How Important Is It to Correct Vitamin D Deficiency in a Critically-Ill Patient?

According to a recent study (NEJM 2019; 381: 2529-40), correction of vitamin D deficiency in critically-ill has NO significant effects on mortality and other non-fatal outcomes.

Link  to abstract: Early High-Dose Vitamin D3 for Critically Ill, Vitamin D–Deficient Patients

The article notes that observational data have indicated that Vitamin D deficiency is common in critically ill patients and has been associated with longer lengths of stay, prolonged ventilation and death.  However, “vitamin D level is considered a marker of coexisting conditions and frailty, and residual confounding may drive theses associations.”

Methods: a randomized, double-blind, placebo-controlled, phase 3 trial of early vitamin D3 supplementation in critically ill, vitamin D–deficient patients who were at high risk for death. Randomization occurred within 12 hours after the decision to admit the patient to an intensive care unit. Eligible patients received a single enteral dose of 540,000 IU of vitamin D3 or matched placebo.

Results:

  • A total of 1360 patients were found to be vitamin D–deficient during point-of-care screening and underwent randomization. Of these patients, 1078 had baseline vitamin D deficiency (25-hydroxyvitamin D level, <20 ng per milliliter [50 nmol per liter]) confirmed by subsequent testing and were included in the primary analysis population.
  • The mean day 3 level of 25-hydroxyvitamin D was 46.9±23.2 ng per milliliter (117±58 nmol per liter) in the vitamin D group and 11.4±5.6 ng per milliliter (28±14 nmol per liter) in the placebo group
  • The 90-day mortality was 23.5% in the vitamin D group (125 of 531 patients) and 20.6% in the placebo group (109 of 528 patients) (difference, 2.9 percentage points; 95% CI, −2.1 to 7.9; P=0.26). There were no clinically important differences between the groups with respect to secondary clinical, physiological, or safety end points.

My take: Correction of low serum vitamin D levels did not improve outcomes.  This likely indicates that low vitamin D levels are often an epiphenomenon of critical illness and not a contributing causal etiology.

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Why I Don’t Check Vitamin D Levels During IBD Flare-ups

A recent study (C Striscuiglio et al. JPGN 2018; 67: 501-6) helps explain the role of inflammation on vitamin D levels in pediatric patients (n=51) with inflammatory bowel disease (IBD).

Key findings:

  • The free/total 25-OH D ratio was higher in patients with newly-diagnosed IBD compared to healthy controls (P< .001)
  • A significant direct correlation was found between free/total 25-O D ratio and the activity index of disease (P= .01)
  • While there was frequent deficiency in total vitamin D levels,  the free 25-OH D which is the active form of vitamin D was normal or elevated in patients with newly-diagnosed IBD; this, in turn, was due to a decrease in vitamin-D binding protein which is related to inflammation. The authors hypothesized that at the cellular level in the intestine, there may be peripheral resistance due to inflammation and even supratherapeutic levels of free vitamin D could be needed to produce the active form (1,25-OH D).

My take: This study shows that 25-OH D levels (total) have almost no value at the onset of IBD.  Even normal or elevated free levels of 25-OH D which were found in this study does not preclude the potential need to supplement with vitamin D according to the study authors. In addition, as noted in previous posts, Vitamin D levels can normalize without supplementation when the patient’s IBD responds to therapy.

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Dangerous animal –seen on our hike to the tea house, Banff

Single High-Dose Oral Vitamin D Therapy (Stoss) for Children with Inflammatory Bowel Disease

A retrospective study (D Shepherd et al. JPGN 2015; 61: 411-14) shows that a single high-dose oral vitamin D3 therapy can be effective for 6 months.  This study involved treatment of 76 children between 2006-2010.

Stoss vitamin D dosing used in this study:

  • < 3 yrs 200,000 IU
  • 3-12 yrs 400,000 IU
  • >12 800,000 IU

Followup levels of Vitamin D (25-OH) and calcium were checked at 1 week, 4 weeks, 3 months and 6 months..

