Vitamin D Deficiency

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What Is Vitamin D?

Vitamin D is the principle regulator of calcium homeostasis (balance) in the body.  This “vitamin” is really a prohormone, meaning it acts like a hormone but is not. Vitamin D does, however, contain cholesterol in its molecular structure like steroid hormones.

The physiological importance of vitamin D encompasses much more than the regulation of bone metabolism although this is a mighty function.

Q: How does vitamin D regulate bone metabolism?

A: In regulation of bone metabolism, vitamin D works in three ways: 1) enables active absorption of calcium from the small intestine, 2) enhances reabsortion of calcium by the kidneys that would otherwise be excreted in urine, and 3) plays an active role in skeletal development and bone mineralization. Mineralization gives strength to living bone tissue.

Vitamin D interacts with receptors within cells to effect transcriptional changes in many cell types including those in gut, bone, breast, prostate, brain, skeletal muscle, and the immune system.1

In regards to the essential role of vitamin D in muscle tissue, it has been recently shown that vitamin D regulates both muscle function and structure of primary myofibers.2

Vitamin D is converted in the body to a molecule that is biologically active. The active form is 1,25-dihydroxyvitamin D, usually referred to as vitamin D3. About 80% comes from sun exposure and the remaining from food.

Vitamin D3 is synthesized in the skin from 7-dehydrocholesterol via photochemical reactions requiring UV light (sunlight). That is, light that contains energy from the sun is incorporated into molecules of  7-dehydrocholesterol in the underlying dermis of skin to make this vitamin. This is why inadequate exposure to sunlight contributes to vitamin D deficiency.

Blood concentration of 25(OH)D is the best indicator of vitamin D status. It reflects vitamin D produced in the skin and that obtained from food and supplements and has a fairly long circulating half-life of 15 days.3

What Is Vitamin D Deficiency In Celiac Disease and/or Gluten Sensitivity?

• Relationship between vitamin D deficiency and celiac disease. Vitamin D deficiency is a classic symptom of celiac disease that results when the level within cells is too low to meet metabolic needs of the body for this nutrient. In testing blood levels, deficiency is 20 ng/dL  while insufficiency is 30 ng/dL.
• Relationship between vitamin D deficiency and signs. Vitamin D deficiency is characterized by impaired bone mineralization, proximal muscle weakness, impaired thinking skills, and alterations in the maintenance of calcium and phosphorus homeostasis, metabolic functions, and male reproduction.
• Relationship between vitamin D deficiency and inflammation. Vitamin D is a potent regulator of inflammation by inhibiting acute pro-inflammatory chemical production (cytokines) and helping to turning off chronic inflammatory responses.
• Relationship between vitamin D deficiency and anemia. A retrospective cross-sectional study of 530 adult patient records at diagnosis of celiac disease with vitamin D deficiency found that vitamin D deficiency was more common in those who presented with anemia (39%) than in those who did not (23%). One widely accepted mechanism is that iron is absorbed by the proximal duodenum, a region of primary involvement in celiac disease and site of fat soluble vitamin absorption which includes vitamin D. Therefore, it is not surprising that patients with celiac disease and anemia might also suffer from vitamin D deficiency. “Considering the overlap between anemia and vitamin D deficiency observed in this study, it could be useful to screen celiac disease patients with anemia for vitamin D deficiency.”4.
• Relationship between vitamin D deficiency and excessive sleepiness. A cross-sectional study involving 153 consecutive patients who admitted to the presence of chronic nonspecific musculoskeletal pain during a comprehensive sleep evaluation at a specialist sleep medicine clinic showed that vitamin D deficiency was prevalent in patients with sleep disorders and chronic nonspecific musculoskeletal pain.5 Also, study of a patient with heavy daytime napping and pervasive fatigue, who had neither sleep disordered breathing nor a sleep related movement disorder, revealed vitamin D deficiency.6
• Relationship between vitamin D deficiency and IBD. Vitamin D deficiency and insufficiency increase susceptibility to inflammatory bowel disease.7
• Relationship between vitamin D deficiency and type I diabetes mellitus. Vitamin D deficiency and insufficiency increase susceptibility to type 1 diabetes.7
• Relationship between vitamin D deficiency and type 2 diabetes mellitus. Vitamin D plays an important role in insulin sensitivity in the body, and deficiency of vitamin D hampers production of insulin hormone by beta cells in the pancreas. People with vitamin D deficiency are at risk for developing type 2 diabetes mellitus. Type 2 diabetes mellitus is characterized by lack of insulin sensitivity in body tissues and inadequate production of insulin hormone in the pancreas.8
• Relationship between vitamin D deficiency and immune-mediated disease. A public health study of patients admitted to a hospital for either vitamin D deficiency (13, 260 patients), osteomalacia (5,191) or rickets (1,228), found there were significantly elevated rates of Addison’s disease, ankylosing spondylitis, autoimmune hemolytic anemia, chronic active hepatitis, celiac disease, Crohn’s disease, diabetes mellitus, pemphigoid, pernicious anemia, primary biliary cirrhosis, rheumatoid arthritis, Sjogren’s syndrome, systemic lupus erythematosus, and thyrotoxicosis in these patients.9
• Relationship between vitamin D deficiency and metabolic syndrome. The frequency of vitamin D deficiency in women with metabolic syndrome was found very high, significantly higher than in women without metabolic syndrome.10
• Relationship between vitamin D deficiency and malignancy. Several observational studies have suggested that vitamin D insufficiency plays a role in the development of cancers of the colon, breast, and prostate, as well as lymphoma.11
• Relationship between vitamin D deficiency and bedwetting. A large study investigating whether there is a relationship between blood levels of 25-hydroxyvitamin D [25(OH)D] in five- to seven-year-old children  with nocturnal enuresis (NE) found that low 25(OH)D was associated with an increased risk of NE (bedwetting) in children aged five to seven years.12
• Relationship between vitamin D deficiency and muscle structure. An epigenetic study showed conclusively that deficient vitamin D status of the mother changes the way muscle cells develop in her offspring. The vitamin D deficiency directly altered genes that controlled muscle development which resulted in smaller muscles.13
• Relationship between vitamin D deficiency and cognitive function. A retrospective review shows that  adequate levels of vitamin D in the elderly are important to maintain cognitive function or thinking skills that include use of language, awareness, social skills, math ability, memory, reasoning, judgment, intellect, learning, and imagination.14
• Relationship between vitamin D and alopecia areata. In a case-control study, blood levels of 25-hydroxy vitamin D levels were significantly lower in 60 people with alopecia areata when compared with healthy subjects. The least values were significantly associated with alopecia totalis/universalis compared with patchy alopecia areata (P < 0.001) and ophiasis (P = 0.04). Severe alopecia areata showed significantly the lowest vitamin D levels compared with cases with mild (P = 0.002) and moderate disease.15

