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Intracellular Micronutrient Analysis

Policy Number: MP-378

Latest Review Date: January 2019

Category:  Laboratory                                                            

Policy Grade: D

Description of Procedure or Service:

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. 

Vitamin Deficiencies

“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 United States; most individuals 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. In addition, some commercial laboratories offer panels of vitamin and mineral testing that also use serum analysis.

Diagnostic Testing

This evidence review evaluates laboratory tests that measures 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 compared with serum levels, because intracellular levels are not influenced by recent nutrition intake. However, the relationship between serum and intracellular levels of micronutrients is complex. The balance of intra-and extracellular levels depend 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 a variety of 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, phosphorous, sodium, and 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 are as follows:

  • Vitamins:  Vitamins A, B1, B2, B3, B6, B12, C, D, K; biotin, folate, pantothenate acid
  • Minerals:  calcium, magnesium, zinc, copper
  • Antioxidants:  α-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.

Policy:

Functional Intracellular Analysis (FIA), intracellular micronutrient panel testing, and all other live blood cell testing of intracellular nutritional status is considered not medically necessary and investigational.

Key Points:

The most recent literature review was updated through October 3, 2018.

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

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 evidence review is: Does intracellular micronutrient analysis testing improve health outcomes in individuals with chronic diseases or nonspecific generalized symptoms?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population of interest is patients with chronic diseases or 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 test accuracy, symptoms, and change in disease status.

Timing

The timeframe for short- and long-term symptom improvement and change in disease status vary by the chronic disease affecting the patient.

Setting

Testing could be ordered in primary care or specialty setting.

Study Selection Criteria

For the evaluation of 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.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review, and alternative sources exist. This evidence review 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. The study described a single center’s experience with micronutrient testing in the management of hypertensive patients. A total of 3,338 patients treated over five years received micronutrient testing. Among the 3,338 patients, 671 (20%) were considered to have hypertension (defined as blood pressure above 140/90 mm Hg). The author stated that there were differences in levels of many micronutrients in the hypertensive versus non-hypertensive 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 optimal diet, exercise, and weight management. The author reported that, after six months, 62% of the hypertensive population had succeeded in reaching their blood pressure goals and had tapered and discontinued hypertensive medication. The article did not report micronutrient levels before or after treatment and did not report 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 generalized symptoms. Moreover, there are not sufficient 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. 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 that evaluated the direct health impact of intracellular micronutrient testing. Moreover, there are not sufficient 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.

Practice Guidelines and Position Statements

No practice guidelines or position statements on intracellular micronutrient testing were identified.

US Preventive Services Task Force

Not applicable.

Key Words:

Functional intracellular analysis (FIA), essential metabolic analysis, micronutrient testing, comprehensive nutritional panel, SpectraCell, IntraCellular Diagnostics, SpectraCell’s micronutrient test, IntraCellular Diagnostics ExaTest, intracellular micronutrient analysis,  SPECTROX®, bostonheart diagnostic®, Fatty Acid Balance test

Approved by Governing Bodies:

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

Benefit Application:

Coverage is subject to member’s specific benefits.  Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP contracts: FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.

Current Coding: 

CPT Codes:

There is no specific CPT code for this panel of testing.

The specific CPT codes for each of the elements of the panel would most likely be reported (e.g., 84590 for vitamin A, 82310 for calcium, 82725 for oleic acid, etc.) along with one unit of a not otherwise specified (i.e., 84591) or unlisted (i.e., 84999) code for the balance of the panel which does not have specific codes.

According to SpectraCell Laboratories, their total antioxidant function testing (which they call SPECTROX®) is reported using CPT code:

86353

Lymphocyte transformation, mitogen (phytomitogen) or antigen induced blastogenesis

IntraCellular Diagnostics uses electron microscopy for which the following CPT code might be reported:

88348

Electron microscopy; diagnostic

References:

  1. Barrett S.  Dubious diagnostic tests.  Quackwatch: Your guide to Quackery, Health Fraud, and Intelligent Decisions, www.quackwatch.org.
  2. Department of Health and Human Services – Office of Inspector General. CLIA Regulation of Unestablished Laboratory Tests. July 2001. oig.hhs.gov/oei/reports/oei-05-00-00250.pdf.
  3. Fairfield KM, et al. Vitamins for chronic disease prevention in adults:  Scientific review. JAMA, June 2002; 287(23): 3116-3126.
  4. Fletcher RH, et al. Vitamins for chronic disease prevention in adults: Clinical applications.  JAMA, June 2002; 287(23): 3127-3129.
  5. Haigney MC, Berger R, Schulman S et al. Tissue magnesium levels and the arrhythmic substrate in humans. J Cardiovasc Electrophysiol 1997;8(9):980-6.
  6. Haigney MC, Silver B, Tanglao E et al. Noninvasive measurement of tissue magnesium and correlation with cardiac levels. Circulation 1995;92(8):2190-7.
  7. 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 2010;493):165-83.

Policy History:

Medical Policy Group, August 2009 (3)

Medical Policy Administration Committee, August 2009

Available for comment August 21-October 5, 2009

Medical Policy Group, August 2010 (1): New key words added, no coverage change

Medial Policy Panel, July 2011

Medical Policy Group, August 2011 (2): Title change, Description change, Addition to coverage policy statement, Update to Key Points, Key Words, Government Approval, References.

Medical Policy Administration Committee, August 2011

Available for comment August 11 – September 26, 2011

Medical Policy Panel, July 2012

Medical Policy Group, September 2012 (2): Key Points updated.

Medical Policy Group, January 2012 (2): Description, Key Points & References updated; policy statement remains unchanged

Medical Policy Panel, July 2013

Medical Policy Group, September 2013 (1): Policy updated with literature search through July 2013; no change to policy statement

Medical Policy Panel, July 2014

Medical Policy Group, July 2014, (1): Policy updated with literature search through June 2014; no change to policy statement

Medical Policy Panel, July 2015

Medical Policy Group, July 2015 (3): 2015 updates to Key Points and Benefit Application, no change to policy statement.

Medical Policy Group, August 2015 (3):  added bostonheart diagnostics® and fatty acid balance test to Key Words

Medical Policy Panel, March 2017

Medical Policy Group, March 2017 (3): 2017 Updates to Key Points, Key Words & Coding Section, no References added; No change to policy statement.

Medical Policy Panel, March 2018

Medical Policy Group, March 2018 (4): Updates to Description and Key Points. No change to policy statement.

Medical Policy Panel, December 2018

Medical Policy Group, January 2019 (9): Annual updates to Description & Key Points. No change to policy statement.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.