Key finding:

  • 25-OHD >50 nmol/L (=20 ng/mL) was seen in 96.6% at 3 months and 76.4% at 6 months.  63% had a level >75 nmol/L (=30 ng/mL) at 1 month.

Bottomline: Authors noted: “Stoss therapy safely and effectively achieved and maintained a level of 25OHD > 50 nmol/L during 6 months in these children with IBD.”

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Atlanta Botanical Gardens

Atlanta Botanical Gardens

Vitamin D in Preterm Infants

Vitamin D has garnered a great deal of attention due to concerns that deficiency worsens the outcomes in so many different conditions, including respiratory tract infections, inflammatory bowel disease, diabetes mellitus (type 1), multiple sclerosis, colorectal cancer, schizophrenia, depression, cardiovascular disease, hepatocellular carcinoma and other conditions.  However, evidence of causation is typically inconclusive.

For preterm infants, a study (Onwuneme C, et al. J Pediatr 2015; 166: 1175-80) notes an association between 25-hydroxy vitamin D (25OHD) levels drawn at 24 hours of life and acute respiratory morbidity.

In this study, levels were also drawn at the time of discharge in the 94 preterm infants.  In addition, maternal 25OHD) levels were checked 24 hours after delivery. These preterm infants were either <32 weeks gestation or <1.5 kg.  The study population was predominantly Caucasian.

Key findings:

  • 92% had 25OHD ≤20 ng/mL (=”<20 group”)
  • 64% had 25OHD ≤12 ng/mL (=”<12 group”)
  • Levels of 25OHD ≤12 ng/mL were associated with increased oxygen requirement (P=.008) and greater need for assisted ventilation (P=.013).  The odds of requiring assisted ventilation were approximately 3-fold higher.
  • The authors state that the baseline characteristics for the <12 group were similar to the <20 group.
  • There was statistical difference in the rate of NEC (Bell stage ≥1) based on the 25OHD levels (P=.048)

The authors note in their discussion that they favor supplementation with 400 IU/day which is in agreement with the American Academy of Pediatrics.  Previous ESPGHAN recommendations were 800-1000 IU/day for infants.

The authors note that 25OHD did not affect sepsis outcome.  In addition, antibiotics during labor was virtually identical between the two groups.  However, no data on CRP values were provided.

Bottomline: This study shows an association between 25OHD values and several important neonatal outcomes.  Whether 25OHD is a marker (eg. epiphenomenon) for these outcomes or whether low 25OHD contributes to these outcomes remains unclear.

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Another Reason for Inflammatory Bowel Disease Patients to Take Vitamin D

According to a recent study (Clin Gastroenterol Hepatol 2014; 12: 821-27), “in a large mulit-institutional IBD cohort, a low plasma level of 25(OH)D was associated with an increased risk of cancer, especially colorectal cancer.”  The study reviewed data from 2809 patients who vitamin D levels check (total cohort 11,028 persons with IBD); nearly a third had vitamin [25(OH)D] levels less than 20 ng/mL.  The median followup was 11 years.  During this period, 7% developed cancer (excluding nonmelanoma skin cancer).  Vitamin D deficiency was associated with an adjusted odds ratio of 1.82 of increased cancer risk.

Like so many other studies, this study is another reason for vitamin D manufacturers to feel pretty good.  The associated editorial provides some helpful context (pgs 828-30). The evidence regarding vitamin D dates back to at least 1980 when there was an observed higher incidence of colorectal cancer (CRC) mortality in regions with low solar radiation levels.  Similar findings were noted with breast cancer.

There is biologic plausibility to the importance of vitamin D with regard to cancer as it is involved in “cell signaling, cell proliferation, cell apoptosis, cell adhesion, angiogenesis and it can up-regulate tumor suppressor genes.” A number of reviews have shown an inverse relationship to vitamin D levels and CRC risk.

The editorial points out a number of potential flaws.  “For instance, those who had vitamin D measured may have been among the more ill patients…they may have been the most malnourished.”  “Whether patients had concurrent …primary sclerosing cholangitis was also omitted.”

