Vitamin D Deficiency

AUTHOR: Daniel K. Asiedu, MD, PhD, FACP

Vitamin D is a hormone and a steroid and, by definition, not a vitamin. There are two forms of vitamin D: Vitamin D₂ and vitamin D₃.
Vitamin D₂ (ergocalciferol) is mainly found in some plant foods.
Vitamin D₃ (cholecalciferol) is produced in skin exposed to ultraviolet (UV) B radiation from sunlight (Fig. E1). Gloson, Whistler, and DeBoot independently described rickets in the mid-seventeenth century. Sniadecki first reported the association of rickets with inadequate exposure to sunlight in 1822.
The major functions of vitamin D include:
1. Increasing calcium, magnesium, and phosphorus absorption from the small intestines
2. Promoting the maturation of osteoclast to resorb calcium from bones

Figure E1 The metabolism and actions of vitamin D.

The primary source of vitamin D in humans is photoactivation in the skin of 7-dehydrocholesterol to cholecalciferol, which is then converted first in the liver to 25-hydroxyvitamin D and subsequently in the kidney to the much more active form, 1,25-dihydroxycholecalciferol (1,25[OH]2,D3). Regulation of the latter step is by parathyroid hormone (PTH), phosphate (PO₄), and feedback inhibition by 1,25(OH)2,D3. This step can also occur in lymphomatous and sarcoid tissue, resulting in the hypercalcemia that may complicate these diseases. UV, Ultraviolet.

From Ballinger A: Kumar & Clark’s essentials of clinical medicine, ed 6, Edinburgh, 2012, Saunders.

Definition

Vitamin D deficiency is characterized by hypocalcemia and/or hypophosphatemia leading to impaired bone mineralization. It is classified as a serum 25-hydroxyvitamin D (25[OH]D) level of <20 ng/ml (50 nmol/L). This standard definition of vitamin D deficiency has been recently challenged, and some endocrinologists recommend a cutoff of 12 mg/ml for vitamin D deficiency. Vitamin D insufficiency is defined as a 25(OH)D between 12 and 20 ng/ml.

The consequences of vitamin D deficiency include:

Bone disease (rickets, osteoporosis, low bone mass)
May impair reproductive success
Decrease the ability to combat infection (especially tuberculosis, influenza, viral infection)
May induce or worsen autoimmune disorders
May increase the incidence of death due to heart disease, inflammatory bowel disease, fracture, and cancer of the breast, colon, and prostate
Subclinical vitamin D deficiency may occur in developed countries and be associated with increased fall risk and osteoporosis

Synonyms

The sunshine vitamin

The antirachitic factor

Cholecalciferol

ICD-10CM CODE
E55.9		Vitamin D deficiency, unspecified

Epidemiology & Demographics

Incidence

Vitamin D insufficiency is very high among older adults and hospitalized and institutionalized people.
Worldwide deficiency and insufficiency affect about 1 billion people.
Children and young adults: 40% to 50% of preadolescent Caucasian girls, and Hispanic and African American adolescents, are vitamin D deficient.

Prevalence

41.6% of adults (at least 20 yr old) have 25(OH)D levels <20 ng/dl.

Predominant Sex & Age

Decreased skin production of vitamin D with age
Increased prevalence among darker-skinned individuals

Peak Incidence

In the U.S., 40% to 100% of the elderly are vitamin D deficient.

Sixty percent of nursing home residents may be vitamin D deficient.

Risk Factors

Age (due to decreased ability to produce D₃)
Sunshine-deficient areas (geographic location, living in higher latitudes)
Dark-skinned individuals (melanin competes with vitamin D₃ precursors for UV photons and thus decreases pre-D₃ formation)
Obese individuals
Institutionalized individuals
Pregnant and lactating women
Use of sunscreen (sun radiation that causes skin cancer also produces pre-vitamin D₃ in skin)
Patients on certain medications that antagonize vitamin D action (phenobarbital, phenytoin)
Intestinal resection
Severe chronic liver diseases (such as cirrhosis)
Kidney disease (e.g., nephritic syndrome)
Sarcoidosis and lymphomas (increased catabolism of 25[OH]D to 1,25[OH]2D)
Intestinal malabsorption disease (caused by celiac sprue, cystic fibrosis, Whipple disease)

