Coverage Policy Manual
Policy #: 2015025
Category: Laboratory
Initiated: August 2015
Last Review: August 2018
  Nutritional Panel Testing (NutrEval®, ONE FMV™)

Description:
Nutritional panel testing aims to identify nutritional deficiencies that will lead to personalized nutritional supplement recommendations. Testing is proposed both for otherwise healthy individuals to optimize health and for patients with chronic conditions such as mood disorders, fibromyalgia and chronic fatigue to specify supplements that will ameliorate symptoms.
 
At least 1 company, Genova Diagnostics, offers nutritional/nutrient panel testing. Among tests offered by this company is the NutrEval® FMV test, which involves analysis of urine and blood samples and provides information on more than 100 markers including organic acids, amino acids, fatty acids, markers of oxidative stress (direct measurement of glutathione and CoQ10, and markers of oxidative injury and DNA damage) and nutrient elements [B vitamins (Thiamin B1, riboflavin B2, niacin B3, pyridoxine B6, biotin B7, folic acid B9, cobalamin B12 ), minerals (magnesium, manganese, molybdenum, zinc), essential fatty acids (Omega-3-oils), digestive support (probiotics, pancreatic enzymes), amino acids (Arginine, asparagine, cysteine, glutamine, glycine, histidine, isoleucine, leucine, lycine, methionine, phenylalanine, serine, taurine, threonine, tryptophan, tyrosine, valine) and other vitamins (Vitamin D)].  
 
The company produces a report that includes test results divided into the categories normal, borderline and high need, along with recommendations for supplements and dosages for items categorized as high need. NutrEval® FMV patient reports can recommend supplementation or any of the following nutrients, if they are found to be areas of high need.
 
A related test, the ONE (Optimal Nutritional Evaluation) FMV™, involves testing limited to the organic acid, amino acid, and oxidative stress markers categories.
 
Regulatory Status
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 Act (CLIA). Nutrient/nutritional panel testing using urine and/or blood samples is offered (eg, NutrEval FMV® and ONE FMV® by Genova Diagnostics) under the auspices of CLIA. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, the US Food and Drug Administration has chosen not to require any regulatory review of this test.
 
Coding
There are no specific codes for these panels of tests. Tests in the panel that have specific CPT codes would be reported using those codes such as folic acid (82746), magnesium (83735), manganese (83785), vitamin A (84590), zinc (84630). There are codes for testing multiple amino acids – 82128 for qualitative testing and 82136 for quantitative testing. The unlisted chemistry code 84999 would be used once for the other tests in the panel that do not have specific codes (or are used incorrectly with multiple units).
 

Policy/
Coverage:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Nutrient/nutritional panel testing for all indications including but not limited to testing for nutritional deficiencies in patients with mood disorders, fibromyalgia, unexplained fatigue and healthy individuals does not meet member benefit certificate primary coverage criteria.
 
For members with contracts without primary coverage criteria, nutrient/nutritional panel testing is considered investigational for all indications including but not limited to testing for nutritional deficiencies in patients with mood disorders, fibromyalgia, unexplained fatigue and healthy individuals. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:
Direct evidence that nutrient/nutritional panel testing improves health outcomes would consist of randomized controlled trials that compare outcomes in patients managed with and without nutrient/nutritional panel testing. In the absence of direct evidence, an indirect chain of evidence can be examined. Nutrient/nutritional panel tests are particularly targeted to patients with mood disorders, fibromyalgia, and chronic fatigue, so these are the conditions that will be the focus of the evidence review.
 
An indirect chain of evidence to support the use of nutrient/nutritional panel would consist of: (1) evidence that specific nutritional deficiencies included in the panel test are significantly associated with mood disorders, fibromyalgia, and/or chronic fatigue; (2) evidence that, in patients with mood disorders, fibromyalgia and/or chronic fatigue, treatment of a patient found to have specific nutritional deficiencies (eg, with nutritional supplements) improves health outcomes and (3) evidence that, if there is sufficient evidence on the first 2 items, panel testing is more appropriate than testing for specific nutrients.
 
