What happens to micronutrient levels in the hospital setting?

When atypical labs need to be obtained, many times this is easier in the hospital setting for logistical reasons including insurance and accessibility to specialty labs.  One group of labs that may be less suited for checking in the hospital, despite convenience, would be micronutrients.  Many of the micronutrients can be affected by systemic inflammatory response (Am J Clin Nutr 2012; 95: 64-71).  Thanks to Kipp Ellsworth for this reference (from his @PedNutritionGuy twitter feed).

Previous studies on systemic inflammatory response (SIR), as assessed by elevated C-reactive protein (CRP) concentrations, has shown that with elective surgery there are transient decreases in plasma concentrations of zinc, selenium, iron, vitamin A, vitamin E, carotenoids, riboflavin, vitamin B-6, vitamin C, and vitamin D.

This current study adds to this body of information.  Between 2001-2011, 2217 whole-blood samples were taken from 1303 patients. Specific micronutrients that were studied: plasma zinc, copper, selenium, vitamins A, B-6, C, and E.  For vitamin D, the authors examined 4327 samples from 3677 patients. The authors did not include manganese, thiamine or riboflavin because these are measured in erythrocytes.

For each analyte, the concentrations were separated according to 6 categories of CRP values: <5, 6-10, 11-20, 21-40, 41-80, and >80 mg/L.

Key finding: Except for copper and vitamin E, all plasma micronutrient concentrations decreased with increasing severity of acute inflammatory response.  For selenium, vitamin B-6, and vitamin C, this occurred with only slight increases in CRP (5 to 10 mg/L).

The magnitude of the SIR effect on micronutrients was quite variable among patients and analytes.  When CRP was >80 mg/L, analyte deficiency rate was noted to be the following:

  • 60 % for selenium (vs. 33% with NL CRP)
  • 48% for vitamin A (vs. 7% with NL CRP)
  • 35% for vitamin B-6 (vs. 14% with NL CRP)
  • 80% for vitamin C (vs. 33% with NL CRP)
  • 88% for vitamin D (vs. 69% with NL CRP)
  • 81% for zinc (vs. 33% with NL CRP)
  • 9% for copper (vs. 4% with NL CRP)
  • 16% for vitamin E (vs. 9% with NL CRP)

**The specific normal value cutoffs and more data at all CRP values are noted in Table 9 of the manuscript.

The implications from this study are clear.  When micronutrient values are derived from plasma during a SIR, a false-positive diagnosis of a micronutrient deficiency is more likely. The study has several limitations and the findings may not be applicable to all types of medical conditions.

Authors conclusion: When CRP concentration is >20 mg/L (>2 mg/dL), “plasma concentrations of selenium, zinc, and vitamins A, B-6, C, and D are clinically uninterpretable.”

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Dietary supplements — safe and effective?

Most people consider dietary supplements as likely to be beneficial but at the very least ‘there not going to make you worse.’  That sentiment is wrong.  A review recently published has shown that some dietary supplements may increase the risk of cancer (Journal of the National Cancer Institute 2012; 104: 732-39).

Nearly half of the US adult population uses one or more dietary supplements but there is very little evidence that these supplements reduce cancer risk; in fact, the contrary is true.  Based on numerous studies, the authors make extensive comments regarding the studies of antioxidants, folic acid, and vitamin D/calcium which are summarized below.

Antioxidants

While observational data has suggested benefits from fruit and vegetable consumption, data on antioxidant supplement consumption has not shown a beneficial effect.  The review highlights a number of studies with regard to β-carotene, vitamin A, vitamin C, and vitamin E/α-tocopherol.  Specifically, vitamin C and E do not protect against total cancer incidence. α-tocopherol and β-carotene do not protect against cancer or cancer mortality.

  • The Selenium and Vitamin E Cancer Prevention Trial (SELECT) followed 35,533 men at average risk for prostate cancer for approximately 5.5 years.  This study was halted due to lack of benefit.  In addition, the extended followup reported that α-tocopherol significantly increased the risk of prostate cancer by 17%.
  • The β-carotene and Retinol Efficacy Trial (CARET) had a 39% increase in lung cancer incidence compared to the placebo arm.
  • In two of three large studies of β-carotene, the intervention increased the risk of all-cause mortality.
  • The Nutritional Prevention of Cancer (NPC) extended followup found that selenium supplementation statistically increased the risk of squamous cell skin cancer by 25% and non-melanoma skin cancer by 17%.

Folic Acid

Folic acid which is a synthetic oxidized form of folate is commonly used in fortification and supplements.  Recent meta-analysis of randomized controlled trials (RCTs) has found no effect of folic acid supplementation on the risk of colorectal adenomas over a 3-year treatment period.  In addition, one study demonstrated an increased risk of advanced colorectal adenomas (relative risk = 1.67).  Also, in observational studies, higher intake of folic acid has been linked with increased prostate cancer risk.

Vitamin D and Calcium

The Institute of Medicine published recommendations with regard to Vitamin D and calcium intake in 2011 and found that “there is not enough evidence to state that there is a causal association between low vitamin D intake and increased cancer risk.”  The authors summarize several conflicting results with regard to breast, colorectal, and prostate cancers. In addition, a recent meta-analysis of RCTs indicated that calcium supplementation was associated with a statistically-increased myocardial infarction risk.

Why are supplements so widespread if they are not beneficial and potentially dangerous?

  • The authors also summarize regulatory efforts.  In 1990, due to unsubstantiated health claims by food manufacturers, Congress passed the Nutrition Labeling Education Act (NLEA).
  • To limit FDA authority over supplements, at the behest of nutritional supplement manufacturers, in 1994 Congress passed the Dietary Supplement Health and Education Act.  This classified supplements as food and limited the role for the FDA.
  • In 2006, in reaction to deaths from ephedra, Congress passed the Dietary Supplement and Non-prescription Drug Consumer Protection Act.  This allows the FDA to collect adverse reports on supplements but did not give additional regulatory powers.

Conclusions from this review

  1. In populations with a high background of normal nutrient status, risk is accentuated if there can be harm at higher doses.  For selenium (in the NPC study), apparent benefits have been confined to individuals with the lowest baseline blood selenium levels.
  2. It is not reasonable to assume that consumption of a single nutrient would exert a chemopreventive effect equally in all tissues.  In addition, there are substantial variations in formulations and doses of supplements available.
  3. Efficacy and harm are typically tested over several years.  Given the natural history of cancer, it may take decades to assess supplement impact.
  4. Multiple consensus recommendations have indicated that supplements do not prevent cancer and do not prevent chronic disease (Table 1 in reference).  The most recent was from the American Cancer Society in 2012. “Present knowledge indicates that dietary supplements do not lower cancer risk.”
  5. Despite the evidence, the authors note that believers in supplements are unlikely to accept ‘mainstream’ science.  Some may think that unconventional treatments are ignored by science for monetary reasons. Some may think that these products are regulated and would not be offered if they were not beneficial.

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