How Prevalent Is Vitamin D Deficiency In Celiac Disease and/or Gluten Sensitivity?

• Vitamin D deficiency is common in patients with untreated celiac disease.16
• Vitamin (25-hydroxy) D deficiency was found in 4.5% of 80 newly diagnosed patients with celiac disease in a prevalence study from the Netherlands.17
• A retrospective cross-sectional study of 530 adult patients with celiac disease who also had a 25-hydroxyvitamin D level on record at Columbia University Medical Center found 133 patients (25%) had vitamin D deficiency. Also, vitamin D deficiency was more common in those who presented with anemia (39%) than in those who did not (23%).18.
• In a study of children at diagnosis and at one year follow-up, forty-three percent (43%) had suboptimal vitamin D status (25(OH)-vitamin D <75 nmol/l) at diagnosis, resolving in nearly half after 1 year on the gluten free diet.19

What Are The Symptoms Of Vitamin D Deficiency?

Vitamin D deficiency  is marked by a range of symptoms which include:

• Alopecia Areata (hair loss).
• Bone pain.
• Difficulty with walking and especially climbing stairs.
• Eye Floaters.
• Falls due to muscle weakness of thighs.
• Fatigue.
• Headache.
• Increased fat stores around organs.
• Muscle pain.
• Muscle weakness, especially thighs and upper arms. Thigh weakness causes difficulty with rising out of a chair, for example, or getting up from a squatting position.
• Osteomalacia in adults, affecting the spine with vertical shortening of the vertebrae, the pelvis with flattening and narrowing of the pelvic outlet and the lower extremities with bowing of the long bones and muscular weakness.
• Sleepiness.
• Waddling gait caused by increased joint space in the hips.
• In children, rickets occur, impairing mineralization of growing weight-bearing bones with bone bending of the weak shaft with delayed walking in 1 to 4 year olds; abnormal enlargement of head and delayed tooth eruption; and hypotonia with muscle wasting.
• In older children walking is painful with development of bowlegs and knock-knees.
• In males, hypogonadism and decreased fertility and spermatogenesis occur.
• Chronic vitamin D deficiency results in decreased calcium absorption, osteoporosis, and secondary hyperparathyroiditis.20

How Does The Body Get Vitamin D?

• Vitamin D is absorbed from the upper small intestine along with lipids (fats) by micelle-dependent diffusion, meaning it does not need to be transported by a carrier protein.20
• Vitamin D is also synthesized from sunlight via absorption through the skin.

What Does Vitamin D Do In The Body?

1. Enhances the active transport of calcium across the gut, which involves stimulation of the production of calcium-binding protein (calbindin) in the mucosal brush border of villi lining the small intestine. This also involves the stimulation of intestinal phosphate transport, perhaps involving acid phosphatase, which is also enabled by vitamin D.
2. Increases zinc and other mineral absorption from the intestine.
3. Functions in conjunction with parathyroid hormone (PTH) and estrogen to regulate the mobilization and deposition of calcium and phosphorus in bones.
4. Increases tubular reabsorption in the kidney of both calcium and phosphate for the purpose of maintaining plasma calcium within a narrow range of concentration.
5. Essential for the functional maintenance of membranes.
6. Involved in the functions of several organs including skin, muscles, the pancreas, nerves, the parathyroid gland, and the immune system.
7. Needed for adequate blood levels of insulin.
8. Demonstrates both immune enhancing and immunosuppressive effects.
9. Demonstrates anti-carcinogenic activity, inducing apoptosis (killing) in many types of cancer cells.