Take-home message (from editorial): “Although the authors have identified an association, for several reasons it may be spurious…the jury is still out as to what impact maintaining normal vitamin D levels may have on reducing inflammation and modulating cancer risk in chronic inflammatory diseases. However, it is healthful to have adequate vitamin D.” In Manitoba, the authors recommend that all of their patients receive vitamin D supplementation.  In areas with more sun, checking levels may be worthwhile.

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Common to be “D-ficient”

Many of the children that a pediatric gastroenterologist sees are at risk for Vitamin D deficiency, including children with inflammatory bowel disease, cystic fibrosis, celiac disease, and liver diseases.  In addition, vitamin D deficiency is widespread: in U.S. 50% of children aged 1-5 years and 70% 6-11 years are vitamin D deficient or insufficient. A thorough review on this “D-lightful” vitamin was in a recent JPEN (JPEN J Parenter Enteral Nutr 2012; 9S-19S).

History: In 1822 Sniadecki recognized children in urban but not rural Poland developed rickets. He postulated the effects of the sun as the reason for rickets; his idea was dismissed.  In 1920s, the concept of irradiating milk to prevent rickets emerged. In 1950s, outbreak of hypercalcemia in infants in Great Britain was thought to be related to vitamin D fortification and curtailed this practice in Europe.  However, these cases were likely due to Williams syndrome.

Sources of vitamin D: oily fish (salmon), cod liver oil, some mushrooms, egg yolk, & sunlight. Exposure of an adult in a bathing suit to one minimal erythemal dose (MED) is equivalent to ingesting 20,000 IUs of Vitamin D. (The minimal dose that induces any visible reddening at that point is defined as one MED.)

Effect of sunscreen: A sun protection factor (SPF) of 30 absorbs approximately 98% of solar ultaviolet radiation & thus lowers vitamin D production by 98%.

Ethnicity: Melanin is an effective SPF.  A person of african-american descent, on average, has an SPF of 15, which reduces vitamin D production by 90%.

Age: Aging decreases 7-dehydrocholesterol in human skin.  Due to this, the elderly produce much less vitamin D.  For example, a 70 year old has a 75% reduction compared to a 20 year old.

Forms of vitamin D:  25-hydroxyvitamin D (25OH-D) is the major circulating form of vitamin D & physicians measure 25OH-D. 25OH-D is metabolized in kidney to 1,25-dihydroxyvitamin D (1,25OH-D), also called calcitriol.  This is the most biologically-active and is responsible for increasing intestinal calcium absorption and mobilizing calcium from bone.  However, 1,25OH-D provides no information vitamin D deficiency; it can be elevated or normal in deficiency states.

  • Cholecalciferol (vitamin D-3) is formed in the skin from 5-dihydrotachysterol.
  • Ergocalciferol (Vitamin D-2) is the form in Drisdol (8000 IU/mL) & Ergocalciferol Capsules (1.25 mg =50,000 USP Units)

Vitamin D deficiency:  The exact numbers are debated.  The institute of medicine (IOM) has considered individuals deficient if 25OH-D is <20 ng/mL.  The Endocrine Society and the author suggest vitamin D deficiency as <20 ng/mL & insufficiency as <30 ng/mL.  The author recommends ideal levels between 40-60 ng/mL.

Consequences of deficiency:

Osteoporosis, Osteopenia, Rickets (see references below): Bone weakening occurs due to loss of phosphorus from the kidneys.  Vitamin D deficiency lowers accrual of calcium in skeleton and leads to osteoporosis, osteopenia, and rickets. Imaging for rickets: the best single radiographic view for infants and children younger than 3 years is an anterior view of the knee that reveals the metaphyseal end and epiphysis of the femur and tibia. This site is best because growth is most rapid in this location, thus the changes are accentuated.

Nonskeletal consequences: vitamin D deficiency is associated with increased risk for preeclampsia, URIs, asthma, diabetes (type 1), multiple sclerosis, hypertension, and schizophrenia.

