signs of vitamin deficiency

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In This Topic

Vitamin D

Vitamin D Deficiency and Dependency

Etiology

Inadequate exposure or intake

Reduced absorption

Abnormal metabolism

Resistance to effects of vitamin D

Symptoms and Signs

Diagnosis

Prevention

Treatment

Vitamin D Toxicity

Symptoms

Diagnosis

Treatment

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Section

Nutritional Disorders

Subject

Vitamin Deficiency, Dependency, and Toxicity

Topics

Introduction· Biotin and Pantothenic Acid· Folate· Niacin· Riboflavin·
Thiamin· Vitamin A· Vitamin B12 · Vitamin B6 · Vitamin C·Vitamin D·
Vitamin E· Vitamin K

Vitamin D

 

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Vitamin D has 2 main forms: D2 ( ergocalciferol Some Trade Names
DRISDOL
Click for Drug Monograph
) and D3 (cholecalciferol); the latter is the naturally occurring form
and the form used for low dose supplementation. Vitamin D3 is
synthesized in skin by exposure to direct sunlight (ultraviolet B
radiation) and obtained in the diet chiefly in fish liver oils and
salt water fish. In some developed countries, milk and other foods are
fortified with vitamin D. Human breast milk is low in vitamin D,
containing an average of only 10% of the amount in fortified cow's
milk. Requirements for vitamin D increase with aging because skin
synthesis declines. Sunscreen use and dark skin pigmentation also
reduce skin synthesis of vitamin D.

Vitamin D is a prohormone with several active metabolites that act as
hormones. Vitamin D is metabolized by the liver to 25(OH)D, which is
then converted by the kidneys to 1,25(OH)2D
(1,25-dihydroxycholecalciferol, calcitriol Some Trade Names
ROCALTROL
Click for Drug Monograph
, or active vitamin D hormone). 25(OH)D, the major circulating form,
has some metabolic activity, but 1,25(OH)2D is the most metabolically
active. The conversion to 1,25(OH)2D is regulated by its own
concentration, parathyroid hormone (PTH), and serum concentrations of
Ca and phosphate.

Vitamin D affects many organ systems (see Table 6: Vitamin Deficiency,
Dependency, and Toxicity: Actions of Vitamin D and Its MetabolitesTables),
but mainly it increases Ca and P absorption from the intestine and
promotes normal bone formation and mineralization. Vitamin D and
related analogs may be used to treat psoriasis, hypoparathyroidism,
renal osteodystrophy, and possibly leukemia, breast, prostate, or
colon cancer; they may also be used for immunosuppression.

Table 6

Actions of Vitamin D and Its Metabolites

Organ

Actions

Bone

Promotes bone formation by maintaining appropriate Ca and P
concentrations

Immune system

Stimulates immunogenic and antitumor activity

Decreases risk of autoimmune disorders

Intestine

Enhances Ca and phosphate transport (absorption)

Kidneys

Enhances Ca reabsorption by the tubules

Parathyroid glands

Inhibits parathyroid hormone secretion

Pancreas

Stimulates insulin production

Vitamin D Deficiency and Dependency

Inadequate exposure to sunlight predisposes to vitamin D deficiency.
Deficiency impairs bone mineralization, causing rickets in children
and osteomalacia in adults and possibly contributing to osteoporosis.
Treatment usually consists of oral vitamin D; Ca and phosphate are
supplemented as needed. Prevention is often possible. Rarely,
hereditary disorders cause impaired metabolism of vitamin D
(dependency).

Vitamin D deficiency is a common cause of rickets and osteomalacia,
but these disorders may also result from other conditions, such as
various renal tubular disorders, familial hypophosphatemic (vitamin
D–resistant) rickets (see Congenital Renal Transport Abnormalities:
Hypophosphatemic Rickets), chronic metabolic acidosis,
hypoparathyroidism (which reduces vitamin D absorption), inadequate
dietary Ca, and disorders or drugs that impair the mineralization of
bone matrix.