How Does Vitamin D Deficiency Develop In Celiac Disease and/or Gluten Sensitivity?

• Vitamin D deficiency in celiac disease results from malabsorption due to gluten enteropathy and defective use in the body.

Does Vitamin D Deficiency Respond To Gluten-Free Diet?

Yes. Celic disease-related Vitamin D deficiency responds to a nutritious gluten free diet containing vitamin D. Supplementation produces rapid resolution of symptoms.20

A study of children at diagnosis of celiac disease showed that after 6 months of a gluten-free diet calcium, vitamin D3 and parathyroid hormone levels normalized, with the improvement of bone mineral density.21

6 Steps To Correct Vitamin D Deficiency:

• 1Meet, or Exceed the RDA (Recommended Dietary Allowances) for Vitamin D in milligrams (mg) per day:

• 2Diet – Include Food Sources Richest in Vitamin D IU per 100 grams (about a cup):

• 3 Diet – Avoid, Limit, or Eat Separately These Foods That Deplete or Interfere With Absorption:

• 4Monitor Medications That Deplete or Interfere With Absorption:

Certain prescription drugs can cause vitamin D deficiency. On the other side, vitamin D supplements have the potential to interact with several types of medications. Ask your doctor or pharmacist about possible interactions between supplements and medications you’re taking to make sure you time the doses correctly. Do not stop taking prescription medications without supervision.

• 
  5Manage Nutritional Supplements to Obtain Vitamin D:

• 6Other Supplements That Deplete or Interfere With Absorption:

Medical Research Findings On Vitamin D Deficiency In Celiac Disease and/or Gluten Sensitivity:

RESEARCH STUDY SUMMARIES

“Vitamin D3 seems more appropriate than D2 to sustain adequate levels of 25OHD: a pharmacokinetic approach. “ This study investigating the superiority of cholecalciferol (D3) over ergocalciferol (D2) in sustaining serum 25-hydroxy vitamin D (25OHD) levels showed initially, D2 and D3 were equally effective at raising serum vitamin D levels but over time, the vitamin D3 group sustained higher levels than both the D2 and placebo groups, which were similar.

Researchers performed a single-blind, placebo-controlled randomized trial spanning 11 weeks. Thirty-three healthy volunteers (aged 33.4±6 years) were divided into three groups of eleven subjects each: D2, D3 and placebo. Treatment started with a loading dose (100,000 IU) followed by 4800 IU/day (d) between d7 and d20 and follow-up until d77. Serum samples were obtained at baseline and at days 3, 7, 14, 21, 35, 49, 63 and 77.

RESULTS: Baseline 25OHD values in the D2 group were lower than those in the D3 and placebo groups (P<0.01). Placebo 25OHD levels never changed. As after the loading dose both D2 and D3 groups had reached similar 25OHD levels, we tested equivalence of the area under the concentration × time curve (AUC) between d7 and d77. The AUC was 28.6% higher for D3 compared with D2, and both were higher with respect to placebo. At d77, D2 25OHD levels were higher than those at baseline, but similar to placebo; both were lower than D3 (P<0.04). According to raw data, the elimination half-life of 25OHD was 84 and 111 days under D2 and D3 supplementation, respectively; after subtracting the placebo values, the corresponding figures were 33 and 82 days.

CONCLUSIONS: D2 and D3 were equally effective in elevating 25OHD levels after a loading dose. In the long term, D3 seems more appropriate for sustaining 25OHD, which could be relevant for classic and non-classic effects of vitamin D.22

“Increased risk for vitamin D deficiency in obese children with both celiac disease and type 1 diabetes.” This study investigating the vitamin D status and the risk for vitamin D deficiency in prepubertal children with both type 1 diabetes (T1D) and celiac disease (CD) compared to controls, T1D, and CD separately found a higher occurrence of vitamin D deficiency in children with T1D + CD (27.3%) compared to the controls (18.4%), CD (22.2%) alone, and T1D (13.6%) alone. It also found that the overweight/obese patients with T1D + CD had significantly lower 25(OH)D concentration compared to the overweight/obese controls, the CD only, and nearly so for T1D. In contrast, the normal-weight subjects showed no significant difference in their serum 25(OH)D concentration between the subgroups.

Characteristics of 62 prepubertal children of age 2-13 years with either CD + T1D (n = 22, 9.9 ± 3.1 y), CD only (n = 18, 8.9 ± 3.3 y), or T1D only (n = 22, 10.1 ± 2.8 y) were compared to 49 controls of the age of 8.0 ± 2.6 years. Vitamin D deficiency was defined as 25(OH)D < 50 nmol/L, overweight as BMI of greater than 85th but less than 95th percentile, and obesity as BMI (body mass index) greater than 95th percentile.

The 4 groups had no difference in 25(OH)D before stratification into normal-weight versus overweight/obese subtypes. Following stratification, 25(OH)D differed significantly between the subgroups. Post-hoc analysis showed a significantly lower 25(OH)D in the overweight/obese CD + T1D compared to the overweight/obese controls and the overweight/obese CD. Subjects with CD + T1D were 3 times more likely to be vitamin D deficient, compared to controls.

