Does Sun Exposure Lower the Risk of Crohn Disease?

An intriguing recent study suggests that individuals who spend more time outside are less likely to develop Crohn disease (CD) (Inflamm Bowel Dis 2014; 20: 75-81).

In this prospective cohort study from France, 123 cases of inflammatory bowel disease (45 CD, 71 ulcerative colitis, and 7 indeterminant colitis)  developed among the 91,870 women in the study.  The study period had a mean followup of 13.1 years and followed women between 40 and 65 years. The authors estimated residential sun exposure by utilizing a database (derived from satellite collection) containing the mean daily ultraviolet radiation dose for each French county.

Key findings:

  • Higher levels of sun exposure were associated with a decreased risk of Crohn disease with a Hazard Ratio (HR) of 0.49.
  • Sun exposure did not affect the likelihood of developing UC (HR 1.21).
  • In women with information about dietary vitamin D intake, higher sun exposure had a HR of 0.29 for developing CD.  That being said, the authors note a low dietary vitamin D intake in their population.

Despite the large cohort, this study has a number of limitations. The absolute number of IBD patients can lead to a Type 1 error (false-positive conclusion).  In addition, the age of the study population and the lack of data regarding individual sun exposure limit the conclusions as well.  Besides these factors, there may be confounders such as changes in diet and soil exposure which are not accounted for.

At the same time, there have been other studies which have shown a latitude effect.  As with this study, those living in sunny areas had a lower incidence of CD.

Bottomline: This study suggests that additional sun exposure is associated with a lower risk of developing Crohn disease.  Whether this lower risk is directly through better vitamin D levels or simply an epiphenomenon is unclear.

Other recent unrelated studies:

Gut 2013; 62: 1122-30.  A randomized phase 1 study of etrolizumab (rhuMAb β-7) in moderate to severe ulcerative colitis.  Etrolizumab is an adhesion cell molecular blocker.

Inflamm Bowel Dis 2014; 20: 21-35.  Meta-analysis of 23 randomized controlled trials of probiotics for UC, Pouchitis, and CD.  Probiotics, in particular VSL#3, increased UC remission rates and helped maintain remission in patients with pouchitis.

Inflamm Bowel Dis 2014; 20: 213-27. Review article of cutaneous manifestations of inflammatory bowel disease.  Good pictures of multiple problems including metastatic Crohn disease, erythema nodosum, pyoderma gangrenosum, Sweet’s syndrome, aseptic abscess syndrome, and epidermolysis bullosa acquisita.

Inflamm Bowel Dis 2013; 19: 1753-63.  Review on hair loss associated with inflammatory bowel disease. Remember telogen effluvium?

Related posts:

For those who read from the top to the very bottom, here’s a tangential question: Do you know what a “sun dog” is?   Sun dog – Wikipedia, the free encyclopedia

Will Vitamin D Prevent Osteoporosis –Probably Not

A recent excerpt from the NY Times regarding a study published online in The Lancet. 

In a large review of studies, researchers have found almost no evidence that taking vitamin D supplements has any effect in preventing osteoporosis in middle-aged adults.

The analysis…included 23 randomized trials that measured the effect of vitamin D on bone density at four sites — spine, neck, hip and forearm — and included more than 4,000 generally healthy participants whose average age was 59.

The studies used dosages that varied from 500 units a day to 800 or more, given on varying schedules. In some studies, the subjects were given calcium as well.

Neither the pooled data nor any single study showed a significant increase in bone density across all four sites….The authors write that the widely believed idea that vitamin D promotes bone mineralization is probably incorrect.

“We’re not talking about people who are really vitamin D deficient,” said the lead author, Dr. Ian R. Reid, a professor of medicine at the University of Auckland in New Zealand. “But for healthy people focused on osteoporosis prevention, vitamin D does not make a positive contribution.”

Related posts:


I had a few free minutes so I decided to take a look at a bunch of upcoming lectures from the 2013 NASPGHAN upcoming meeting.  With electronic media, it is easy to take a quick glance.  Here’s the master link to all of the following talks:

Annual Meeting page.

