vitamin%20d%20deficiency
VITAMIN D DEFICIENCY

Vitamin D deficiency is a condition wherein there is low circulating levels of vitamin D. Vitamin D is an essential steroid hormone found in the body.

It results from inadequate sunlight exposure, malabsorptions &/or inadequate nutrition.

Vitamin D insufficiency is a less severe state of calcidiol deficiency and associated w/ parathyroid hormones and osteoporosis.

 

Vitamin%20d%20deficiency Diagnosis

Classification

Vitamin D Insufficiency

  • Less severe state of calcidiol-deficiency
  • Common among older adults and hospitalized and institutionalized individuals
  • Occurs in 40-50% pre-adolescent Caucasian girls and in 17% of chronic kidney disease patients
  • Typical calcidiol range is 21-29 ng/mL (525 to 725 nmol/L)
  • Associated with increased parathyroid hormones (PTH) and osteoporosis

Vitamin D Deficiency

  • Results from inadequate sunlight exposure, malabsorptions and/or inadequate nutrition
  • Classified as serum 25-hydroxyvitamin D(25-[OH]D) levels of <20 ng/mL (50 nmol/L)
  • Common in 40-50% of Hispanic and African American adolescents and 29% of chronic kidney disease patients
  • Affects 40-100% of elderly and 60% of nursing home residents
  • Vitamin D deficiency rickets is most prevalent in children <2 years old with peak incidence between 3-18 months
  • Osteomalacia due to vitamin D deficiency may be found in 30% of gastric surgery or bypass for obese patients
  • Adolescents with low serum vitamin D levels are associated with increased risk of hyperglycemia, hypertension and metabolic syndrome
  • Pregnant and lactating women taking prenatal vitamins and calcium supplements with vitamin D remains at risk for vitamin D deficiency
  • Associated with increased risk of gestational diabetes mellitus, pre-eclampsia, pre-term birth, small-for-gestational age (SGA) infants, impaired fetal skeletal formation leading to infant rickets and reduction in bone mass
  • Mothers who are vitamin D deficient will have infants with rickets and no vitamin D stores at birth
  • Important etiologic factors:
    • Autoimmune diseases (eg multiple sclerosis, diabetes mellitus type 1)
    • Cancer (eg colon cancer, breast cancer, non-Hodgkin’s lymphoma)
    • Cardiovascular diseases (eg hypertension, heart failure, sudden cardiac death)
    • Inflammatory bowel disease (eg Crohn’s disease)
    • Infections
    • Immune deficiency
    • Neurocognitive disorders (eg Alzheimer’s disease)
  • Stages of vitamin D deficiency:
    • Stage 1 presents as decreased 25-OH-D levels, unchanged or increased 1,25-OH2-D leading to hypocalcemia and euphosphatemia
    • Stage 2 presents with continued decreased 25-OH-D levels, slight increased in skeletal alkaline phosphatase levels, eucalcemia, hypophosphatemia and PTH maintains calcium through bone demineralization
    • Stage 3 manifests as severe 25-OH-D deficiency with increased alkaline phosphatase, hypocalcemia, decreased bone mass and increased fracture risk
  • Complications:
    • Bone disease (eg rickets, osteoporosis, low bone mass)
    • Decreased immunity to fight of infection (eg tuberculosis, influenza, viral infection)
    • Increased incidence of death caused by cancer (eg breast, colon, prostate), fracture, heart disease, inflammatory bowel disease, and respiratory diseases
    • May affect reproductive success

Physical Examination

Clinical Presentation:

  • Fracture with minimal trauma
  • Hypophosphatemia
  • Muscle cramps
  • Neuromuscular
  • Paresthesia
  • Severe hypocalcemia - seen in later stages of vitamin D deficiency causing seizure tetany

Laboratory Tests

Serum 25(OH)D

  • Good indicator of vitamin D status and stores
  • Used to evaluate vitamin D status in patients at risk for deficiency
  • Normal value: 30-40 ng/mL (75-100 nmol/L) in adults
  • Indications for screening:
    • African-American and Hispanic adults and children
    • Chronic kidney disease
    • Granuloma-forming disorders (eg berylliosis, coccidiomycosis, histoplasmosis, sarcoidosis, tuberculosis)
    • Hepatic failure
    • Hyperparathyroidism
    • Malabsorption syndromes - eg bariatric surgery, Crohn’s disease, cystic fibrosis, inflammatory bowel disease, radiation enteritis
    • Medications (eg anticonvulsants, antifungals, antiretrovirals, cholestyramine, glucocorticoids)
    • Obese adults and children (BMI >30 kg/m2)
    • Older adults with history of falls and/or nontraumatic fractures
    • Osteomalacia
    • Osteoporosis
    • Pregnant and lactating women

Serum 1,25-dihyroxyvitamin D

  • Elevated in cases of concomitant hyperparathyroidism
  • Significant in cases of vitamin D resistance or defective 1-hydroxylation which appears in low levels

Parathyroid Hormone (PTH)

  • Marker of vitamin D insufficiency
  • Elevated in vitamin D insufficiency

Serum or Bone Alkaline Phosphatase

  • Increased activity is associated with osteomalacia due to vitamin D deficiency
  • May present as normal or borderline in some patients