Conclusions. The coexistence of T1D and CD in overweight/obese prepubertal children may be associated with lower vitamin D concentration.23

“Relationships between 25-hydroxyvitamin D and nocturnal enuresis in five- to seven-year-old children.” This study investigating whether there is a relationship between serum 25-hydroxyvitamin D [25(OH)D] concentrations in five- to seven-year-old children  with nocturnal enuresis (NE) found that low 25(OH)D was associated with an increased risk of NE (bedwetting) in children aged five to seven years.

Two hundred forty-seven five- to seven-year-old children were recruited from Taizhou, Zhejiang Province, China. Serum 25(OH)D concentrations were measured, and the structured questionnaire was administered to the parents of all children. Low 25(OH)D was defined as serum 25(OH)D concentrations below 20 ng/ml.

The prevalence of NE was 7.3% in the group of children with 25(OH)D concentrations that exceeded 20 ng/ml; this prevalence was much lower than the 17.5% observed in the group of children with 25(OH)D concentrations below 20 ng/ml. After adjusting for potential confounders, serum 25(OH)D (≥20 ng/ml) was significantly associated with NE and represented a protective factor against NE. A nonlinear relationship between 25(OH)D and NE was observed. The prevalence of NE decreased with increasing 25(OH)D concentrations above 19 ng/ml. Additionally, children exhibiting higher frequencies of bedwetting had lower 25(OH)D concentrations [5-7 times/week: 18.3 ng/ml plus or minus 4.8; 2-4 times/week: 20.9 ng/ml plus or minus 4.1; 0-1 times/week: 23.6 ng/ml plus or minus 6.4].12

“Maternal vitamin D deficiency causes smaller muscle fibers and altered transcript levels of genes involved in protein degradation, myogenesis, and cytoskeleton organization in the newborn rat.“ This study investigating the structure and genetics of gastrocnemius muscle (calf muscle) in newborns in response to maternal vitamin D deficiency found that maternal vitamin D deficiency has a major impact on structural development and gene expression profile of skeletal muscle in newborns.

In this study, 14 female rats were fed either a vitamin D₃ deficient (0 IU/kg) or a vitamin D₃ adequate diet (1000 IU/kg) 8 weeks prior to conception, during pregnancy, and lactation. Analysis of cholecalciferol, 25(OH)D₃ and 1,25-dihydroxyvitamin D₃ show that dams fed the vitamin D deficient diet and their newborns suffered from a relevant vitamin D deficiency. Muscle cells of vitamin D deficient newborns were smaller than those of vitamin D adequate newborns. Muscle transcriptome of the newborns revealed 426 probe sets as differentially expressed (259 upregulated, 167 downregulated) in response to vitamin D deficiency. The effected genes are involved in protein catabolism, cell differentiation and proliferation, muscle cell development, and cytoskeleton organization.13

“Vitamin and mineral deficiencies are highly prevalent in newly diagnosed celiac disease patients.” This study aiming to assess the nutritional and vitamin/mineral status of current “early diagnosed” untreated adult celiac disease (CD)-patients in the Netherlands found that vitamin/mineral deficiencies are still common in newly “early diagnosed” CD-patients, even though the prevalence of obesity at initial diagnosis is rising. Vitamin (25-hydroxy) D deficiency was found in 4.5% of these study patients.

Eighty newly diagnosed adult CD-patients were included and a comparable sample of 24 healthy Dutch subjects was added to compare vitamin concentrations. Nutritional status and serum concentrations of folic acid, vitamin A, vitamin B6, vitamin B12, and (25-hydroxy) vitamin D, zinc, hemoglobin (Hb) and ferritin were determined before prescribing gluten free diet. Almost all CD-patients (87%) had at least one value below the lower limit of reference.

Vitamin/mineral deficiencies were counter-intuitively not associated with a (higher) grade of histological intestinal damage or (impaired) nutritional status. Extensive nutritional assessments seem warranted to guide nutritional advices and follow-up in CD treatment.24

“Vitamin D status and concomitant autoimmunity in celiac disease.” This retrospective cross-sectional study of 530 adult patients with celiac disease and a 25-hydroxyvitamin D level on record at Columbia University Medical Center found 133 patients (25%) had vitamin D deficiency. The prevalence of autoimmune disease was similar among those with normal vitamin D levels (11%), insufficiency (9%), and deficiency (12%). The risk of psoriasis was higher in patients with vitamin D deficiency (7% vs. 3%). However, vitamin D deficiency was more common in those who presented with anemia (39%) than in those who did not (23%).

While the pathophysiology of anemia is likely multi-factorial, one widely accepted mechanism is that iron is absorbed by the proximal duodenum, a region of primary involvement in celiac disease and site of fat soluble vitamin absorption. Therefore, it is not surprising that patients with celiac disease and anemia might also suffer from vitamin D deficiency. Considering the overlap between anemia and vitamin D deficiency observed in this study, it could be useful to screen celiac disease patients with anemia for vitamin D deficiency.25

“Nonspecific pain is a marker for hypovitaminosis D in patients undergoing evaluation for sleep disorders: a pilot study.“ This cross-sectional study investigated the hypothesis that serum vitamin D levels are abnormally low in sleep clinic patients admitting to chronic nonspecific musculoskeletal pain and assessed the associated risk factors. A secondary purpose was to identify a clinical biomarker for vitamin D deficiency. This study showed that vitamin D deficiency was prevalent in patients with sleep disorders and chronic nonspecific musculoskeletal pain.

