNJ applies the above medical policy.

FIDE SNP:

For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

[RATIONALE: This policy was created in 2011 and has been updated regularly with searches of the MEDLINE database. The most recent literature update was performed through October 14, 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.

Intracellular Micronutrient Analysis

Clinical Context and Test Purpose

“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.

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 question addressed in this policy is: Does intracellular micronutrient analysis testing improve health outcomes in individuals with chronic diseases or nonspecific generalized symptoms?

The following PICOs were used to select literature to inform this policy.

Patients

The relevant populations of interest are patients with chronic diseases or with nonspecific generalized symptoms.

Interventions

The test being considered is intracellular micronutrient analysis. Testing can be ordered in the primary care or specialty setting.

Comparators

The following practices are currently being used to identify micronutrient deficiencies: serum testing for individual nutritional deficiencies or standard management without nutritional testing. Testing can be ordered in the primary care or specialty setting.

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

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

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 (e.g., 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.^1, 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 six-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 observational studies. The 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 the effects of the technology on health outcomes.

SUPPLEMENTAL INFORMATION

Practice Guidelines and Position Statements

No guidelines or statements were identified.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

A search of ClinicalTrials.gov in October 2019 did not identify any ongoing or unpublished trials that would likely influence this review.]
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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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Index:
Intracellular Micronutrient Analysis
Micronutrient Analysis
IntraCellular Diagnostics
Exa Test
SpectraCell Micronutrients Panel Test

References:
1. 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):165-183. PMID 20400494

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

84999