Vitamin D in Critical illness

OVERVIEW

Vitamin D is a fat soluble vitamin with dermal synthesis being the major natural source

• Main clinically significant role is in maintaining calcium homeostasis and bone metabolism
• There is an increasing appreciation for its pleiotropic effects, including immunomodulatory and other cellular functions

Vitamin D deficiency is common in the general population as well as the critically ill

• Severe deficiencies result in the clinical syndromes of rickets and osteomalacia
• Low levels of vitamin D have been associated with poorer outcomes in the critically ill however causality has not been proven

EFFECTS OF VITAMIN D

• Regulates calcium and bone metabolism
• Inhibiting cellular proliferation
• Inhibiting angiogenesis
• Stimulating insulin production
• Inhibiting renin production
• Modulating immune function

PHYSIOLOGY OF VITAMIN D

Vitamin D exists as three forms:

• Vitamin D1 (combo of ergocalciferol and lumisterol)
• Vitamin D2 (ergocalciferol)
• Vitamin D3 (cholecalciferol)

Major source is cutaneous synthesis through the effects of UV light on skin

• Cutaneous 7-dehydrocholesterol → exposed to UV light → converted to cholecalciferol in keratinocytes
• Two-step hydroxylation process occurs: liver (→ 25D aka calcidiol) then kidney (→ 1,25D aka calcitriol: active form)

Hydroxylation is under endocrine and paracrine regulation

• Calcitriol formation (renal) is simulated by PTH and hypophosphatemia → as an attempt to maintain Ca and PO4 balance
• Calcidiol formation (hepatic) is substrate-dependent (not hormonally regulated)

Most is bound to vitamin D-binding protein (88%) and albumin

• 0.03% is free only
• Serum 1,25D tightly regulated by PTH, Ca and FGF-23

MECHANISM OF PLEIOTROPIC ACTIONS

Regulation of plasma Ca and PO4 concentrations (from UTD)

• Main action of calcitriol is to enhance availability of Ca and PO4 for new bone formation and prevention of symptomatic hypoCa and hypoPO4, via
  • Increased bone resorption
  • Increased intestinal absorption
  • Increased renal tubular Ca++ reabsorption
  • Enhanced PTH-induced stimulation of bone resorption and distal reabsorption
  • Regulation of hormone secretion
  • Inhibits PTH synthesis / secretion
  • Stimulates insulin secretion
  • Stimulates FGF-23 production by osteoblasts and osteocytes (predominantly)
• Regulation of immune function
  • Adaptive:
    • Inhibits production of pro-inflammatory / increases production of anti-inflammatory cytokines produced by T-helper cells
    • Exerts inhibitory action overall → beneficial in autoimmune disease
  • Innate:
    • Activates toll-like receptors in leukocytes → induction of antimicrobial peptides that kill organisms (predominantly cathelicidin)
    • Cathelicidins = family of antimicrobial peptides with activity against gram-positive, gram-negative and some viruses / fungi
• Regulation of cellular proliferation and differentiation
  • Stimulates cell cycle inhibitors p21 and p27 and cell adhesion molecules → may reduce cancer risk

ASSESSMENT OF VITAMIN D LEVELS

• Serum vitamin D status is assessed using 25-D levels: inactive form but stable, longer half-life
• Cut-offs for optimal vitamin D levels vary. In practice:
  • > 50 nmol/L: sufficient
  • 25 – 50 nmol/L: insufficient
  • < 25 nmol/L: deficient

ROLE IN CRITICAL ILLNESS

Hypovitaminosis D

• Common in critical illness
• Associated with multiple diseases in ambulatory non-critically ill people
• No proven causative role in critical illness
• No trials demonstrating benefit of vitamin D supplementation in critically ill

Observational studies among critically ill

• Association between reduced 25D levels and adverse outcomes including LOS, infection, AKI and mortality

EVIDENCE

Leaf et al. Randomised controlled trial of calcitriol in severe sepsis. Am J Resp Crit Care Med, 2014; 190(5) 483 – 485