Researchers enrolled 153 consecutive patients who admitted to the presence of chronic nonspecific musculoskeletal pain during a comprehensive sleep evaluation at a specialist sleep medicine clinic within an academic center. Venous blood sampling was performed for determination of serum 25-hydroxyvitamin D.

The mean serum 25-hydroxyvitamin D level was 19.8 ± 11.1, with 54% of the study population having vitamin D deficiency. This mean 25-hydroxyvitamin D level was lower than that observed historically in healthy controls, and was either similar or lower than in all but one representative historical cohort formed on the basis of chronic nonspecific musculoskeletal pain.5

“Vitamin D, cognition, and dementia: a systematic review and meta-analysis.” This meta-analysis examining the association between cognitive function and dementia with vitamin D concentration in adults showed results suggesting that lower vitamin D concentrations are associated with poorer cognitive function.

To understand better the association among vitamin D concentration, cognitive function, and dementia, the evidence was examined explicitly by conducting a comprehensive systematic literature review and meta-analysis.

Five databases were searched for English-language studies up to August 2010, and included all study designs with a comparative group. Cognitive function or impairment was defined by tests of global or domain-specific cognitive performance and dementia was diagnosed according to recognized criteria. A vitamin D measurement was required. Two authors independently extracted data and assessed study quality using predefined criteria. The Q statistic and I² methods were used to test for heterogeneity. We conducted meta-analyses using random effects models for the weighted mean difference (WMD) and Hedge’s g.

Thirty-seven studies were included; 8 contained data allowing mean Mini-Mental State Examination (MMSE) scores to be compared between participants with vitamin D blood level less than 50 nmol/L to those with values 50 nmol/L or greater. There was significant heterogeneity among the studies that compared the WMD for MMSE but an overall positive effect for the higher vitamin D group. Further studies are required to determine the significance and potential public health benefit of this association because vitamin D insufficiency may be a modifiable risk factor for dementia.26

“Vitamin D and K status influences bone mineral density and bone accrual in children and adolescents with celiac disease.” This study investigating the interrelationships between vitamin K /vitamin D status and lifestyle variables on bone mineral density (BMD) in children and adolescents with celiac disease at diagnosis and after 1 year on the gluten-free diet found that children and adolescents with celiac disease are at risk for suboptimal bone health at time of diagnosis and after 1 year on gluten free diet (GFD) likely due in part to suboptimal vitamin D /vitamin K status. “Therapeutic strategies aimed at optimizing these vitamin intakes may contribute to improved BMD in children with celiac disease.”

Children and adolescents aged 3-17 years with biopsy proven CD at diagnosis and after 1 year on the GFD were studied. BMD was measured using dual-energy X-ray absorptiometry. Relevant variables included: anthropometrics, vitamin D/K status, diet, physical activity and sunlight exposure.

Whole-body and lumbar-spine BMD-z scores were low (< or = -1) at diagnosis (10-20%) and after 1 year (30-32%) in the children, independent of symptoms. Whole-body BMD-z scores (-0.55±0.7 versus 0.72±1.5) and serum levels of 25(OH) vitamin D (90.3±24.8 versus 70.5±19.8 nmol/l) were significantly lower in older children (>10 years) when compared with younger children (< or =10 years) (P<0.001). Forty-three percent had suboptimal vitamin D status (25(OH)-vitamin D <75 nmol/l) at diagnosis, resolving in nearly half after 1 year on the GFD. Twenty-five percent had suboptimal vitamin K status at diagnosis; all resolved after 1 year.19

“Prevalence and predictors of abnormal bone mineral metabolism in recently diagnosed adult celiac patients.” This study investigating the prevalence of low bone mineral density (BMD) in recently diagnosed adult celiac patients and aiming to identify the factors associated with this found that low BMD is common in newly diagnosed adult celiac patients with approximately one fifth of them having osteoporosis and low vitamin D level.

BMD was measured in 54 newly diagnosed adult celiac patients between February 2008 and April 2009 and its correlation with clinical and biochemical parameters was analyzed. Fifty-four (24 male) newly diagnosed celiac patients ages 18-50 were included. Thirty-nine (72.2 %) presented with intestinal symptoms and the rest with extraintestinal symptoms. Low vitamin D levels were seen in 11 (20.3 %) patients and elevated iPTH (secondary hyperparathyroidism) in 12 (22.2 %) patients. Twenty-one (39 %) patients had normal BMD, 23 (43 %) had osteopenia (T-score -1 to -2.5), and 10 (18 %) patients had osteoporosis (T-score <-2.5). A statistically significant association was seen between BMD and age of onset, duration of illness, serum tTGA levels, serum vitamin D levels, and cellular changes seen on biopsy. BMD should be measured in all newly diagnosed celiac patients and calcium and vitamin D supplementation included in the treatment regimen.27

“Calcium and vitamin D supplementation is associated with decreased abdominal visceral adipose tissue in overweight and obese adults.” This study  investigating the effect of  calcium and vitamin D on obesity showed findings that suggest calcium and/or vitamin D supplementation contributes to a beneficial reduction of visceral abdominal fat (VAT).