Treatment:

  • Infants who are breastfed should be receiving supplemental vitamin D, 400 IU/day.
  • Adults/children (>1 year) RDA 600 IU/day –mostly from diet per IOM. Yet author states, “it is unrealistic to believe that diet alone can ….provide this requirement.”
  • In vitamin D deficient patients: (initial treatment) 2000 IU/day or 50,000 IU/week for 6 weeks.
Toxicity from vitamin D (from NEJM 2010; 364: 248-254.): “Toxicity from vitamin D supplementation is rare and consists principally of acute hypercalcemia, which usually results from doses that exceed 10,000 IU per day; associated serum levels of 25-hydroxyvitamin D are well above 150 ng per milliliter (375 nmol per liter). The tolerable upper level of daily vitamin D intake recently set by the Institute of Medicine (IOM) is 4000 IU.”

Additional references:

  • -Pediatrics 2008; 122: 398. Should give 400 IU/day to breastfed babies. Consequences of Vit D deficiency: increased risk for DM, multiple sclerosis, cancer (breast, prostate,colon), rickets, and schizophrenia. Article lists vit D content of foods (high in cod liver oil, shrimp, fortified milk, many fish). Severe deficiency when < 5ng/mL, deficient if < 15 ng/mL; probably should be >32 ng/mL. Causes of vit D deficiency: decreased synthesis (due to lack of sun -skin pigmentation, sunscreen/clothing, geography, clouds), decreased intake, decreased maternal stores & breastfeeding, malabsorption (eg celiac, CF, EHBA, cholestasis), increased degradation; treatment of rickets: double-dose of vitamin d (~1000 IU/day for babies & 5000 for older kids) x 3-4 months along with calcium (30-75/mg/kg/day). Follow Ca/phos/alk phos monthly. Alternatively, give ~100,000 units over 1-5 days.
  • -JPEN J Parenter Enteral Nutr. 2011;35:308-316-Results: The study included 504 IBD patients (403 Crohn’s disease [CD] and 101 ulcerative colitis [UC]) who had a mean disease duration of 15.5 years in CD patients and 10.9 years in UC patients; 49.8% were vitamin D deficient, with 10.9% having severe deficiency. Vitamin D deficiency was associated with lower HRQOL (regression coefficient –2.21, 95% confidence interval [CI], –4.10 to –0.33) in CD but not UC (regression coefficient 0.41, 95% CI, –2.91 to 3.73). Vitamin D deficiency was also associated with increased disease activity in CD (regression coefficient 1.07, 95% CI, 0.43 to 1.71). Conclusions: Vitamin D deficiency is common in IBD and is independently associated with lower HRQOL and greater disease activity in CD. There is a need for prospective studies to assess this correlation and examine the impact of vitamin D supplementation on disease course.
  • -JPGN 2011;53: 361. similar prevalence of low Vitamin D as general population –58% with less than 32.
  • -JPGN 2011; 53: 11. Guidelines for bone disease with inflammatory bowel disease.
  • -Pediatrics 2010; 125: 633. Increasing Vit D deficiency noted in minority children. n=290. 22% w levels <20, 74% <30.
  • -Hepatology 2011; 53: 1118. Good vitamin D levels are another favorable predictive factor in antiviral response to Hep C along with IL28B.
  • -NEJM 2010; 364: 248-254. Vitamin D insufficiency. Levels between 20-30 may be OK -not enough evidence to determine conclusively whether this level is detrimental
  • -J Pediatr 2010; 156: 948. High rate among african americans with asthma, 86%. n=63.
  • -Pediatrics 2009; 124:e362. n=6275. 9% of pediatric patients vit D deficient & 61% were insufficient.
  • -Pediatrics 2009; 124:e371. n=3577. low 25OH-D levels inversely assoc with SBP/metabolic syndrome.
  • -NEJM 2009; 360: 398. case report of rickets
  • -J Pediatr 2003; 143: 422 & 434
  • -Pediatrics 2003; 111: 908. 200 IU Vit D recommended for all breastfed infants.
  • -J Pediatr 2000;137: 153 & 143.. Nutritional rickets–primarily in blacks; rec vitamin D 400 IU per day.