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• Credits
  - Section Writer: Dr. Om J Lakhani
  - Section Editor: Dr. Om J Lakhani

Also, see Non-Calciotropic actions of Vitamin D

• Topic 1: Vitamin D and Diabetes

• Q. Can vitamin D reverse Prediabetes ?

  • Yes
  • Benefit was found in nonobese subjects (RR 0.73 [95% CI 0.57–0.92]) but not in obese subjects (RR 0.95 [95% CI 0.84–1.08]) (__P__interaction = 0.048). [Ref: Zhang Y, Tan H, Tang J, Li J, Chong W, Hai Y, Feng Y, Lunsford LD, Xu P, Jia D, Fang F. Effects of vitamin D supplementation on prevention of type 2 diabetes in patients with prediabetes: a systematic review and meta-analysis. Diabetes Care. 2020 Jul 1;43(7):1650-8.]
  • The reversion of prediabetes to normoglycemia occurred in 116 of 548 (21.2%) participants in the vitamin D group and 75 of 532 (14.1%) in the control group. Thus, vitamin D supplementation increased the reversion rate of prediabetes to normoglycemia (RR 1.48 [95% CI 1.14–1.92]; __I__2 = 0%.)
  • In persons with prediabetes, vitamin D supplementation reduces the risk of T2DM and increases the reversion rate of prediabetes to normoglycemia.
  • The benefit of the prevention of T2DM could be limited to non-obese subjects.
  • 

• Q. But the D2D trial was negative! Shouldn't we go by this trial?

  • Actually, No
  • The subanalysis of the D2D trial looking at patients with vitamin D deficiency was POSITIVE
  • 
  • In a post hoc analysis of data from participants with a baseline 25-hydroxyvitamin D level of less than 12 ng per milliliter (30 nmol per liter) (103 participants), the hazard ratio in the vitamin D group was 0.38 (95% CI, 0.18 to 0.80).

• Q. Can Vitamin D help improve glycemic control in patients with established Type 2 Diabetes mellitus ?

  • Yes.
  • Meta-analysis by Wu et al ^[1]
  • Subgroup analyses suggested that vitamin D supplementation was associated with reduced HbA1c levels (SMD -0.39 [-0.67 to -0.10]) and FBG (SMD -0.27 [-0.46 to -0.07]) among patients with 25-hydroxyvitamin D (25(OH) D) deficiency at baseline.
  • Significantly reduced HbA1c levels were also observed in association with vitamin D supplementation in the subgroup, including type 2 diabetes patients with a body mass index (BMI) <30kg m-2 (SMD -0.30 [-0.54 to -0.07]).
  • Conclusion: Vitamin D supplementation could effectively improve glycemic control in vitamin D deficient or non-obese type 2 diabetes patients.
  • 

• Q. Can Vitamin D reduce the incidence of Type 1 Diabetes in children?

  • Yes
  • Meta-analysis of the results of observational studies suggests that the risk of type 1 diabetes is significantly reduced in those who were supplemented in childhood with vitamin D compared to those who were not supplemented (odds ratio 0.71, 95% CI 0.60 to 0.84). ^[2]
  • Conclusion: Vitamin D supplementation in early childhood may offer protection against the development of type 1 diabetes. The evidence for this is based on observational studies
  • NOTE: The meta-analysis DID NOT include an RCT
  • 

• Summary and Conclusion on Vitamin D and Diabetes

  • Q. Can Vitamin D reverse diabetes?
    • Can Vitamin D reverse diabetes - No.
    • There is no evidence of Vitamin D "reversing" or producing remission in patients with established Type 1 and Type 2 Diabetes
  • Q. Can Vitamin D reverse diabetes? No
  • Q. Can Vitamin D reverse Prediabetes ? Yes
  • Q. Can Vitamin D improve glycemic control in patients with established Type 2 diabetes? Yes
  • Q. Can vitamin D prevent type 1 diabetes in children? Yes (*No RCT)

• Topic 2: Vitamin D and Hair

• Q. Is Vitamin D deficiency more common in people who have alopecia areata?

  • Yes
  • Alopecia areata is an autoimmune disease
  • A meta-analysis by Lee et al. - The subjects with alopecia areata had lower serum 25-hydroxyvitamin D level, and vitamin D deficiency was highly prevalent compared to non-AA controls. ^[3]
  • Whether treatment with vitamin D has any benefit is debatable

• Q. What are the potential mechanism by which Vitamin D deficiency is associated with Alopecia areata?

