CAM 204136

Nutrient/Nutritional Panel Testing

Category:Medicine   Last Reviewed:August 2018
Department(s):Medical Affairs   Next Review:August 2019
Original Date:August 2015    

Description
Multimarker nutritional panel testing is proposed for patients with certain chronic conditions (e.g., mood disorders, fibromyalgia, unexplained fatigue) as well as for healthy individuals seeking to optimize health and/or fitness.

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.

Background
Nutritional panel testing aims to identify nutritional deficiencies that will lead to personalized nutritional supplement recommendations. Testing is proposed both for healthy individuals to optimize health and for patients with chronic conditions (e.g., mood disorders, fibromyalgia, chronic fatigue) to specify supplements that will ameliorate symptoms.

Genova Diagnostics offers nutritional/nutrient panel testing. Among tests this company offers is NutrEval FMV, 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 (see Table 1).1

Genova Diagnostics produces a report that includes test results categorized as 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 nutrients listed in Table 1 if they are found to be areas of high need.

A related test, the ONE (Optimal Nutritional Evaluation) FMV also by Genova Diagnostics, limits testing to the organic acid, amino acid, and oxidative stress marker categories.

SpectraCell Laboratories offers a micronutrient test that measures functional deficiencies at the cellular level. The test assesses how well the body uses 33 vitamins, minerals, amino and fatty acids, antioxidants, and metabolites (see Table 1). SpectraCell categorizes test results into adequate, borderline, and deficient, and offers supplementation suggestions based on each patient’s deficiencies. 

Table 1. Components of the NutrEval FMV Test

Category

NutrEval

SpectraCell Nutrient Testing

B vitamins

Thiamin B1, riboflavin B2, niacin B3, pyridoxine B6, biotin B7, folic acid B9, cobalamin B12

Vitamin A, vitamin B1, vitamin B2, vitamin B3, vitamin B6, vitamin B12, biotin, folate, pantothenate, vitamin C, vitamin D, vitamin K

Minerals

Magnesium, manganese, molybdenum, zinc

Calcium, magnesium, manganese, zinc, copper

Fatty acids

Omega-3-oils

Oleic acid

Digestive support

Probiotics, pancreatic enzymes 

Other vitamins 

Vitamin D 

Amino acids

Arginine, asparagine, cysteine, glutamine, glycine, histidine, isoleucine, leucine, lycine, methionine, phenylalanine, serine, taurine, threonine, tryptophan, tyrosine, valine

Asparagine, glutamine, serine

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 (e.g., 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.

Related Policies 
20423 Homocysteine Testing in the Screening, Diagnosis and Management of Cardiovascular Disease
20473 Intracellular Micronutrient Analysis
204100 Cardiovascular Risk Panels

Policy 
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.

Policy Guidelines
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).

Rationale 
This evidence review was created in August 2015 and has been updated regularly with searches of the MEDLINE database. The most recent literature update was performed through November 7, 2017.

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.

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, a chain of evidence can be examined. Nutrient/nutritional panel tests are specifically targeted at patients with mood disorders, fibromyalgia, and chronic fatigue so that this review will focus on those conditions. The following is a summary of the key literature.

NUTRIENT/NUTRITIONAL PANEL TESTING
Clinical Context and Test Purpose
The purpose of nutrient/nutritional panel testing in patients who have mood disorders, fibromyalgia, or unexplained fatigue or in healthy individuals seeking to optimize health and fitness is to inform a decision whether the patient might benefit from specific nutrient supplementation.

The question addressed in this evidence review is: Does nutrient/nutritional panel testing, to identify nutrient deficiencies, result in improved health outcomes among patients with mood disorders, fibromyalgia, or unexplained fatigue or among healthy individuals seeking to optimize health and fitness compared with standard of care.

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

Patients
The relevant populations of interest are patients with mood disorders, fibromyalgia, or unexplained fatigue, or healthy individuals seeking to optimize health and fitness.

Interventions
The relevant intervention of interest is nutrient/nutritional panel testing.

Comparators
The relevant comparator of interest is standard of care.

Outcomes
The potential beneficial outcomes of primary interest would be an improvement in symptoms, change in disease status, and functional outcomes. The potential harmful outcomes are those resulting from a false test result. False-positive or false-negative test results can lead to the initiation of unnecessary treatment and adverse events from that overtreatment or undertreatment. 

Timing
Nutrient/nutritional panel testing might be conducted before or after starting specific therapy for the specific conditions addressed herein or as a screening test for healthy individuals seeking to optimize health and fitness.

Setting
Ordering and interpreting nutrient/nutritional panel testing should be done by physicians in an outpatient or inpatient setting.