Some of the power point lectures that I’ve seen so far:

  • Is my PPI dangerous for me? Eric Hassall MBChB, University of British Columbia One point in his slides that I had not seen much about was a hypothesis that PPI use may predispose to the development of eosinophilic esophagitis by allowing food proteins to be more intact ( attributed to Merwat, Spechler. Am J Gastro ’09).  He explains that “acid reflux” is a clever marketing term and has a slide with Madmen actors.  If there is “acid,” one must need acid suppression.
  • My child doesn’t go to school Lynne Walker MD, Vanderbilt University.  Lynne shows an interesting fax from a parent that asks if the problem is physical, how will she help? And, if it is psychological, how can this be remedied?  She outlines a lot of pain theory and indicates that parents need to become health coaches, avoid catastrophizing (?spelling), and encourages mental health evaluation.  Use the parents words ‘I’m going to refer xxx for relaxation and stress management.’
  • My child’s H. pylori will not go away – (the resistant bug) Benjamin Gold MD, Children’s Center for Digestive Healthcare. Ben manages to stuff so much information into his talk.  His talk is like one of those clown cars where more and more people keep coming out.  He has slides with worldwide resistance maps, slides with treatment regimens and algorithms, and the reasons for treatment failure. Perhaps I can convince him to give a live preview.
  • Administrative/executive functioning Richard Colletti MD, Fletcher Allen Healthcare. Offers personal and pragmatic advice for career advancement.  His slides indicate that he started his GI fellowship at age 40.  One of his quotes, “80% of success is showing up” (Woody Allen) is definitely true.  It’s pretty much akin to what I learned about success in medical school.  You need the three As: availability, affability, and ability.  My mentor said the first was what people needed most.
  • The changing face of intestinal transplantation
    Simon Horslen MD, Seattle Children’s Hospital.  Lecture notes that number of intestinal transplants have decreased dramatically, particularly in children. In 2012, only about 100 intestinal transplants were performed whereas it had peaked at nearly 200.  Much of the credit is due to intestinal rehabilitation work and adjustments in parenteral nutrition (eg. lipid minimization, line care).  Two most common reasons for intestinal transplantation at this time are gastroschisis and volvulus.
  •  Gluten sensitivity: Fact or fiction Alessio Fasano MD, MassGeneral Hospital for Children. This blog has covered a lot of the same material, but Alessio’s slides are pretty impressive.  Also, I was not aware that Lady Gaga consumes a gluten-free diet
  • Controversies in parenteral nutrition Christopher Duggan MD, Boston Children’s Hospital.  This lecture provides a timely update on nutrient deficiencies due to component shortages and discusses lipid minimization compared with fish oil-based lipid emulsions.
  • Vitamin D and immunity James Heubi MD, Cincinnati Children’s Hospital and Medical Center.  In the beginning of the slides, Jim provides a very user-friendly definition of an expert and a suitable picture.  He indicates that in 2011 there were 3746 vitamin D publications but inexplicably only chooses to review a tiny fraction.

At the time of this posting, I haven’t had a chance to look through these talks:



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.”

Related blog entries:

Quality improvement and better outcomes in Pediatric Inflammatory Bowel Disease

More information on outcomes and quality improvement (QI) efforts are available from Cincinnati Children’s Hospital (JPGN 2012; 55: 679-88).  The QI efforts at Cincinnati are part of a broader effort in QI in pediatric IBD that has been discussed on a previous post (see below).

Our group has rejoined Improve Care Now (ICN) and I look forward to gaining more first hand experience.  Some of the ICN target goals:

  • 80% remission rate among each center and sustained remission rate of 45%
  • 76% steroid-free remission
  • 90% checking TPMT if using thiopurine
  • 95% checking PPD/chest xray if using biologic therapy
  • 95% using accepted methotrexate dosing

As I look at these goals, I wonder whether the remission rate is feasible and about the variation in different centers. For example, among the groups with >75% enrollment of their patients, one center reports a 89% remission rate and another center 64% remission rate.  Given the limited number of therapeutic agents, how could there be such a difference?  Some explanations could include variation in the use of more potent biologic agents as well as capturing/assuring followup of more patients who are doing well.

Given this backdrop, I looked at this most recent publication to learn how their QI practices could translate into better care for my patients.

In this retrospective chart review study of 505 patients, who were followed from 2007-2010 at the IBD center, the remission rate increased from 59% to 76%.  The data were captured prospectively.  This corresponded to improved patient global assessment (>7) from 69% to 80%.  Repeated steroid use dropped from 17% to 10%.  Vitamin D (25-OH D) improved and this also correlated with quiescent disease.

Remission rates were defined by a pediatric Crohn clinical disease index, the sPCDAI, or PUCAI for Ulcerative colitis.