  • Anagen stage hair follicles (HFs) exhibit “immune privilege (IP)” from the level of the bulge downwards to the bulb.
  • Both passive and active IP mechanisms protect HFs from physiologically undesired immune responses and limit immune surveillance
  • IP collapse is a key element in AA immunopathogenesis.
  • IFN-γ is what leads to the collapse of IP
  • Vitamin D may contribute to maintaining the IP of HF by decreasing the production of IFN-γ ^[4]
  • 

• Q. Does treatment of vitamin D deficiency have any benefit on alopecia areata?

  • This is not clear
  • Calcipotriol, a vitamin D analog, has been reported to be topically used in treating alopecia areata, with promising results
  • Topical Calcipotriol is more beneficial than oral vitamin D supplementation in AA (Ref: Abd-ElRaheem et al.)
  • " Studies using topical vitamin D in alopecia are inconsistent and limited by small sample size or lack of appropriate controls. Preliminary results suggest a potential therapeutic benefit for topical vitamin D, with minor side effects." ^[5]

• Q. What is the lesson to be learned from this pathogenesis?

  • Vitamin D may have a role in other autoimmune diseases

• Summary and Conclusion

• Q. Can vitamin d deficiency cause hair loss?

  • Patients having alopecia areata, a specific and important cause of hair loss, are more likely to have vitamin D deficiency.
  • However, association does not always mean causation
  • Correction of vitamin D deficiency may or may not have any impact on hair loss. There is little evidence to prove the same
  • Topical Calcipotriol, a vitamin D analog, may have some role in managing alopecia areata.
  • Most notably, Vitamin D deficiency indeed has a correlation with autoimmune diseases

• Topic 3: Vitamin D and Obesity

• Q. Do obese people have less vitamin D levels?

  • Yes, and this is well known
  • Meta-analysis by M Pereira-Santos et al. have suggested ^[6]
    • The prevalence of vitamin D deficiency was 35% higher in obese subjects compared to the eutrophic group (PR: 1.35; 95% CI: 1.21-1.50) and 24% higher than in the overweight group (PR: 1.24; 95% CI: 1.14-1.34).
    • These results indicate that the prevalence of vitamin D deficiency was more elevated in obese subjects.
    • The vitamin D deficiency was associated with obesity irrespective of age, latitude, cut-offs to define vitamin D deficiency, and the Human Development Index of the study location.

• Q. Why do obese people have lower vitamin D?

  • There are several reasons for this, but the most likely being that obese people have large fat stores leading to lower 25 hydroxyvitamin D levels
  • "High prevalence of vitamin D (VD) deficiency in obese subjects is a well-documented finding, most probably due to volumetric dilution into the greater volumes of fat, serum, liver, and muscle." ^[7]
  • 

• Q. Does VItamin D deficiency cause obesity?

  • Probably, not
  • No data to suggest it

• Q. Does Vitamin D deficiency CONTRIBUTE to obesity?

  • Yes
  • Vitamin D deficiency has a link with depression which in turn is linked with obesity
  • Vitamin D deficiency is linked with increased muscle strength

• Q. What is the link between Vitamin D deficiency and depression?

  • Google Question: How much vitamin D should I take for depression?
  • Spedding S et al. meta-analysis ^[8]
  • A meta-analysis of all studies without flaws demonstrated a statistically significant improvement in depression with Vitamin D supplements (+0.78 CI +0.24, +1.27).
  • Vitamin D supplementation (≥800 I.U. daily) was somewhat favorable in managing depression in studies that demonstrate a change in vitamin levels, and the effect size was comparable to that of anti-depressant medication.

• Q. Does VItamin D supplementation improve muscle strength?

  • Yes, it does
  • Beaudet et al. meta-analysis ^[9]
  • Results revealed a small but significant positive effect of vitamin D supplementation on global muscle strength with a standardized mean difference (SMD) of 0.17 (P = .02).
  • Results on muscle strength were significantly more important with people who presented a 25-hydroxyvitamin D level <30 nmol/L.
  • Supplementation seems also more effective on people aged 65 years or older compared to younger subjects (SMD 0.25; 95% CI 0.01 to 0.48 vs SMD 0.03; 95% CI -0.08 to 0.14)

• Summary and Conclusion

• Q. Can vitamin D deficiency cause weight gain? No

  • Q. Do obese people have lower vitamin D ? Yes
  • Q. Does Vitamin D supplementation help in depression? Yes
  • Q. Does vitamin D supplementation help muscle strength? Yes

• Topic 4: Other Topocs

• Q. Are people with Vitamin D deficiency more likely to develop COVID-19 infection?