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
Evidence to support the clinical validity of nutrient/nutritional panel testing would require studies that report the sensitivity, specificity, and positive and negative predictive values of these tests in detecting nutritional deficiency compared with a criterion standard test, preferably among the study population of interest. Currently, there is no literature reporting on the clinical validity of nutrient/nutritional panel tests in this target population.

Clinically Useful
The chain of evidence to support the clinical utility of the use of nutrient/nutritional panel testing 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 (e.g., 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 a chain of evidence is examined next.

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, and they are described in Table 2. 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.

Table 2. Systematic Reviews on the Association Between Nutritional Deficiencies and Mood Disorders, Fibromyalgia, and Unexplained Fatigue

Study

Nutrient

No. of Studies

Specified Cutoff for Nutrient Deficiency

Key Findings

Depression

Swardfager et al (2013)2

Zinc

17

No

Mean serum zinc concentrations of -1.85 μmol/L (95% CI, -2.52 to -1.19 μmol/L) in depressed patients vs nondepressed controls (p<0.001)

Anglin et al (2013)3

Vitamin D

14

No

Cross-sectional studies:

  • OR of depression, highest vs lowest vitamin D categories: 1.31 (95% CI, 1.00 to 1.71; p=0.03)

Prospective series:

  • Risk of developing depression significantly higher in patients with lower vitamin D (HR=2.21; 95% CI, 1.40 to 3.49; p=0.028)

Petridou et al (2015)4

Folate and vitamin B12

11

No

Odds of having depression significantly associated with low folate and vitamin B levels:

  • Folate: OR=1.27 (95% CI, 1.07 to 1.43)
  • Vitamin B: OR=1.20 (95% CI, 1.02 to 1.42)

Cheungpasitporn et al (2015)5 

Magnesium

 6

NO 

Pooled RR of depression in patients with hypomagnesemia (3 cohort studies, 2 cross-sectional studies, 1 case-control study combined; N=19,137 patients):

  • 1.34 (95% CI, 1.01 to 1.79; I2=33%)

Pooled RR excluding the cross-sectional studies:

  • 1.38 (95% CI, 0.92 to 2.07; I2=24%)

Fibromyalgia

Daniel and Pitotta (2011)6 

Vitamin D 

 

No 

No pooled analyses. Lower quality studies tended to find positive associations between fibromyalgia and low vitamin D levels; studies with control groups found no significant associations; larger population-based studies had mixed findings

Hsiao et al (2015)7 

Vitamin D

12 

No 

Significantly higher odds of hypovitaminosis D among patients with chronic pain including fibromyalgia vs control group:

  • Crude OR=1.63 (95% CI, 1.20 to 2.23)
  • Adjusted OR=1.41 (95% CI, 1.00 to 2.00)

CI: confidence interval; HR: hazard ratio; OR: odds ratio; RR: relative risk.

Subsection Summary: Mood Disorders, Fibromyalgia, or Unexplained Fatigue
Evidence from multiple systematic reviews and meta-analyses of observational studies have indicated an association between deficiency of nutrients (vitamin B12, vitamin D, folate, magnesium, zinc) and different outcomes (depression, fibromyalgia). There is no evidence whether screening for these nutrient deficiencies results in improved health outcome compared with no screening.

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, and they are described in Table 3. 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.

Table 3. Systematic Reviews on Interventions for Patients With Mood Disorders, Fibromyalgia, and/or Unexplained Fatigue Diagnosed With Nutritional Deficiencies

Study

Intervention and Comparator

No. and Type of Studies

Patients Diagnosed With Nutritional Deficiencies

Key Findings

Depression

Taylor et al (2003)8

Folic acid (alone or as adjunctive treatment) vs antidepressant mediation

3 RCTs

No

Difference in HDRS scores significantly lower in patients taking folic acid plus antidepressants vs antidepressants alone (MD = -2.65; 95% CI, -4.93 to -0.038)

Gowda et al (2015)9

Vitamin D

9 RCTs

  • No in overall analysis
  • Yes in subgroup analysis
  • No significant difference found in depression after supplementation with vitamin D vs placebo (SMD=0.28; 95% CI, -0.14 to 0.69)
  • No significant difference found in depression with vitamin D vs placebo in patients with baseline vitamin D >50 nmol/L or in patients with baseline vitamin D <50 nmol/L

CI: confidence interval; HDRS: Hamilton Depression Rating Scale; MD: mean difference; RCT: randomized controlled trial; SMD: standard mean difference.

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).10 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).

Subsection Summary: Treatment of Mood Disorders, Fibromyalgia, or Unexplained Fatigue in Patients With Nutritional Deficiencies
A systematic review and meta-analysis of randomized controlled trials have suggested that folate might have a role as a supplement to other therapies. However, it is unclear whether folate supplement would benefit both people with normal folate level and those with folate deficiency. A meta-analysis of randomized controlled trials has suggested no significant benefit of vitamin D supplementation vs placebo in the case of depression. There is no evidence whether screening for these nutrient deficiencies (vs no screening) would result in significant improvement in outcomes.

