Learning objectives
- •
Factors modulating vitamin D metabolism.
- •
The diagnosis and management of hypovitaminosis D.
The case study
Reason for seeking medical help
- •
PDH, a 56-year-old Caucasian woman, is referred because about a year ago she was found to have hypovitaminosis D: serum 25-hydroxy-vitamin D: 16 ng/mL and osteopenia: T-score −1.1 at the upper 4 lumbar vertebrae. She received 2 courses of 3-month ergocalciferol supplements (50,000 IU once a week), 3 months of cholecalciferol 2000 units daily, and another 3 months of cholecalciferol 5000 units with little change in her serum vitamin D level: 15, 17, 17, and 16 ng/mL at 3, 6, 9, and 12 months, respectively. She was adherent to the prescribed medication. About 3 weeks ago she tried sublingual vitamin D tablets but could not tolerate them: they caused severe oral irritation.
Past medical and surgical history
- •
No relevant medical history.
- •
Natural menopause about 2 years ago, no HRT.
- •
Several allergies.
Personal habits
- •
Physically active lifestyle: night nurse on ICU.
- •
Avoids outdoor activities because of allergies.
- •
Avoids milk and dairy products, thinks she may be lactose intolerant.
- •
No cigarette smoking.
- •
No excessive sodium, caffeine, or alcohol intake.
Medications
- •
Calcium carbonate 1200 mg daily.
- •
Multivitamin tablet daily.
- •
Cholecalciferol, 2000 units daily with breakfast.
Family history
- •
Negative for osteoporosis, malabsorption, and lactose intolerance.
Clinical examination
- •
Weight 98 pounds, height 62″. She always had a low body weight.
- •
No significant clinical findings.
Laboratory result(s)
- •
Comprehensive metabolic profile: no abnormality except from marginally elevated alkaline phosphatase: 130 UL.
- •
Thyroid stimulation hormone (TSH), sedimentation rate: within normal limits.
- •
Serum 25-hydroxy-vitamin D/16 ng/mL, parathyroid hormone (PTH) 112 pg/mL, and calcium 8.9 mg/dL.
Multiple choice questions
- 1.
In PDH’s case, the following tests are indicated:
- A.
Tissue transglutaminase.
- B.
Serum 1,25-hydroxy-vitamin D.
- C.
24-h urinary calcium and sodium excretion.
- D.
A and B.
- E.
A and C.
Correct answer: A
Comment:
PDH’s serum 25-hydroxy-vitamin D level has essentially remained unchanged for the past year even though she has been on several courses of different vitamin D supplements. Given her low body weight, she may have malabsorption which may be the reason for her nonresponse to orally administered vitamin D and her low body weight. Assaying the serum tissue transglutaminase level is the next step. If positive, a duodenal biopsy may be indicated. Patients with gluten sensitivity respond well to gluten-free diets.
In PDH’s case, at this stage, it is not necessary to assay the 24-h urine sodium and calcium excretion. The pressing issue is to identify the reason for her not responding to orally administered vitamin D. Besides, her vitamin D deficiency and associated secondary hyperparathyroidism will increase the tubular calcium resorption and affect the urine calcium excretion.
- A.
- 2.
Hypovitaminosis D may present with:
- A.
Proximal muscle weakness.
- B.
Repeated falls.
- C.
Stress fractures.
- D.
A and B.
- E.
A, B, and C.
Correct answer: E
Comment:
Muscle weakness, especially proximal muscle weakness, is a cardinal clinical feature of hypovitaminosis D. In late stages the myopathy is such that patients have a waddling gait. Several studies also documented decreased reaction time, impaired balance, and an increased risk of falls especially in older people with low serum vitamin D levels. Conversely, vitamin D supplementation was associated with improvements in muscle strength, walking distance, and a decrease in general discomfort.
The positive effects of vitamin D supplementation on falls and fracture risk have been reported by several investigators and a meta-analysis of 11 randomized clinical trials concluded that hip fractures and nonvertebral fractures are reduced by 30% and 14%, respectively, when vitamin D is administered in mean doses of 800 IU/day (range 792–2000). Another meta-analysis concluded that the more pronounced benefits were observed at mean doses of vitamin D between 700 and 1000 IU daily to maintain serum vitamin D levels between 30 and 44 ng/mL. Stress fractures occur more frequently in subjects with serum vitamin D levels below 30 ng/mL than in those with higher levels.
- A.
- 3.
The diagnosis of hypovitaminosis D is confirmed by finding:
- A.
Low serum 25-OHD.
- B.
Low serum 1,25-OHD.