No studies were identified that directly evaluated the impact of nutrient/nutritional panel testing on health outcomes. Evidence for an indirect chain of evidence is examined next.
 
Evidence on the Association Between Nutritional Deficiencies and Mood Disorders,
Fibromyalgia, or Unexplained Fatigue
Several systematic reviews and meta-analyses evaluating associations between the indications of interest and specific nutrient deficiencies were identified (Swardfager, 2013; Anglin, 2013; Petridou, 2015; Daniel, 2011;). No systematic reviews or meta-analyses were identified on the association between nutritional deficiencies and unexplained fatigue. A limitation of all reviews is that, although they compared low and high levels of nutrient levels, none addressed whether these low levels constituted actual deficiencies in a particular nutrient.
 
Evidence that Treatment of Patients With Mood Disorders, Fibromyalgia, or Unexplained Fatigue Found to Have Nutritional Deficiencies Improves Condition-Specific Symptoms
Several systematic reviews and meta-analyses evaluating health outcomes in patients with depression treated with nutritional supplementation were identified (Taylor, 2003; Gowda, 2015). In the review by Taylor and colleagues (Taylor, 2013) the difference in HDRS scores were significantly lower in patients taking folic acid plus antidepressants vs antidepressants alone. In the review by Gowda et al, there was no significant differences found in depression after supplementation with vitamin D versus placebo (Gowda, 2015).  A limitation of all of the reviews is that they did not require patients to have an established deficiency of any nutrient. No systematic reviews or meta-analyses were identified on nutritional interventions in patients with fibromyalgia or unexplained fatigue.
 
Evidence on Panel Testing Versus Testing for Individual Nutrients
There is no evidence on any indication to suggest that nutritional panel testing improves the net health outcome compared with testing for 1 or several individual nutrients. This includes patients with mood disorders, fibromyalgia, and/or unexplained fatigue, as well as healthy individuals seeking to optimize health and/or sports fitness. Moreover, with nutritional panel testing, there is a potential for incidental findings that could cause harm. Examples of potential harms include unnecessary confirmatory tests, unnecessary treatments provided for clinically insignificant conditions, and toxicity related to supplementation or interactions between nutritional supplements and prescription medication.
 
Ongoing and Unpublished Clinical Trials
A search of ClinicalTrials.gov in July 2015 did not identify any ongoing or unpublished trials that would likely influence this review.
 
Summary of Evidence
The evidence for nutritional panel testing in patients who have mood disorders, fibromyalgia, or unexplained fatigue includes several systematic reviews on the association between a single condition and a single nutrient and on treatment of specific conditions with nutritional supplements. Relevant outcomes are symptoms, change in disease status, and functional outcomes. There was no evidence of associations between fibromyalgia or unexplained fatigue and nutrient deficiencies. Systematic reviews found statistically significant associations between depression and levels of several nutrients; however, there was no evidence that treatment of depressed patients with nutrient supplementation improved health outcomes. In addition, there was no direct evidence on health benefits of nutritional panel testing for any condition, including testing healthy individuals, and no evidence that nutritional panel testing is superior to testing for individual nutrients for any condition. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2018. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Mood Disorders, Fibromyalgia, or Unexplained Fatigue
 
Several systematic reviews and meta-analyses evaluating associations between the indications of interest and specific nutrient deficiencies were identified. No systematic reviews or meta-analyses were identified on the association between nutritional deficiencies and unexplained fatigue. A limitation of all reviews is that, although they compared low and high levels of nutrient levels, none addressed whether these low levels constituted actual deficiencies in a particular nutrient
 
 
Treatment of Mood Disorders, Fibromyalgia, or Unexplained Fatigue in Patients With Nutritional Deficiencies
Several systematic reviews and meta-analyses evaluating health outcomes in patients with depression treated with nutritional supplementation were identified. A limitation of all of the reviews is that they did not require patients to have an established deficiency of any nutrient. No systematic reviews or meta-analyses were identified on nutritional interventions in patients with fibromyalgia or unexplained fatigue.
 