Two parallel double-blind, placebo-controlled trials were conducted in which 171 people were given either orange juice fortified with 350mg of calcium and 100 IU of vitamin D (CaD) or non-fortified orange calcium and vitamin D juice. After four months, the average weight loss in both groups was the same – about 5.5 pounds. Scans revealed that in the group supplemented with calcium and vitamin D, the loss of visceral (abdominal) fat was significantly greater than the loss of subcutaneous fat, which is fat under the skin.

After 16 wk, the average weight loss (about 2.45 kg) did not differ significantly between groups. In the regular orange juice trial, the reduction of VAT was significantly greater in the CaD group (-12.7 ± 25.0 cm(2)) than in the control group (-1.3 ± 13.6 cm(2)). In the lite orange juice trial, the reduction of VAT was significantly greater in the CaD group (-13.1 ± 18.4 cm(2)) than in the control group (-6.4 ± 17.5 cm(2)) after control for baseline VAT. The effect of calcium and vitamin D on VAT remained highly significant when the results of the 2 trials were combined.28

“Calcium plus vitamin D3 supplementation facilitated fat loss in overweight and obese college students with very-low calcium consumption: a randomized controlled trial.” This study investigating  the effect of calcium plus vitamin D3 (calcium+D) supplementation on anthropometric and metabolic profiles during energy restriction in healthy, overweight and obese adults with very-low calcium consumption found that calcium plus vitamin D3 supplementation for 12 weeks augmented body fat and visceral fat loss in very-low calcium consumers during energy restriction.

Fifty-three subjects were randomly assigned in an open-label, randomized controlled trial to receive either an energy-restricted diet (about 500 kcal/d) supplemented with 600 mg elemental calcium and 125 IU vitamin D3 or energy restriction alone for 12 weeks. Repeated measurements of variance were performed to evaluate the differences between groups for changes in body weight, BMI, body composition, waist circumference, and blood pressures, as well as in plasma TG, TC, HDL, LDL, glucose and insulin concentrations.

Eighty-one percent of participants completed the trial (85% from the calcium + D group; 78% from the control group). A significantly greater decrease in fat mass loss was observed in the calcium + D group (-2.8±1.3 vs.-1.8±1.3 kg; P=0.02) than in the control group, although there was no significant difference in body weight change between groups. The calcium + D group also exhibited greater decrease in visceral fat mass and visceral fat area. No significant difference was detected for changes in metabolic variables.29

“Bone metabolism in celiac disease.” This study investigating the prevalence of both calcium metabolism alterations and bone defects in 54 untreated children with celiac disease (mean age, 7 years), found that calcium metabolism defects are common in untreated children with celiac disease, and they returned to normal after gluten-free diet.

Serum concentration of calcium, magnesium, vitamin D3, alkaline phosphatase, and parathyroid hormone (PTH) of patients with celiac disease was compared with those of 60 healthy children. Children with celiac disease with 2 laboratory alterations further underwent DEXA examination (bone density test), which was evaluated after 6 months of a gluten-free diet. The calcium and the vitamin D3 levels were lower in children with celiac disease than in control subjects, and the PTH level was higher in children with celiac disease than in control subjects. Hyperparathyroidism was found in 29 children with celiac disease. Twenty patients tested positive for 2 laboratory alterations, and 10 of them were osteopenic. After 6 months of a gluten-free diet calcium, vitamin D3 and PTH levels normalized, with the improvement of bone mineral density.30

“­­­­­­­­­­­­­­­­­Is Vitamin D Important for Preserving Cognition? A Positive Correlation of Serum.” This retrospective study investigating the association of vitamin D status with cognitive function shows that  adequate levels of vitamin D in the elderly are important to maintain cognitive function or thinking skills that include use of language, awareness, social skills, math ability, memory, reasoning, judgment, intellect, learning, and imagination.

A retrospective review of older adults presenting to a university-affiliated clinic providing consultative assessments for memory problems was performed. Charts of all patients presenting for initial visits were reviewed to identify those who had serum vitamin D, vitamin B12, and mini-mental state examination score (MMSE) all obtained on their first visit. Correlation analyses between MMSE and vitamin D and vitamin B12 levels were performed. Serum vitamin D concentration and MMSE showed a positive correlation; no correlation was observed between serum B12 concentration and MMSE.14

“Osteomalacia due to vitamin D depletion: a neglected consequence of intestinal malabsorption.” This study investigating the belief that vitamin D depletion is rare in the United States because of the routine fortification of milk and other dairy products with vitamin D shows that osteomalacia due to vitamin D depletion appears not to be suspected or diagnosed promptly in susceptible patients. Researchers present a series of patients with histologically verified osteomalacia due to vitamin D depletion to emphasize the need for more careful and systematic surveillance of patients at risk of this metabolic bone disease.