• Double-blinded RCT
  • n = 67, adults with septic shock
  • Single dose calcitriol (2mcg 1,25 D IV) Vs placebo
• • Results
  • Calcitriol resulted in vit D level 75.5 vs placebo 16.9 at 6-hrs post dose
  • No difference in plasma cytokines or hCAP-18 levels (immunological protein with inverse relation of level with susceptibility to sepsis)
  • Increased expression of h-CAP mRNA, IL-10 mRNA in calcitriol group at 24 hrs
  • No difference in renal injury markers
  • No difference in clinical outcomes (NB but wasn’t powered to detect this)
• Conclusions
  • Insufficient to warrant phase III studies
  • Perhaps additional phase II studies may be warranted – do higher / repeated doses of calcitriol affect immune function?

VITdAL-ICU study, JAMA 2014

• Single-centre DB RCT, 5 ICUs
• n = 475 critically ill adult white patients with vitamin D deficiency (≤ 20ng/mL)
• Intervention: Vitamin D3 enterally Vs placebo; Vitamin D3 dose: 540,000IU load then 90,000 IU monthly for 5 months
• Outcomes
  • Primary: hospital length of stay (LOS)
  • Secondary: ICU LOS, percentage of 25-OH D levels higher than 30ng/mL at day 7,
• Results
  • Hospital LOS: no significant difference (28.3 % 25-OH D Vs 35.3% placebo)
  • Hospital and 6-month mortality: no difference
  • D3 associated with better hand grip and physical performance at 6-months
  • A-priori subgroup analysis of severe deficiency (≤ 12ng/mL, n = 200) found
    • lower hospital mortality (28.6% [95% CI, 19.9%-38.6%]) for vitamin D3 compared with 47 deaths among 102 patients (46.1% [95% CI, 36.2%-56.2%])
    • no statistically significant difference in 6-month mortality (34.7% [95% CI, 25.4%-45.0%] for vitamin D3 vs 50.0% [95% CI, 39.9%-60.1%])
• Comments and criticisms
  • Strengths: well-matched at baseline, large study, selected patients with deficiency (rather than all-comers), supplemented vitamin D for a long period and long-term follow-up (6 months)
  • Vitamin D supplementation led to non-significant but large difference in primary outcome, and significant improvements in physical function
  • Possible mortality benefit in the group with severe deficiency is hypothesis-generating

AN APPROACH

• Hypovitaminosis D is common in the critically ill, yet has not been proven to be causative of poorer outcomes and may simply be association with increasing illness severity
• The ‘severe Vitamin D deficiency’ subgroup analysis finding of a lower in-hospital mortality with Vitamin D supplementation  – that was not statistically significant at 6 months – requires further investigation
• There is currently no role for routine supplementation vitamin D in critically ill patients

References and Links

Journal articles

• Amrein K, Venkatesh B. Vitamin D and the critically ill patient. Curr Opin Clin Nutr Metab Care. 2012 Mar;15(2):188-93. doi: 10.1097/MCO.0b013e32834f0027. Review. PubMed PMID: 22186356.
• Amrein K, Schnedl C, Holl A et al. Effect of high-dose vitamin D3 on hospital length of stay in critically ill patients with vitamin D deficiency: The VITdAL-ICU Randomised Clinical Trial. JAMA 2014 Sept 20 [Epub ahead of print]. PMID: 25268295
• Holick MF. Vitamin D deficiency. N Engl J Med. 2007 Jul 19;357(3):266-81. Review. PubMed PMID: 17634462.
• Leaf DE, Raed A, Donnino MW, Ginde AA, Waikar SS. Randomized controlled trial of calcitriol in severe sepsis. Am J Respir Crit Care Med. 2014 Sep 1;190(5):533-41. doi: 10.1164/rccm.201405-0988OC. PubMed PMID: 25029202.
• Nair P, Venkatesh B. Vitamin D in the ICU: anything new under the sun? Crit Care Resusc. 2012 Dec;14(4):268-73. Review. PubMed PMID: 23230875.