Key observations:

  • There was a trend towards increased use of anti-TNFα therapy (along with decreased use of 6-mercaptopurine) during the study period, but this did not reach statistical significance. No statistical difference was identified in the use of any major IBD medication class.
  • Despite target goals, the only drug class with a statistically significant change in dosing was 5-ASA (from 42 mg/kg to 50 mg/kg).
  • Fecal calprotectin monitoring increased.  The QI team recommended that IBD patients with ‘inactive’ disease have a fecal calprotectin measured every 6 months.  Those with elevated values had therapeutic drug monitoring implemented.  “Fecal calprotectin >400 μg/g is associated with a higher chance of relapse in a pediatric cohort.”
  • Starting in 2009, increased vitamin D monitoring was implemented (every 6 months).  In patients with a serum 25-OHD level < 30 ng/mL, treatment with 50,000 units weekly (for 6-8 weeks) was recommended (8000 units if weight <20 kg).  Once serum 25-OHD was >30 ng/mL, patients were maintained on monthly dosing.
  • Preclinic planning also increased and corresponded to improved remission rates which were 67% in 2009 and 76% in 2010.
  • The authors conclude: “Our results show that significant improvement in patient outcomes were achieved following QI efforts that did not rely on new medications or therapies, rather through initiating novel care processes and standardization of care.”

I think this conclusion is misleading.  First of all, as the authors point out, they did change their therapeutic approach.  They started vitamin D in more patients, used anti-TNFα therapy in more patients, and increased dosing of 5-ASA agents.  Other gains in remission rate could have been related to improved followup of patients who were doing well.

Despite my skepticism about the conclusion, I think the overall achievements are laudable.  Decreasing variation of care and assuring that all patients receive the best care possible with our diagnostic tests and current therapies is certainly worthwhile.  When patient care is studied carefully, this makes sure that “standard” practice like checking TPMT status before thiopurine use, checking PPDs before anti-TNFα therapy, and using optimal drug dosing occur in virtually all patients.

Developing a checklist for each patient can help assure that best practices occur.  For those with electronic medical records, this may mean putting in more “hard stops.”  A hard stop means the physician cannot sign out of a chart without paying attention to a specific detail.  For example, if a physician orders methotrexate, a “hard stop” could come up if the dosing was not in the typical target range.

Useful link:

Link for disease classification (quiescent, mild, moderate, severe):

Related blog entries:

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.


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.

Related post:

common to be “d-ficient” | gutsandgrowth

Fat soluble vitamin deficiency -sometimes the rule rather than the exception

While it is well-known that cholestasis predisposes individuals to develop fat-soluble vitamin (FSV) deficiencies, the exact frequency is not clear.

A recent prospective multi center study of infants with biliary atresia (BA) indicates that FSV deficiency is quite frequent –thanks to Kipp Ellsworth for forwarding this article (DOI: 10.1542/peds.2011-1423;  “Infants with BA are at risk for malabsorption of dietary lipid and fat-soluble vitamins (FSVs) due to insufficient intraluminal bile acid concentrations.”

To determine the frequency of FSV deficiencies, this study examined 92 infants with BA who were enrolled in a randomized double-blinded, placebo-controlled trial of corticosteroid therapy after hepatoportoenterostomy (HPE).  This study was conducted by the Biliary Atresia Research Consortium (BARC) between 2005-2008.

All infants were treated with a standardized dose of a liquid multiple FSV/d-α tocopheryl polyethylene glycol-1000 succinate (TPGS; a micelle forming water-soluble form of vitamin E).  Infants received initially ADEKs; later in the study, ∼32 months after start, participants were changed to AquADEKs due to a manufacturer’s change.  In addition, all infants received supplemental vitamin K, initially 2.5 mg three times per week.  As noted in supplement to article, the two study multivitamins have particularly low amounts of vitamin D (800 units) and vitamin E (80-100 units) compared to frequent dosing in clinical practice for severe cholestasis (see below).

TABLE 1 from study: Target FSV Levels and Replacement Regimens

  • Vitamin A (retinol)

Target:  19–77 mg/dL retinol:RBP molar ratio >0.8

Supplement strategy:  Increments of 5000 IU (up to 25–50 000 IU/d) orally or monthly intramuscular administration of 50 000 IU

  • D (25-hydroxy vitamin D)

Target: 15–45 ng/mL

Supplement: Increments of 1200 to 8000 IU orally daily of cholecalciferol or ergocalciferol; alternatively calcitriol at 0.05 to 0.20 mg/kg per day

  • E (α tocopherol) 

Target: 3.8–20.3 mg/mL & vitamin E:total serum lipids ratio >0.6 mg/g

Supplement: Increments of 25 IU/kg of TPGS orally daily (to 100 IU/kg per d)

  • K (phytonadione)

Target: INR ≤1.2

Supplementation Strategy:

  • <1.2-1.5  INR:  2.5 mg vitamin K orally daily
  • 1.5-1.8  INR: 1.8  2.0–5.0 mg vitamin K intramuscular and 2.5 mg vitamin K orally daily
  • >1.8 INR:  2.0–5.0 mg vitamin K intramuscular and 5.0 mg vitamin K orally daily

Results: FSV was common in infants with total bilirubin (TB) ≥2 mg/dL. At three months post HPE, only 3 infants with this degree of cholestasis were sufficient for all four vitamins.; at 6 months post HPE, all 24 infants with TB ≥2 mg/dL had at least one FSV deficiency: “100%, 79%, 50%, and 46%, respectively, for vitamins A, D, E, and K .”   Also, the incidence of vitamin D deficiency would be higher if the authors had chosen a higher target.