Panel Testing vs 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 one 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 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.

SUMMARY OF EVIDENCE
For individuals who have mood disorders, fibromyalgia, or unexplained fatigue, or healthy individuals who seek to optimize health and fitness who receive nutritional panel testing, the evidence includes several systematic reviews on the association between a single condition and a single nutrient and on the 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 have found statistically significant associations between depression and levels of several nutrients; however, there is no evidence that nutrient supplementation for patients with depression improves health outcomes. Also, there is no direct evidence on the 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.

PRACTICE GUIDELINES AND POSITION STATEMENTS
No guidelines or statements were identified.

U.S. PREVENTIVE SERVICES TASK FORCE RECOMMENDATIONS
The U.S. Preventive Services Task Force has not addressed nutritional panel testing. The Task Force has made several recommendations addressing screening for individual nutrients. The Task Force concluded that there is insufficient evidence to recommend for or against screening for iron deficiency anemia in asymptomatic children and vitamin D deficiency in asymptomatic adults.11,12 Screening for iron deficiency anemia is recommended in pregnant women.  

ONGOING AND UNPUBLISHED CLINICAL TRIALS
A search of ClinicalTrials.gov in November 2017 did not identify any ongoing or unpublished trials that would likely influence this review.

References 

  1. Genova Diagnostics. NutrEval FMV. 2015; https://www.gdx.net/product/nutreval-fmv-nutritional-test-blood-urine. Accessed November 21, 2017.
  2. Swardfager W, Herrmann N, Mazereeuw G, et al. Zinc in depression: a meta-analysis. Biol Psychiatry. Dec 15 2013;74(12):872-878. PMID 23806573
  3. Anglin RE, Samaan Z, Walter SD, et al. Vitamin D deficiency and depression in adults: systematic review and meta-analysis. Br J Psychiatry. Feb 2013;202:100-107. PMID 23377209
  4. Petridou ET, Kousoulis AA, Michelakos T, et al. 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
  5. Cheungpasitporn W, Thongprayoon C, Mao MA, et al. Hypomagnesaemia linked to depression: a systematic review and meta-analysis. Intern Med J. Apr 2015;45(4):436-440. PMID 25827510
  6. Daniel D, Pirotta MV. Fibromyalgia--should we be testing and treating for vitamin D deficiency? Aust Fam Physician. Sep 2011;40(9):712-716. PMID 21894281
  7. Hsiao MY, Hung CY, Chang KV, et al. 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
  8. Taylor MJ, Carney S, Geddes J, et al. Folate for depressive disorders. Cochrane Database Syst Rev. Jun 2003(2):CD003390. PMID 12804463
  9. Gowda U, Mutowo MP, Smith BJ, et al. Vitamin D supplementation to reduce depression in adults: meta-analysis of randomized controlled trials. Nutrition. Mar 2015;31(3):421-429. PMID 25701329
  10. Nowak A, Boesch L, Andres E, et al. Effect of vitamin D3 on self-perceived fatigue: A double-blind randomized placebo-controlled trial. Medicine (Baltimore). Dec 2016;95(52):e5353. PMID 28033244
  11. U.S. Preventive Services Task Force (USPSTF). Iron Deficiency Anemia: Screening. 2006; http://www.uspreventiveservicestaskforce.org/Page/Topic/recommendation-summary/iron-deficiency-anemia-screening. Accessed November 7, 2017.
  12. U.S. Preventive Services Task Force (USPSTF). Vitamin D Deficiency: Screening. 2014; http://www.uspreventiveservicestaskforce.org/Page/Topic/recommendation-summary/vitamin-d-deficiency-screening. Accessed November 7, 2017.

Coding Section 

Codes Number Description
CPT  

No specific code. See Policy Guidelines

ICD-9 DIAGNOSIS  

Investigational for all indications

HCPCS    
ICD-10-CM (effective 10/01/15)  

Investigational for all indications

  F30.10-F39

Mood [affective] disorders code range

  M79.7

Fibromyalgia

  R53.81-R53.73

Other malaise and fatigue code range

ICD-10-PCS (effective 10/01/15)  

Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests

Type of Service    
Place of Service    

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology© American Medical Association.  All Rights Reserved" 

History From 2015 Forward     

08/21/2018 

Annual review, no change to policy intent. Updating background, rationale and references. 

08/09/2017 

Annual review, no change to policy intent. Updated Review Date. 

08/02/2016 

Annual review, no change to policy intent. 

08/25/2015

NEW POLICY

 


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