Between 1989 and 1994, 17 patients with osteomalacia due to vitamin D depletion were seen in the Bone and Mineral Division of Henry Ford Health System, Detroit. All patients had a transiliac bone biopsy. Biochemical indexes of vitamin D nutritional status, parathyroid function, markers of bone turnover, and bone mineral density were assessed at the time of bone biopsy. The duration of symptoms, the lag between the cause of vitamin D depletion and the development of symptoms, and the x-ray findings were recorded.

Osteomalacia was suspected by the referring physician in only 4 of the 17 patients, although a gastrointestinal disorder that can lead to vitamin D depletion was present in every patient. Thirteen of the patients had sustained at least one osteoporotic fracture (wrist, spine, or hip), and most had low appendicular and axial bone mineral density. All patients had one or more biochemical abnormalities consistent with vitamin D depletion. In 4 patients, a progressive rise in the serum alkaline phosphatase level was recorded but was not investigated until the patient presented with bone pain, muscle weakness, or fracture.31

“Improvement in glucose tolerance and beta-cell function in a patient with vitamin D deficiency during treatment with vitamin D.” This study investigating glucose metabolism in a patient with vitamin D deficiency during treatment with small doses of vitamin D found that Beta-cell function improved from 101% at diagnosis to 126%, 147%, 173% and 198% at 0.5, 1, 3 and 5 months, respectively.

A continuous infusion of glucose test was performed to assess glucose tolerance and insulin sensitivity and beta-cell function were derived by mathematical modelling. Fasting glucose was 5.6 mmol/l and achieved glucose after the infusion was 10.4 mmol/l confirming diabetes. The test was repeated 0.5, 1, 3 and 5 months after starting treatment.

Serum calcium increased glucose intolerance from 1.76 to 2.0, 2.08, 1.96 and 2.0 mmol/l, respectively; vitamin D reached supraphysiological levels initially and returned to normal levels, and parathyroid hormone levels were normalized. Her weight did not change during treatment. Glucose tolerance improved during treatment and achieved glucose was 9.4, 8.6, 9.2 and 9.0 mmol/l at 0.5, 1, 3 and 5 months, respectively; insulin sensitivity did not change. Improvement in beta-cell function and consequently in glucose tolerance is likely to have been due to correction of hypocalcemia, vitamin D deficiency and secondary hyperparathyroidism.32

CASE REPORT SUMMARIES

“Bone pain and extremely low bone mineral density due to severe vitamin D deficiency in celiac disease.” This case study describes finding a non-detectible vitamin D blood level in a 29-year-old wheelchair-bound woman who had lived in the Netherlands all her life and was born of Moroccan parents. Her medical history revealed iron deficiency, growth retardation, and celiac disease, for which she was put on a gluten-free diet but did not follow.

She had progressive bone pain for 2 years, difficulty with walking, and about 15 kg weight loss. She had a short stature, scoliosis (curvature), and pronounced kyphosis of the spine with thoracic and lumbar percussion pain (pain on tapping). Pelvis and shoulders also were painful on touching. There was muscle atrophy and symmetrical loss of proximal muscle strength. She was short of breath during normal daily activities and poor condition of her teeth. She had a regular menstrual cycle, and her menarche was at 17 years of age. She had neither abdominal complaints nor diarrhea. On physical examination, she was pale. Her body height was 148 cm (previously 156 cm) and her weight, 38 kg.

Laboratory results showed hypocalcemia, an immeasurable serum 25-hydroxyvitamin D level, and elevated parathyroid hormone and alkaline phosphatase levels. Spinal rx-rays showed unsharp, low contrast vertebrae. Bone mineral density (bone scan) measurement at the lumbar spine and hip showed a T-score of -6.0 and -6.5, respectively. A bone scintigraphy showed multiple hotspots in ribs, sternum, mandible, and long bones. A bone biopsy showed severe osteomalacia but normal bone volume. A duodenal biopsy revealed villous atrophy (Marsh 3C) and positive antibodies against endomysium, transglutaminase, and gliadin, compatible with active celiac disease She was treated with calcium intravenously and later orally. Furthermore, she was treated with high oral doses of vitamin D and a gluten-free diet. After a few weeks of treatment, her bone pain decreased, and her muscle strength improved.33

“Resolution of hypersomnia following identification and treatment of vitamin D deficiency.” This case report describes diagnosis of vitamin D deficiency in a  28-year-old woman who was evaluated for 4 months of excessive daytime sleepiness (EDS), after an overnight polysomnogram (PSG) revealed neither sleep disordered breathing nor a sleep related movement disorder. A full sleep evaluation revealed the presence of heavy daytime napping and pervasive fatigue.

Epworth Sleepiness Scale (ESS) Score was 10/24. No features characteristic for depression or narcolepsy were present. Chronic pain in the low back and thighs, as well as, chronic daily headaches were identified as potential sleep-disrupting forces. Risk factors for hypovitaminosis D included limited natural sun exposure, dark skin tone, and obesity. A 25-hydroxyvitamin D level was low, at 5.9 ng/mL.