- C.
Elevated serum iPTH level.
- D.
A and B.
- E.
A, B, and C.
Correct answer: A.
Comment:
Low serum 25-OH vitamin D is the gold standard to diagnose vitamin D deficiency. Unfortunately, there is no uniform assay methodology and no agreement as to what the “normal” serum 25-OHD level is. The guidelines of the Institute of Medicine (IOM) consider a serum level of 20 ng/mL as “sufficient.” The US Endocrine Society guidelines state this level should be 30 ng/mL. The US Endocrine Society also recommends that “deficiency” be defined as 20 ng/mL or less, “insufficiency” at levels between 20 and 29 ng/mL, and “sufficiency” at levels 30 ng/mL or higher.
It is also suggested that a level between 40 and 60 ng/mL is ideal and that levels up to 100 ng/mL are “safe.” Furthermore, whereas the IOM guidelines are that the upper limit of vitamin D intake should not exceed 4000 IU, the Endocrine Society considers the upper limit to be 10,000 IU daily. Patients with low 25-OHD often have secondary hyperparathyroidism; the serum calcium level, however, remains within the normal range until very late cases when secondary hyperparathyroidism is no longer able to compensate for the low vitamin D level.
- A.
- 4.
Comparing ergocalciferol (D2) to cholecalciferol (D3), the following is/are true:
- A.
D2 induces larger initial increases in serum 25-hydroxy-vitamin D (25-OHD) levels.
- B.
D3-induced increases in 25-OHD last longer than those induced by D2.
- C.
Peak serum 25-OHD concentration is reached 12 h after oral administration.
- D.
A and B.
- E.
A, B, and C.
Correct answer: B
Comment:
The relative potencies of ergocalciferol (D 2 ) and cholecalciferol (D 3 ) were evaluated by administering a single 50,000 IU dose of each compound to a group of healthy male volunteers. Over the first 3 days both vitamin D preparations induced similar increases in the serum vitamin D level. Subsequently, however, the increase in vitamin D level induced by D3 continued to rise for the following 14 days, whereas the increases induced by D2 rapidly fell and by day 14 were not different from baseline values. The 28-day area under the curve postoral administration was 60.2 ng/dL and 204.7 ng/dL for D2 and D3, respectively ( P < .002). The relative potency D3:D2 was 9.5:1. For each 100 IU vitamin D ingested, the serum 25-hydroxy-vitamin D level is expected to increase by 0.6–1.0 ng/mL.
- A.
- 5.
Vitamin D deficiency leads to bone demineralization by affecting:
- A.
Calcium absorption through the intestinal tract.
- B.
Rate of bone resorption.
- C.
Urinary calcium excretion.
- D.
A and B.
- E.
A, B, and C.
Correct answer: E
Comment:
The ionized serum calcium level which is essential for most cellular functions is maintained within a narrow range of normality through a finely balanced and acutely responsive calcium/parathyroid hormone/vitamin D axis. Low serum vitamin D levels lead to impaired absorption of calcium from the duodenum and trigger a negative calcium balance which initially is swiftly counteracted by an increased parathyroid hormone secretion, which increases renal calcium resorption and rapidly mobilizes and activates osteoclasts to increase bone resorption and transfer calcium from bones to the circulation.
- A.
- 6.
Skin production of vitamin D:
- A.
Ordinary glass blocks UV-B.
- B.
Is not affected by sunscreen lotions.
- C.
May reach toxic levels if exposure is too intense.
- D.
A and B.
- E.
A, B, and C.
Correct answer: A
Comment:
UV-B rays do not sufficiently penetrate glass and therefore not enough vitamin D may be produced if sun exposure is through glass. Vitamin D can be ingested or produced in the skin through the action of UV light (UV-B wavelength: 290–315 nm) on 7-dehydrocholesterol. Several factors affect the rate at which vitamin D is produced in the skin, including geographical latitude, ozone levels, season, time of day, clear or cloudy sky, air pollution, clothes worn, skin pigmentation, and use of sunscreen products. A properly applied sunscreen with a sun-protecting factor of 15 blocks almost completely the production of vitamin D in the skin. Vitamin D synthesis occurs mostly between 10:00 am and 3:00 pm. Five to 15 min of unprotected exposure to sunshine during this time period, when UV-B rays are available from the sun, is adequate to provide enough vitamin D for 1 day. Excessive sun exposure does not lead to high serum vitamin D levels because of its rapid photodegradation into biologically inactive metabolites. Relatively few foods naturally contain vitamin D and include egg yolk, fish oil, and fatty fish such as mackerel, salmon, and herring. Several foods, however, are fortified with vitamin D.