Vitamin D deficiency causes hypocalcemia, which stimulates production
of PTH, causing hyperparathyroidism. Hyperparathyroidism increases
absorption, bone mobilization, and renal conservation of Ca but
increases excretion of phosphate. As a result, the serum level of Ca
may be normal, but because of hypophosphatemia, bone mineralization is
impaired.

Etiology

Vitamin D deficiency may result from the following:

Inadequate exposure or intake: Inadequate direct sunlight exposure (or
sunscreen use) and inadequate intake usually occur simultaneously to
result in clinical deficiency. Susceptible people include the elderly
(who are often undernourished and are not exposed to enough sunlight),
and certain communities (eg, women and children who are confined to
the home or who wear clothing that covers the entire body and face).
Inadequate vitamin D stores are common among the elderly, particularly
those who are housebound, institutionalized, or hospitalized or who
have had a hip fracture. Recommended direct sunlight exposure is 5 to
15 min (suberythemal dose) to arms and legs, or face, arms and hands,
at least 3 times a week.

Reduced absorption: Malabsorption can deprive the body of dietary
vitamin D; only a small amount of 25(OH)D is recirculated
enterohepatically.

Abnormal metabolism: Vitamin D deficiency may result from defects in
the production of 25(OH)D or 1,25(OH)2D. People with a chronic renal
disorder commonly develop rickets or osteomalacia because renal
production of 1,25 (OH)2D is decreased and phosphate levels are
elevated. Hepatic dysfunction can also interfere with production of
active vitamin D metabolites

Type I hereditary vitamin D-dependent rickets is an autosomal
recessive disorder characterized by absent or defective conversion of
25(OH)D to 1,25(OH)2D in the kidneys. X-linked familial
hypophosphatemia reduces vitamin D synthesis in the kidneys. Many
anticonvulsants, and glucocorticoid use increase the need for vitamin
D supplementation.

Resistance to effects of vitamin D: Type II hereditary vitamin
D-dependent rickets has several forms and is due to mutations in the
1,25(OH)2D receptor. This receptor affects the metabolism of gut,
kidney, bone, and other cells. In this disorder, 1,25(OH)2D is
abundant but ineffective because the receptor is not functional.

Symptoms and Signs

Vitamin D deficiency can cause muscle aches, muscle weakness, and bone
pain at any age.

Vitamin D deficiency in a pregnant woman causes deficiency in the
fetus. Occasionally, deficiency severe enough to cause maternal
osteomalacia results in rickets with metaphyseal lesions in neonates.
In young infants, rickets causes softening of the entire skull
(craniotabes). When palpated, the occiput and posterior parietal bones
feel like a ping pong ball. In older infants with rickets, sitting and
crawling are delayed, as is fontanelle closure; there is bossing of
the skull and costochondral thickening. Costochondral thickening can
look like beadlike prominences along the lateral chest wall (rachitic
rosary). In children 1 to 4 yr, epiphyseal cartilage at the lower ends
of the radius, ulna, tibia, and fibula enlarge; kyphoscoliosis
develops, and walking is delayed. In older children and adolescents,
walking is painful; in extreme cases, deformities such as bowlegs and
knock-knees develop.

Tetany is caused by hypocalcemia and may accompany infantile or adult
vitamin D deficiency. Tetany may cause paresthesias of the lips,
tongue, and fingers; carpopedal and facial spasm; and, if very severe,
seizures. Maternal deficiency can cause tetany in neonates.

Osteomalacia predisposes to fractures. In the elderly, hip fractures
may result from only minimal trauma.

Diagnosis

Levels of 25(OH)D (D2+D3)

Diagnosis may be suspected based on any of the following:

A history of inadequate sunlight exposure or dietary intake

Symptoms and signs of rickets, osteomalacia, or neonatal tetany

Characteristic bone changes seen on x‑ray

X‑rays of the radius and ulna plus serum levels of Ca, phosphate,
alkaline phosphatase, PTH, and 25(OH)D are needed to differentiate
vitamin D deficiency from other causes of bone demineralization.

