| Coverage Policy Manual | |
| Policy #: | 2010047 |
| Category: | Laboratory |
| Initiated: | January 2011 |
| Last Review: | January 2025 |
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| Functional Intracellular Analysis | |
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| Description: |
Functional Intracellular Analysis (FIA), also known as Essential Metabolic Analysis (EMA) or Intracellular Micronutrient Analysis, is a series of laboratory tests performed in an attempt to identify intracellular nutritional deficiencies and antioxidant functions. Potential uses of this test include screening for nutritional deficiencies in healthy individuals or those with chronic disease and aiding in the diagnosis of disease in patients with generalized symptoms.
“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.
This policy addresses a novel laboratory test 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 than serum levels and 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 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 a variety of micronutrients (e.g., 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 (i.e., magnesium, calcium, potassium, phosphorous, sodium, and chloride) (IntraCellular Diagnostics, 2021). SpectraCell Laboratories offers a panel of tests that evaluates the intracellular status of micronutrients within lymphocytes in blood samples (SpectraCell Laboratories, 2021). The micronutrients measured by the test includes:
The SpectraCell micronutrient panel also may include SPECTROX™ for evaluation of 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.
Coding
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 multiple units of not otherwise specified (i.e., 84591) or unlisted (i.e., 84999) codes for elements of the panel which don’t have specific codes.
According to SpectraCell Laboratories, their total antioxidant function testing (which they call SPECTROX®) is reported using CPT code 86353.
IntraCellular Diagnostics uses electron microscopy for which CPT code 88348 might be reported.
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Policy/ Coverage: |
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Functional Intracellular Analysis testing does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, Functional Intracellular Analysis testing is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
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| Rationale: |
A search of the MEDLINE database was conducted through December 2011. There were no published studies identified that assessed the clinical utility of Functional Intracellular Analysis testing.
2014 Update
A literature search conducted through August 2014 did not reveal any new information that would prompt a change in the coverage statement.
2012 Update
An updated literature search was conducted through August 2012. There was no new information identified that would prompt a change in the coverage statement. Following is a summary of the key literature to date.
One proposed use of intracellular micronutrient testing is as a screening test in individuals who do not have signs or symptoms of nutritional deficiency. The appropriate study design to evaluate the clinical benefit of a screening test is a randomized controlled trial (RCT) comparing health outcomes in a screened and unscreened population. No such studies were identified in the literature search. In addition, no controlled observational (non-randomized) studies were identified.
In 2010, Houston published an article on screening asymptomatic patients using micronutrient testing (Houston, 2010). The article was primarily a review but presented data on one center’s experience with micronutrient testing in the management of hypertensive patients. A total of 3,338 patients treated over 5 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 6 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 6-month blood pressure data for a comparison group of hypertensive patients who did not undergo micronutrient testing.
Intracellular micronutrient testing is also proposed to aid in the diagnosis of patients with generalized symptoms with no identified disease source. No studies were identified evaluating this potential application of intracellular micronutrient testing.
Another possible application of intracellular micronutrient testing is as an alternative to serum testing for the diagnosis of specific nutritional deficiencies in patients with signs or symptoms of a nutritional disorder. A related application would be using intracellular micronutrient testing instead of serum testing for asymptomatic patients who have been diagnosed with a disease associated with a specific nutritional deficiency. No studies comparing the diagnostic accuracy or clinical utility of intracellular versus serum testing were identified for any particular micronutrient in either of the above patient populations.