Physical Findings & Clinical Presentation

Clinical presentation of vitamin D deficiency is dependent on the duration and severity of deficiency
Most patients with mild to moderate vitamin D deficiency are asymptomatic
Severe deficiency may lead to rickets (in children), osteomalacia (in adults), bone demineralization, hypokalemia, and phosphaturia
Mild deficiency can lead to hypocalcemia and hyperparathyroidism
Rickets: Seen in children; caused by defective mineralization in the skeleton (Fig. E2)
1. Bowing of the legs
2. Leg bone pain
3. Delayed growth
4. Seizure due to hypocalcemia
Osteomalacia: Seen in adults with severe and prolonged vitamin D deficiency
1. Periosteal bone pain (best detected by putting firm pressure on tibia or sternal bones)
2. Proximal muscle weakness
3. Chronic muscle aches/pain
Fracture with very minimal trauma (brittle and easily broken bones)
Severe hypocalcemia: Especially in late vitamin D deficiency leading to seizure tetany
Hypophosphatemia
Paresthesia
Tetany
Muscle cramps

Figure E2 Radiographs of a Child with Vitamin D Deficiency Rickets, Demonstrating Bowing of the Femurs and Tibias (A) and Widened, Frayed, Demineralized Epiphyseal Plates (B and C)

From Hochberg MC et al: Rheumatology, ed 5, St Louis, 2011, Mosby.

Etiology

Inadequate exposure to sunlight, such as:
1. During winter
2. In nursing home and health care institution residents
3. With excessive use of sunscreen
Medications: Individuals on certain medications, such as phenobarbital, phenytoin, and rifampin (antagonize vitamin D action/increase vitamin D catabolism)
Diseases and disease states:
1. Diseases causing vitamin D malabsorption:
  1. Cystic fibrosis
  2. Whipple disease
  3. Celiac sprue
2. Diseases increasing vitamin D catabolism:
  1. Lymphoma
  2. Sarcoidosis
3. Intestinal resection
4. Decreased 25(OH)D production:
  1. Kidney disease
  2. Liver cirrhosis

Diagnosis ⬆ ⬇

Differential Diagnosis

Arthritis
Fibromyalgia

Workup

Population-wide screening for vitamin D deficiency is not recommended because evidence to support this practice is lacking. Appropriate to screen high-risk individuals.
Screening is needed for individuals at risk (osteoporosis, history of falls, obese persons, pregnant and lactating women, diseases causing vitamin D malabsorption, African Americans). Workup involves blood and urine tests as well as radiography, as outlined in the next section.

TABLE 1 Laboratory Tests

	Serum			URINE
	Calcium	Phosphorus	Alkaline phosphatase	Calcium
*Osteoporosis*	N	N	N	N
*Hyperparathyroidism*
Primary	↑		N or ↑	N or ↑
Secondary	N or ↑	↑	↑	↓
Tertiary	↑	N or ↓	N or ↑	N or ↑
*Hypoparathyroidism*	↓	↑	N	↓
*Pseudohypoparathyroidism*	↓	↑	N	↓
*Rickets/osteomalacia*
Vit D deficient	↓	↓	↑
Vit D refractory	N	↓	↑	↓
Hypophosphatasia	N or ↑	N	↓	N or ↑

Vit, Vitamin.

From Grant LA: Grainger & Allison’s diagnostic radiology essentials, ed 2, Philadelphia, 2019, Elsevier.

Laboratory Tests (Table 1

Serum 25(OH)D: This is the best test to determine vitamin D status.
Parathyroid hormone (PTH): Increased levels in vitamin D insufficiency. It is a marker of vitamin D insufficiency.
Increased (serum or bone) alkaline phosphatase.
Decreased 24-h urine calcium (patient should not be on a thiazide).
In patients at risk for osteomalacia [s-25(OH)D is less than 10 ng/ml], check calcium, Ph, alkaline phosphatase, PTH, basic metabolic panel, and tissue transglutaminase antibodies.

Imaging Studies

Radiographs may show:
1. Pseudofractures of the pelvis, femur, metatarsals
2. Nontraumatic fractures
Bone density:
1. Decreased bone mineral density (osteopenia or osteoporosis). Note that bone mineral density is not routinely performed in patients whose only risk factor is decreased Vitamin D levels.