Nowak et al (2016) conducted a single-center, double-blind, placebo-controlled trial to determine whether a single vitamin D dose would reduce fatigue after 30 days among 120 otherwise healthy persons with low serum 25-hydroxyvitamin D (25(OH)D) levels (mean age, 29 years; 53% women) (Nowak, 2016). The outcome was measured using the Fatigue Assessment Scale. The vitamin D group had a significantly greater decrease in mean (standard deviation [SD]) Fatigue Assessment Scale score (-3.3, SD=5.3) than the placebo group (-0.8, SD=5.3; p=0.01). Improvements were reported more frequently in the vitamin D group (42 [72%]) than in placebo group (31 [50%]; p=0.01; odds ratio, 2.63; 95% confidence interval for odds ratio, 1.23 to 5.62). Among all participants, improvement in Fatigue Assessment Scale correlated with the rise in 25(OH)D levels (r=0.22, p=0.02).

CPT/HCPCS:
84999Unlisted chemistry procedure

References: Anglin RE, Samaan Z, Walter SD, et al.(2013) Vitamin D deficiency and depression in adults: systematic review and meta-analysis. Br J Psychiatry. Feb 2013;202:100-107. PMID 23377209

Cheungpasitporn W, Thongprayoon C, Mao MA, et al.(2015) Hypomagnesaemia linked to depression: a systematic review and meta-analysis. Intern Med J. Apr 2015;45(4):436-440. PMID 25827510

Daniel D, Pirotta MV.(2011) Fibromyalgia--should we be testing and treating for vitamin D deficiency? Aust Fam Physician. Sep 2011;40(9):712-716. PMID 21894281

Daniel D, Pirotta MV.(2011) Fibromyalgia--should we be testing and treating for vitamin D deficiency? Aust Fam Physician. Sep 2011;40(9):712-716. PMID 21894281

Gowda U, Mutowo MP, Smith BJ, et al.(2015) Vitamin D supplementation to reduce depression in adults: meta-analysis of randomized controlled trials. Nutrition. Mar 2015;31(3):421-429. PMID 25701329

Gowda U, Mutowo MP, Smith BJ, et al.(2015) Vitamin D supplementation to reduce depression in adults: meta-analysis of randomized controlled trials. Nutrition. Mar 2015;31(3):421-429. PMID 25701329

Hsiao MY, Hung CY, Chang KV, et al.(2015) Is serum hypovitaminosis D associated with chronic widespread pain including fibromyalgia? A meta-analysis of observational studies. Pain Physician. Sep-Oct 2015;18(5):E877-887. PMID 26431141

Nowak A, Boesch L, Andres E, et al.(2016) Effect of vitamin D3 on self-perceived fatigue: A double-blind randomized placebo-controlled trial. Medicine (Baltimore). Dec 2016;95(52):e5353. PMID 28033244

Petridou ET, Kousoulis AA, Michelakos T, et al.(2015) Folate and B12 serum levels in association with depression in the aged: a systematic review and meta-analysis. Aging Ment Health. Jun 8 2015:1-9. PMID 26055921

Swardfager W, Herrmann N, Mazereeuw G, et al.(2013) Zinc in depression: a meta-analysis. Biol Psychiatry. Biol Psychiatry. Dec 15 2013;74(12):872-878. PMID 23806573

Taylor MJ, Carney S, Geddes J, et al.(2003) Folate for depressive disorders. Cochrane Database Syst Rev. Jun 2003(2):CD003390. PMID 12804463

Taylor MJ, Carney S, Geddes J, et al.(2003) Folate for depressive disorders. Cochrane Database Syst Rev. Cochrane Database Syst Rev. 2003(2):CD003390. PMID 12804463

U.S. Preventive Services Task Force (USPSTF).(2006) Iron Deficiency Anemia: Screening. http://www.uspreventiveservicestaskforce.org/Page/Topic/recommendation-summary/iron-deficiency-anemia-screening. Accessed July 15, 2015.

Vitamin D Deficiency: Screening.(2015) U.S. Preventive Services Task Force (USPSTF). http://www.uspreventiveservicestaskforce.org/Page/Topic/recommendation-summary/vitamin-d-deficiency-screening. Accessed July 14, 2015.


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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