Vitamin D supplementation was initiated at a dose of 50,000 IU once weekly, and EDS improved within 2 weeks. One week later, a PSG with next-day multiple sleep latency testing (MSLT) failed to show significant pathology. At follow-up, she reported resolution of thigh pain and headaches, with a significant improvement in her low back pain syndrome. EDS had resolved, and her ESS score was 1/24. Follow-up 25-hydroxyvitamin D level was normal at 39 ng/mL.

Mechanisms for her clinical improvement could include enhanced sleep quality due to resolution of hypovitaminosis D-associated noninflammatory myopathy, or a possible immunomodulatory effect of vitamin D decreasing central nervous system (CNS) homeostatic sleep pressure via its effects on tumor necrosis factor-alpha (TNF-α) and/or prostaglandin D2. More research is needed to determine if patients presenting with EDS should be more broadly screened for vitamin D deficiency.6

“Severe primary hyperparathyroidism masked by asymptomatic celiac disease.” This case report describes the presence of asymptomatic celiac disease as the underlying cause of  severe primary hyperparathyroidism in a 24-year-old woman who had a normal calcium blood level on presentation but vitamin D level was deficient (25-hydroxyvitamin D, less than 13 nmol/L). Normal range for this lab result was 22 to 116.

The patient presented with a 5-year history of generalized weakness, which had progressed until use of a wheelchair became necessary. She also had sustained low-trauma fragility fractures of the right tibia and left femur. She had no symptoms suggestive of celiac disease. Physical examination revealed severe proximal myopathy (arms and legs).

Laboratory data (and reference ranges) were as follows: serum calcium, 2.34 mmol/L (2.1 to 2.6); phosphorus, 0.91 mmol/L (0.90 to 1.50); alkaline phosphatase, 421 U/L (40 to 135); albumin, 37 g/L (35 to 45); parathyroid hormone, 874 ng/L (15 to 65); urine calcium, 3.76 mmol/d (2.5 to 8); and 25-hydroxyvitamin D, <13 nmol/L (22 to 116). She was treated with increasing doses of calcitriol, ergocalciferol, and calcium carbonate, but the serum calcium concentration did not increase substantially (reaching a maximum of 2.70 mmol/L on suprapharmacologic doses of these agents). Malabsorption was considered as an explanation for this apparent resistance to these medications. The result of antibody screening for celiac disease was highly positive, and a distal duodenal biopsy confirmed the diagnosis of celiac disease. A technetium Tc 99m sestamibi scan revealed uptake in the neck that was consistent with a single parathyroid adenoma, which was surgically removed. Treatment with a gluten-free diet, calcium carbonate, and ergocalciferol (vitamin D) yielded remarkable clinical, biochemical, and radiologic improvement.34

“Carpopedal spasm in an elderly man: an unusual presentation of celiac disease.” This case report describes diagnosis of celiac disease in a 68-year-old single Caucasian man admitted to the hospital with a 24-hour history of carpopedal spasm of both hands. Apart from generalized weakness, he reported no other symptoms. Physical examination revealed carpopedal spasm, clubbing of fingers and cachexia (body mass index 14 kg/m2). This patient was found to have several unusual features of celiac disease, including a low vitamin D level, severe hypocalcemia, and elevated parathyroid hormone levels in the presence of minimal gastrointestinal symptoms and negative tTG-antibodies

Blood tests showed severe hypocalcemia, with a total serum calcium of 1.06 mmol/L (normal range [NR] 2.05-2.55 mmol/L). He also had low serum potassium (2.8 mmol/L; NR 3.5-5.5 mmol/L) and magnesium (0.36 mmol/L; NR 0.65-1.05 mmol/L). Other significant results included hemoglobin 10.6 g/dL (NR 13-18 g/dL), mean corpuscular volume 98.1 fl (NR 82-98 fl), vitamin B12 157 ng/L (NR > 165 ng/L), folate 2.8 g/L (NR 3.1-17.5 μg/L), ferritin 252 μg/L (NR 30-250 μg/L), prothrombin time 20 s (NR 11-14 s), thyroid stimulating hormone 0.87 mu/L (NR 0.35-4.5 mu/L), phosphate 0.57 mmol/L (NR 0.8-1.45 mmol/L), albumin 32 g/L (NR 34-48 g/L) and alkaline phosphatase 313 IU/L (NR 47-141 IU/L). Subsequent results revealed vitamin D deficiency with a low serum 25-OH vitamin D of < 7 μg/L (NR 7-40 μg/L), a low 24-hour urinary calcium excretion of 0.9 mmol (NR 2.5-7.5 mmol) and a raised serum parathyroid hormone of 22.7 pmol/L (NR 1.6-6.9 pmol/L). Serology for tissue transglutaminase (tTG) antibodies was negative, and a serum IgA level of 4.95 g/L (NR 0.8-4.0 g/L) excluded selective IgA deficiency. Electrocardiograph at admission showed prolonged QT interval.

In view of cachexia, clubbing and negative tTG-antibodies, he was further investigated for an occult malignancy. Barium meal and follow through showed dilated proximal bowel loops and absence of normal feathery pattern of the jejunum, features suggestive of a malabsorptive state. Upper gastroscopic examination was normal; however, the duodenal biopsy showed partial and subtotal villous atrophy with increased intra-epithelial lymphocyte infiltration, consistent with the diagnosis of celiac disease.35

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