Cleveland Clinic Journal of MedicineThe Constellation of Vitamin D, the Acute-phase Response, and Inflammation

Vitamin D’s Complex Role: Negative Acute-Phase Reactant in Inflammatory States

The article examines the widespread increase in vitamin D testing and supplementation, questioning its evidence-based rationale. It highlights the complexity of interpreting vitamin D levels, particularly 25-hydroxyvitamin D (25[OH]D), in the context of inflammation. The authors present evidence suggesting that 25(OH)D may act as a negative acute-phase reactant, complicating the assessment of true vitamin D deficiency and the justification for supplementation in many cases.

Key Points:

• Vitamin D testing and supplementation have increased dramatically:
  • Medicare patients’ vitamin D tests increased 547% from 2007 to 2016
  • Vitamin D supplement sales reached $936 million in 2017, a 9-fold increase over the previous decade
  • Projected supplement sales to reach $1.3 billion by 2025
• Vitamin D status evaluation is problematic:
  • Debate over which blood test (1,25-dihydroxyvitamin D or 25[OH]D) is most informative
  • Lack of consensus on optimal blood levels and cutoff points for deficiency/insufficiency
• Prevalence of vitamin D deficiency is considered high:
  • 41.6% of American adults had serum 25(OH)D levels below 20 ng/mL in 2011
  • Estimated 1 billion people worldwide have vitamin D deficiency or insufficiency
• Evidence supports 25(OH)D as a negative acute-phase reactant:
  • Inverse association between serum C-reactive protein and 25(OH)D levels
  • Low 25(OH)D levels associated with various inflammatory states
  • 25(OH)D levels decrease after inflammatory insults (e.g., surgery)
  • Persistent low levels in obesity despite aggressive supplementation
• Acute-phase response involves various physiological changes during inflammation:
  • C-reactive protein and fibrinogen are positive acute-phase proteins
  • Albumin and transferrin are negative acute-phase proteins
  • Some vitamins, including vitamin D, may exhibit negative acute-phase behavior
• Low-grade inflammation (metaflammation) is common:
  • Affects approximately 30% of the US population
  • Associated with numerous conditions and lifestyles
  • Triggered by sentinel cells monitoring deviations from homeostasis
• Vitamin D’s proposed roles beyond skeletal health:
  • Modulation of immune responses
  • Potential inhibition of inflammation
  • Possible reduction in cancer and cardiovascular events
• Clinical trials on vitamin D supplementation:
  • No significant reduction in all-cause mortality, cancer, or cardiovascular disease
  • No significant difference in major health-related outcomes for COVID-19
• Recommendations for vitamin D testing:
  • “Choosing Wisely” campaigns advise against population-based testing
  • Testing recommended only for select medical conditions
• Interpreting low vitamin D levels:
  • Consider the presence of systemic inflammation (eg, elevated C-reactive protein)
  • Low 25(OH)D may reflect inflammation rather than true deficiency

HCN Medical Memo
Physicians should exercise caution when interpreting low vitamin D levels and prescribing supplements. Consider the patient’s overall inflammatory status and focus on vitamin D testing in specific high-risk populations rather than as a routine screening tool.

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