Assessment of vitamin D status and serologic tests for syphilis can be
considered for infants with craniotabes based on the history and
physical, but most cases of craniotabes resolve spontaneously. Rickets
can be distinguished from chondrodystrophy because the latter is
characterized by a large head, short extremities, thick bones, and
normal serum Ca, phosphate, and alkaline phosphatase levels.

Tetany due to infantile rickets may be clinically indistinguishable
from seizures due to other causes. Blood tests and clinical history
may help distinguish them.

Bone changes, seen on x‑rays, precede clinical signs. In rickets,
changes are most evident at the lower ends of the radius and ulna. The
diaphyseal ends lose their sharp, clear outline; they are cup-shaped
and show a spotty or fringy rarefaction. Later, because the ends of
the radius and ulna have become noncalcified and radiolucent, the
distance between them and the metacarpal bones appears increased. The
bone matrix elsewhere also becomes more radiolucent. Characteristic
deformities result from the bones bending at the cartilage-shaft
junction because the shaft is weak. As healing begins, a thin white
line of calcification appears at the epiphysis, becoming denser and
thicker as calcification proceeds. Later, the bone matrix becomes
calcified and opacified at the subperiosteal level.

In adults, bone demineralization, particularly in the spine, pelvis,
and lower extremities, can be seen on x‑rays; the fibrous lamellae can
also be seen, and incomplete ribbonlike areas of demineralization
(pseudofractures, Looser's lines, Milkman's syndrome) appear in the
cortex.

Because levels of serum 25(OH)D reflect body stores of vitamin D and
correlate with symptoms and signs of vitamin D deficiency better than
levels of other vitamin D metabolites, 25(OH)D (D2+D3) measurement is
generally considered the best way to diagnose deficiency. Goal 25(OH)D
levels are 30 to 40 ng/mL (about 75 to 100 nmol/L); whether levels
above this may be beneficial remains uncertain.

If the diagnosis is unclear, serum levels of 1,25(OH)2D and urinary Ca
concentration can be measured. In severe deficiency, serum 1,25(OH)2D
is abnormally low, usually undetectable. Urinary Ca is low in all
forms of the deficiency except those associated with acidosis.

In vitamin D deficiency, serum Ca may be low or, because of secondary
hyperparathyroidism, may be normal. Serum phosphate usually decreases,
and serum alkaline phosphatase usually increases. Serum PTH is
elevated.

Type I hereditary vitamin D–dependent rickets results in normal serum
25(OH)D, low serum 1,25(OH)2D and Ca, and normal or low serum
phosphate.

Prevention

Dietary counseling is particularly important in communities whose
members are at risk of vitamin D deficiency. Fortifying unleavened
chapati flour with vitamin D (125 μg/kg) has been effective among
Indian immigrants in Britain. The benefits of sunlight exposure for
vitamin D status must be weighed against the increased skin damage and
skin cancer risks.

All breastfed infants should be given supplemental vitamin D 5 μg (200
IU) once/day from birth to 6 mo; at 6 mo, a more diversified diet is
available. For adolescents at risk, a single IM dose of ergocalciferol
Some Trade Names
DRISDOL
Click for Drug Monograph
2.5 mg (100,000 IU) given in the fall can maintain adequate 25(OH)D
levels throughout the winter. The RDA for vitamin D intake for ages 51
to 70 is 400 IU and for age >70 is 600 IU; this intake is now
considered too low, and the 2005 Dietary Guidelines for Americans
recommends that healthy older adults consume 1000 IU/day.