Treatment ⬆ ⬇

Nonpharmacologic Therapy

Natural sources of vitamin D. These include:
1. Exposure to sunlight. A mild sunburn is equivalent to consuming 10,000 to 25,000 IU of dietary vitamin D.
2. Dietary sources are not enough to meet daily requirements. Oily fish such as salmon, cod, and mackerel are rich sources of vitamin D₃.
Foods fortified with vitamin D
1. Mainly fortified dairy products
2. Fortified orange juice

Acute General Rx

Treating deficiency (general population): Cholecalciferol (vitamin D₃), when available, is preferred for vitamin D supplementation
1. 50,000 IU of vitamin D every week for 8 wk, or
2. 6000 IU daily to achieve a serum level of 25(OH)D of at least 30 ng/ml
Maintenance measures after treatment (general population): 1500 to 2000 IU daily
Treating deficiency (obese patients, patients with malabsorption syndromes, or those taking certain medications, as indicated earlier)
1. 10,000 IU daily maintenance dose is recommended once s-25(OH)D level exceeds 30 ng/ml.
2. After treating deficiency, recheck 25(OH)D in 12 to 16 wk.
3. Maintenance measures after treatment (obese patients, patients with malabsorption syndromes, or those taking certain medications, as indicated earlier): 3000 to 6000 IU daily.
4. If deficiency persists after several attempts at treatment, try UV B light therapy.

Referral

Referral to an endocrinologist is recommended if there is no response to treatment.

Prevention

Food fortification with vitamin D₂ or vitamin D₃.
Adequate sun exposure, for example, exposure in the middle of the day (between 10:00 A.M. and 3:00 P.M.).
Use vitamin D₃ for supplementation when available.
Vitamin D supplementation (per the Endocrine Society):
1. Infants (age range 1 to 12 mo) require at least 400 IU/day of vitamin D
2. Children (age range 1 to 18 yr) require 600 IU/day of vitamin D
3. Adult supplementation (adults 19 to 70 yr): 600 IU of vitamin D daily
4. Adult supplementation (persons ≥70 yr): 800 IU of vitamin D daily
5. Exceptions: Pregnant or lactating women, obese persons, and patients on antiseizure medications, steroids, antifungals, and AIDS medications should be given 2× to 3× more vitamin D
6. To reduce the risk of fracture and falls, the American Geriatric Society recommends a daily intake of at least 1000 IU and the National Osteoporosis Foundation 800 to 1000 IU in adults 65 yr or older

Screening

Routine screening for low-risk adults is not recommended. Screening is recommended only for individuals at high risk for vitamin D deficiency such as Blacks and Hispanics, obese individuals (body mass index >30 kg/m²), patients with osteoporosis, the elderly, and patients with certain chronic diseases (see “Risk Factors”). According to the U.S. Preventive Services Task Force, current evidence is insufficient to assess the balance of benefits and harms of screening for vitamin D deficiency in asymptomatic adults.

Pearls & Considerations ⬆ ⬇

In the U.S., vitamin D supplements are available by prescription as vitamin D₂ (ergocalciferol) or over the counter as vitamin D₃ (cholecalciferol, usually in 400- to 1000-IU doses). Both vitamin D₂ and vitamin D₃ are acceptable as supplements. On average, oral vitamin D₃ raises blood levels more than does vitamin D₂.
Upper limit of maintenance tolerability in healthy adults is 4000 IU a day. More than 4000 IU of vitamin D daily in nondeficient individuals increases the risk of harm. High-level supplements (>10,000 IU daily) are associated with kidney and tissue damage.
Vitamin D supplementation is recommended for fall prevention. A recent study showed that vitamin D supplementation did not result in a significant lower risk of fractures. Trials have revealed that Vitamin D supplementation at doses of 1000 IU daily or higher did not prevent falls in older adults, and fall risk increased with higher doses.¹
Prescribing more than the recommended daily amount to improve quality of life or prevent cardiovascular disease or death is not advised.
Trials have shown that low vitamin D levels are associated with depressive symptoms, especially in persons with a history of depression. These findings suggest that measuring vitamin D levels may be useful in patients with a history of depression.
Recent data suggest that vitamin D deficiency is associated with the risk of developing certain cancers (including breast, colon, and prostate).
A randomized trial has shown that 5 yr of routing vitamin D supplementation does not lower 6 yr mortality in older adults.²
Vitamin D deficiency is associated with some autoimmune diseases (types 1 and 2 diabetes, metabolic syndrome, multiple sclerosis). Daily vitamin D supplementation was found to be beneficial in preventing some new autoimmune diseases in older adults.³

Related Content

Vitamin D Deficiency (Patient Information)

Osteomalacia and Rickets (Related Key Topic)

Vitamin Deficiency (Related Key Topic)

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Basic Information ⬇

Diagnosis ⬆ ⬇

Treatment ⬆ ⬇

Pearls & Considerations ⬆ ⬇

Related Content ⬆