  • Meta-analysis by Teshome et al
  • "The pooled analysis showed that individuals with Vitamin-D deficiency were 80% more likely to acquire COVID-19 infection as compared to those who have sufficient Vitamin D levels (OR = 1.80; 95%CI: 1.72, 1.88). Begg's test also revealed that there was no significant publication bias between the studies (P = 0.764)." ^[10]

• Q. Is there a link between VItamin D deficiency and increased risk of death due to COVID-19 infection?

  • Meta-analysis by Bassatne A et al ^[11]

  • "While the available evidence to date, from largely poor-quality observational studies, may be viewed as showing a trend for an association between low serum 25(OH)D levels and COVID-19 related health outcomes, this relationship was not found to be statistically significant.""

  • Recent trial published in the JCEM ^[12]

  • Case-control study done in 900 patients with calcifediol

  • "Out of 447 patients treated with calcifediol at admission, 20 (4.5%) required ICU, compared to 82 (21%) out of 391 non-treated (p-value<0.0001)"

  • In the Intention-to-Treat analysis, 21 (4.7%) out of 447 patients treated with calcifediol at admission died compared to 62 patients (15.9%) out of 391 non-treated (p=0.0001)

  • In patients hospitalized with COVID-19, calcifediol treatment significantly reduced ICU admission and mortality.

• Q. Does Vitamin D deficiency lead to increased cardiovascular disease ?

• Meta-analaysis by Barbarawi et al ^[13]

• 21 RCT were included- more than 80,000 patients

• Vitamin D supplementation compared with placebo was not associated with reduced major adverse cardiovascular events (RR, 1.00 [95% CI, 0.95-1.06]; P = .85)

• Nor the secondary end points of myocardial infarction (RR, 1.00 [95% CI, 0.93-1.08]; P = .92), stroke (RR, 1.06 [95% CI, 0.98-1.15]; P = .16), CVD mortality (RR, 0.98 [95% CI, 0.90-1.07]; P = .68), or all-cause mortality (RR, 0.97 [95% CI, 0.93-1.02]; P = .23

• Vitamin D supplementation was not associated with reduced major adverse cardiovascular events, individual CVD endpoints (myocardial infarction, stroke, CVD mortality), or all-cause mortality. The findings suggest that vitamin D supplementation does not confer cardiovascular protection and is not indicated for this purpose.

• Q. Does Vitamin D help in the prevention of cancer?

• “Vitamin D was not associated with significant reduction of cancer incidence (RR: 0.96; 95% CI: 0.86–1.07; P = 0.46; I2 = 31%)" ^[14]

• Colon cancer:

  • Meta-analysis of the WHO working group
  • Compared with 25(OH)D levels of 20 to <25 ng/mL (50 to <62.5 nmol/L), a 25(OH)D level of <12 ng/mL (30 nmol/L) was associated with a higher risk of colorectal cancer (RR 1.31, 95% CI 1.05-1.62), whereas 25(OH)D levels ≥30 ng/mL (75 nmol/L) were associated with a lower risk (RRs 0.81, 95% CI 0.67-0.99 and 0.73, 95% CI 0.59-0.91, for levels of 30 to <35 ng/mL [75 to <87.5 nmol/L] and 35 to <40 ng/mL [87.5 to <100 nmol/L], respectively).

• Breast cancer

  • A meta-analysis of prospective studies examining the relationship between serum 25(OH)D concentrations and breast cancer risk showed a significant inverse association in post- but not premenopausal women. The risk of postmenopausal breast cancer decreased with 25(OH)D levels between 27 and <35 ng/mL (67 to 87 nmol/L), with no further reduction for levels above 35 ng/mL.

• Prostate cancer- there is no evidence from a meta-analysis

• Q. Does Vitamin D reduce mortality in patients with cancer?

• Vitamin D was associated with significant reduction of cancer-related mortality compared with placebo (RR 0.87; 95% CI: 0.79–0.96; P = 0.05: I2 = 0%) ^[15]

• 

Video on the topic by Dr. Om J Lakhani