Treatment

Correction of Ca and P deficiencies

Supplemental vitamin D

Ca deficiency (which is common) and P deficiency should be corrected.
As long as Ca and P intake is adequate, adults with osteomalacia and
children with uncomplicated rickets can be cured by giving vitamin D
40 μg (1600 IU) po once/day. Serum 25(OH)D and 1,25(OH)2D begin to
increase within 1 or 2 days. Serum Ca and phosphate increase and serum
alkaline phosphatase decreases within about 10 days. During the 3rd
wk, enough Ca and P are deposited in bones to be visible on x‑rays.
After about 1 mo, the dose can usually be reduced gradually to the
usual maintenance level of 10 to 15 μg (400 to 600 IU) once/day. If
tetany is present, vitamin D should be supplemented with IV Ca salts
for up to 1 wk (see Fluid and Electrolyte Metabolism: Treatment).
Older persons may need 25 to > 50 μg (1000 to = 2000 IU) daily to
maintain a 25(OH)D level > 30 ng/mL (> 75 nmol/L); this is higher than
the RDA for persons > 70 years old (600 IU) and may exceed the current
UL of 2000 IU/d.

Because rickets and osteomalacia due to defective production of
vitamin D metabolites are vitamin D–resistant, they do not respond to
the doses usually effective for rickets due to inadequate intake.
Endocrinologic evaluation is required because treatment depends on the
specific defect. When 25(OH)D production is defective, vitamin D 50 μg
(2000 IU) once/day increases serum levels and results in clinical
improvement. Patients with kidney disorders often need 1,25(OH)2D
supplementation.

Type I hereditary vitamin D–dependent rickets responds to 1,25(OH)2D 1
to 2 μg po once/day. Some patients with type II hereditary vitamin
D–dependent rickets respond to very high doses (eg, 10 to 24 μg/day)
of 1,25(OH)2D; others require long-term infusions of Ca.

Vitamin D Toxicity

Usually, vitamin D toxicity results from taking excessive amounts.
Marked hypercalcemia commonly causes symptoms. Diagnosis is typically
based on elevated blood levels of 25(OH)D. Treatment consists of
stopping vitamin D, restricting dietary Ca, restoring intravascular
volume deficits, and, if toxicity is severe, giving corticosteroids or
bisphosphonates.

Because synthesis of 1,25(OH)2D (the most active metabolite of vitamin
D) is tightly regulated, vitamin D toxicity usually occurs only if
excessive doses (prescription or megavitamin) are taken. Vitamin D
1000 μg (40,000 IU)/day produces toxicity within 1 to 4 mo in infants.
In adults, taking 1250 μg (50,000 IU)/day for several months can
produce toxicity. Vitamin D toxicity can occur iatrogenically when
hypoparathyroidism is treated too aggressively (see Fluid and
Electrolyte Metabolism: Treatment).

Symptoms

The main symptoms result from hypercalcemia. Anorexia, nausea, and
vomiting can develop, often followed by polyuria, polydipsia,
weakness, nervousness, pruritus, and eventually renal failure.
Proteinuria, urinary casts, azotemia, and metastatic calcifications
(particularly in the kidneys) can develop.

Diagnosis

Hypercalcemia plus risk factors or elevated serum 25(OH)D levels

A history of excessive vitamin D intake may be the only clue
differentiating vitamin D toxicity from other causes of hypercalcemia.
Elevated serum Ca levels of 12 to 16 mg/dL (3 to 4 mmol/L) are a
constant finding when toxic symptoms occur. Serum 25(OH)D levels are
usually elevated >150 ng/mL (>375 nmol/L). Levels of 1,25(OH)2D, which
need not be measured to confirm the diagnosis, may be normal.

Serum Ca should be measured often (weekly at first, then monthly) in
all patients receiving large doses of vitamin D, particularly the
potent 1,25(OH)2D.

Treatment

IV hydration plus corticosteroids or bisphosphonates

After stopping vitamin D intake, hydration with IV normal saline and
corticosteroids or bisphosphonates (which inhibit bone resorption) are
used to reduce blood Ca levels.

Kidney damage or metastatic calcifications, if present, may be
irreversible.

Last full review/revision April 2007 by Larry E. Johnson, MD, PhD

Content last modified April 2007

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