Take-home points:

  • FSV deficiencies are common particularly in patients with TB > 2mg/dL; thus careful monitoring is worthwhile
  • There is no current multivitamin that is adequate.  A better strategy is to individualize the dosing for each vitamin and consider injection (except for vitamin E) if needed

Initial individualized dosing of FSV supplementation in clinical practice for severe cholestasis (prior to deficiencies):

Vitamin A: start with ~5000 units daily.

Vitamin D: See previous posts for more information on dosing.  Two options include: Drisdol® (8000 IU/ml) 0.125ml/kg/day (=1000 IU/kg/day) and Bio-D-Mulsion Forte® -each drop = 2,000 IU (also inexpensive)

Vitamin E (Liqui-E®/Nutr-E sol®26.6 IU/ml) 1ml/kg/day
with tocopherol polyethylene glycol succinate.  Alternative is AquaE®(Yasoo

Vitamin K (phytonadione) 2.5mg QOD

Related posts:

Diagnosing biliary atresia earlier

Common to be “D-ficient”

Outcomes of Biliary Atresia

MicroRNAs and biliary atresia

Bleeding due to vitamin K deficiency

A cautionary vitamin D tale?

A recent case report indicates that pharmacologic doses of vitamin D can cause hypercalcemia and hypervitaminosis D (Pediatrics 2012; 129: e1060-63).  The three cases all document good reasons for instituting therapy: craniotabes, hypocalcemic seizures, and tibial bowing.  The total dose that the patients received over 7-12 weeks ranged from 112,000 IU to 168,000 IU.  The ages of the patients ranged from 2 weeks to 33 months.   The peak abnormal calcium for all three patients was 11 mg/dL and the peak 25-hydroxy vitamin D was 102 ng/dL.  There were no clinical symptoms in these three patients due to increased calcium.  A fourth oh-by-the-way patient was described as well.  This patient was receiving vitamin D for an “inappropriate indication” (failure to thrive) and had received 3.6 million IU without monitoring.  This led to the development of a multitude of symptoms associated with a calcium level of 17.4 mg/dL.

My take-home points:

  • If giving generous doses of vitamin D, obtain a followup calcium several weeks into therapy. However, pharmacologic doses of vitamin D for valid indications pose a very low risk.
  • Excessive doses of vitamin D can be detrimental. (This last statement may be akin to the warning “hot coffee might cause a burn.”)

Related blog entries:

Common to be “D-ficient”

Vitamin D, IBD, and Causality

Vitamin D, IBD, and Causality

The importance of vitamin D has been noted in this blog previously (Common to be “D-ficient” ).  Now a study implicates vitamin D as a risk factor for developing inflammatory bowel disease, especially for Crohn’s disease (Gastroenterology 2012: 142: 482-89).  It is known that vitamin D influences innate immunity.  As such, it may play a role in the susceptibility to Crohn’s disease (CD) and Ulcerative colitis (UC).

This prospective study included 72,719 women (age 40-73) enrolled in the Nurses’ Health Study.  Research subjects completed an assessment of diet and lifestyle along with 25-hydroxy vitamin D [25(OH)D] levels.  The 25(OH)D levels were predicted; this prediction was based on a validated model which included vitamin D intake, sun exposure, race, and body mass index (J Natl Cancer Inst 2006; 98: 451-9).  This model was validated against directly measured 25(OH)D levels.

During nearly 1.5 million person-years of followup, 122 incident cases of CD and 123 cases of UC occurred.  The adjusted hazard ratio (HR) for the highest quartile of 25(OH)D was 0.54 for CD and 0.65 for UC compared to the lowest quartile.  Compared with a level less than 20, the highest quartile HR was 0.38 for CD and 0.57 for UC.

In addition, the authors identified a significant inverse association between dietary supplemental vitamin D and UC; an insignificant reduction in CD risk was noted with dietary intake.  Although it is difficult to determine causality, these data convincingly show that ‘healthy’ levels of vitamin D are associated with a lower risk of IBD.

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.


  • 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.