- A.
- 7.
Steps in the formation and activation of vitamin D include:
- A.
Binding to vitamin D binding protein (DBP).
- B.
Hepatic hydroxylation to 25-hydroxy-vitamin D.
- C.
Renal hydroxylation to 1,25-di-hydroxy-vitamin D.
- D.
B and C.
- E.
A, B, and C.
Correct answer: E
Comment:
Whether absorbed through the intestinal tract or formed in the skin, once vitamin D reaches the circulation it is bound to vitamin D Binding Protein (DBP). In the liver it is hydroxylated to become 25-hydroxy-vitamin D (25-OHD) and has a half-life of 2–3 weeks. In the kidneys, under the influence of parathyroid hormone, it is further hydroxylated either by 1α-hydroxylase enzyme to 1,25-di-hydroxy-vitamin D: (1,25(OH) 2 D): the most active metabolite or by other enzymes to form fewer active metabolites.
1,25(OH) 2 D also can be produced for local use by some cells. When it reaches the target cells 1,25(OH) 2 D diffuses through the cell and nuclear membranes, binds to intranuclear vitamin D receptors (VDR), acts as a transcription factor, and modifies the expression of a number of genes associated with metabolic pathways. 1,25(OH) 2 D also binds to Membrane-Associated Rapid Response Steroid-binding (MARRS) vitamin D receptors located in plasma membrane caveolae to regulate cytosolic calcium concentration and affect the activity of a number of enzymes. Vitamin D receptors have been identified in a number of tissues, including parathyroid glands, brain, pancreas, stomach, ovaries, and testicles.
- A.
- 8.
Low serum vitamin D levels are associated with increased risks of:
- A.
Depression.
- B.
Dementia.
- C.
Overall mortality.
- D.
A and C.
- E.
A, B, and C.
Correct answer: E.
Comment:
Vitamin D regulates cellular calcium homeostasis and has neuroprotective functions. Vitamin D receptors are found in the brain and regulate several cellular functions including the production and release of neurotrophic factors such as nerve growth factor and the synthesis of neurotransmitters, including acetylcholine, GABA, and catecholamines.
There is evidence to show an increased risk of neuropsychological diseases in patients with low vitamin D levels : specifically depression, dementia, including Alzheimer’s disease, epilepsy, multiple sclerosis, and schizophrenia. It is, however, still not clear whether this is a causal or associative relationship. Several studies have documented an increased overall mortality with lower serum vitamin D levels.
- A.
- 9.
Patients with low serum vitamin D levels are more at risk of:
- A.
Prostate cancer.
- B.
Colon cancer.
- C.
Breast cancer.
- D.
A and B.
- E.
A, B, and C.
Correct answer: E
Comment:
A number of studies have shown that patients with low serum vitamin D levels are more at risk of developing cancer and that higher levels of serum vitamin D levels may exert a protective effect against some types of cancer including prostate, breast, and colorectal. Other studies did not identify this tendency, and definite proof of a causative relationship is lacking.
A meta-analysis concluded that for each 4 ng/mL increase in the serum vitamin D level, the risk of colorectal cancer was reduced by 6%. Several other studies have documented negative effects of low serum vitamin D levels on different types of cancer incidence and mortality. There is also mounting evidence that the relationship between serum vitamin D levels and cancer incidence may be U-shaped or J-shaped, with those at the lowest and highest levels having a higher risk than those at midrange levels. A large study on 247,574 individuals suggested a J-shaped or U-shaped relationship between overall mortality and serum vitamin D levels, with the lowest mortality at levels between 20 and 24 ng/mL.
- A.
- 10.
Patients with low serum vitamin D levels are more at risk of:
- A.
Chronic kidney disease.
- B.
Diabetes mellitus, type 2.
- C.
Autoimmune diseases.
- D.
A and B.
- E.
A, B, and C.
Correct answer: E
Comment:
Vitamin D deficiency is prevalent among patients with chronic kidney diseases and accelerates its progression. A 5-year prospective on 6180 adults documented that patients with serum vitamin D levels less than 15 ng/mL at baseline had a higher incidence of albuminuria and low eGFR. Observational studies have shown an association between serum 25-OHD levels below 30 ng/mL, hypertension, and the metabolic syndrome. Several observational studies also documented an association between serum 25-OHD levels and type 2 diabetes mellitus, autoimmune diseases, and respiratory tract diseases. It is nevertheless still debatable whether these associations are true causative ones or merely associations due to some other common factor(s).
- A.
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