There are, however, some published data from the 1990s by Haigney and colleagues examining intracellular and serum magnesium levels in patients with heart disease. (Magnesium sulfate is an accepted treatment in selected patients with ventricular arrhythmias.) (Zipes, 2006) In a study with 40 patients referred for arrhythmia evaluation, there was a statistically significant correlation between intracellular magnesium levels and increased QT interval dispersion (dQT), defined as the difference between the longest and shortest QT interval (Haigney, 1997). The correlation was r: 0.22, p<0.22. There was not a significant correlation between serum magnesium and the dQT; r: 0.03, p>0.05. Another study by this research team included 18 patients admitted to the hospital for cardiac surgery, 21 control patients admitted with acute medical illnesses, and 15 healthy controls (Haigney, 1995). The mean serum magnesium levels were within the normal range for the cardiac surgery patients (1.87 +/- 0.06 milliequivalents per liter [mEq/L]). However, the mean intracellular magnesium level was significantly lower in cardiac surgery patients than healthy volunteers (32.1 +/- 0.2 vs. 33.7 +/- 0.5 mEq/L, respectively), p<001. The Haigney et al. studies did not assess the accuracy of intracellular versus serum testing of magnesium levels and did not evaluate the impact of testing on health outcomes.
Practice Guidelines and Position Statements
No practice guidelines or position statements on intracellular micronutrient testing were identified.
Summary
No studies were identified that evaluated the accuracy or clinical utility of intracellular micronutrient testing compared to standard testing for vitamin or mineral levels. In addition, no controlled studies were identified that evaluated the health impact of any potential clinical application of intracellular micronutrient testing including diagnosing patients with generalized symptoms or screening individuals for nutrient deficiencies. Limited data are available on correlations between serum and intracellular micronutrient levels.
2013 Update
A literature search conducted using the MEDLINE database through August 2013 did not reveal any new information that would prompt a change in the coverage statement.
2015 Update
A literature search conducted through August 2015 did not reveal any new information that would prompt a change in the coverage statement.
2016 Update
A literature search conducted through August 2016 did not reveal any new information that would prompt a change in the coverage statement.
2017 Update
A literature search conducted through July 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
INTRACELLULAR MICRONUTRIENT ANALYSIS IN PATIENTS WITH CHRONIC DISEASES OR
NONSPECIFIC GENERALIZED SYMPTOMS
Analytic Validity
No studies on analytic validity were identified.
Clinical Validity
No studies on the sensitivity and specificity of intracellular micronutrient analysis tests compared with a reference standard (eg, serum testing) were identified.
Clinical Utility
Direct Evidence
No studies were identified reporting on the clinical utility of intracellular micronutrient analysis. The ideal study would be an RCT evaluating health outcomes in patients who did and did not undergo intracellular micronutrient testing.
Clinical Utility
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.
ONGOING AND UNPUBLISHED CLINICAL TRIALS
A search of ClinicalTrials.gov in June 2017 did not identify any ongoing or unpublished trials that would likely influence this review.
2018 Update
A literature search was conducted through August 2018. There was no new information identified that would prompt a change in the coverage statement.
2019 Update
A literature search was conducted through August 2019. There was no new information identified that would prompt a change in the coverage statement.
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2020. No new literature was 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 August 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 August 2022. No new literature was identified that would prompt a change in the coverage statement.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2023. No new literature was identified that would prompt a change in the coverage statement.
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2023. No new literature was identified that would prompt a change in the coverage statement.
2025 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2024. No new literature was identified that would prompt a change in the coverage statement.
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| References: |
Haigney MC, Berger R, Schulman S et al.(1997) Tissue magnesium levels and the arrhythmic substrate in humans. J Cardiovasc Electrophysiol 1997; 8(9):980-6. Haigney MC, Silver B, Tanglao E et al.(1995) Noninvasive measurement of tissue magnesium and correlation with cardiac levels. Circulation 1995; 92(8):2190-7. Houston MC.(2010) 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; 4(3):165-83. IntraCellular Diagnostics.(2021) Mitochondria: Exploration of Intracellular Space. https://www.exatest.com/. Accessed October 22, 2021. SpectraCell Laboratories.(2021) Micronutrient Test. https://spectracell.sitewrench.com/search-tests. Accessed October 22, 2021 Zipes DP, Camm AJ, Borggrefe M et al.(2006) ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death). J Am Coll Cardiol 2006; 48(5):e247-346. |
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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.
CPT Codes Copyright © 2025 American Medical Association. |
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