24-hour Urine Calcium

  • Not indicated in patients taking thiazides

Imaging

Radiologic Findings:

  • In children with rickets, epiphyseal growth plate appears widened in the context of cupped metaphysis and an ill-defined diaphyseal border caused by decreased mineralization
  • Stage I rickets presents as demineralization of the calvarium and loss of definition of skull sutures
  • Poorly defined trabecular pattern of the metaphyses with bowed and thinned cortices of diaphyses
  • In osteomalacia, absence or blurred margins with thin cortices may be noted on cancellous bones
  • Looser’s zones
    • Also known as Milkman’s fractures or pseudofractures
    • Pathognomonic of osteomalacia
    • Bilateral, thin (2-3 mm), radioluscent bands
    • Perpendicular to periosteal surface in femoral neck, ribs, ischial and pubic rami, metatarsals and below the glenoid fossa on the outer border of the scapula
    • Appears as increased uptake on bone scans which may lead to search for primary malignancies
  • In secondary hyperparathyroidism, subperiosteal erosions along the cortices may be seen
  • Sacroiliac joint pseudowidening or widening with hazy margins have been observed
  • Bone mineral density T-scores between -3 and -4 with radial diaphyseal density lower than the lumbar spine or total proximal femur

Screening

Quantitative Histologic Findings:

  • Examination of undecalcified bone is required in order to establish unequivocal presence of osteomalacia
  • Trabeculae covered with abnormally thickened osteoid seams
  • Findings in osteomalacia:
    • Osteoid width augmentation of >15 µm (normal value = 4-12 µm)
    • >10% osteoid area of cancellous bone area (normal value = <4%)
    • >100 days of mineralization lag time (normal value = 9-20 days)
      • Determined by osteoid width divided by distance between and linear extent of double tetracycline labels observed in bones after 2 time-spaced oral tetracycline course
  • 2 time-spaced course of Tetracycline
    • Deposited Tetracycline in the hydroxyapatite crystal formation early in the course generates bright stripes at the mineralized bone and osteoid interface when viewed with fluorescent microscopy
    • Courses of Tetracycline 1g/day for 3 days are given on a 14-day interval
    • Mineralization rate (µm/day) = average distance between double labels / number of days between 2 courses
    • Results:
      • Increased bone turnover when numerous and widely spaced double labels with intact mineralizations and excess osteoid
      • Delayed or ceased mineralization of osteomalacia once paucity of tetracyline labels are narrowly spaced in the presence of excessive osteoid

Rickets

  • Seen in children
  • Due to defective mineralization of cartilaginous growth plate and endochondral bone formation
  • Stages of rickets:
    • Stage 1 - early clinical manifestations of vitamin D deficiency related to hypocalcemia with clinical signs of hypocalcemia which is commonly seen in infants <6 months old
      • Presents with apneic episodes, convulsions or tetany with no clinical signs of rickets
    • Stage 2 - impaired bone mineralization is apparent
    • Stage 3 - presents with signs of hypocalcemia and severe rickets
  • Manifestation:
    • Bowing of the legs - genu varum (bowed legs) or genu valgum (“knock knees”)
    • Craniotabes - highly suggestive in the absence of hydrocephalus and osteogenesis imperfecta
    • Delayed tooth eruption
    • Teeth enamel hypoplasia
    • “Hot-cross bun appearance” - delayed fontanelles closure and growth with frontal and parietal bossing
    • Harrison’s groove/sulcus - lower anterior thoracic wall indentation
    • Hypocalcemia-induced seizure - observed only in severe vitamin D deficiency
    • Increased susceptibility to infections
    • Leg bone pain
    • Metaphyseal flaring/widening
    • Motor delays
    • Poor growth
    • Rachitic rosary - costochondral junction prominence influenced by difference in individual bone growth rates
    • Violin vase deformity - narrowing of lateral diameter of the chest due to negative intrapleural pressure associated with breathing
  • Presents as border-normal or low total calcium levels, low phosphate levels, elevated alkaline phosphatase activity and PTH concentrations
  • May also occur in severe recessive form of osteopetrosis

Osteomalacia

  • Seen in adults or adolescents after epiphyseal closure
  • Softening of bones referring to defective or delayed mineralization disorder of formed bones
  • Depends on overlapping manifestation:
    • Due to underlying disorder such as gastrointestinal disease or surgery (eg troublesome gastric resection, stapling or bypass for obesity, and intestinal malabsorption)
    • Hypocalcemia or hypophosphatemia
    • Directly due to bone disease
  • Manifestation:
    • Bone tenderness
      • Elicited by pressing on tibia, wrist, pubic rami or iliac crests or rib cage compression
    • Chronic muscle pain
      • May be worse at night and after sudden movements
    • Hypocalcemia
      • Severe cases presents with muscle cramps, paresthesias, positive Chvostek’s sign, and seizures
    • Periosteal bone pain
      • Detected by putting firm pressure on the tibia or sternal bones
      • Usually nonspecific and poorly localized
    • Proximal muscle weakness
      • Patients usually complain of difficulty in climbing stairs or rising from sitting in a chair or on toilet
      • Absent in patients with X-linked hypophosphatemia
      • Often occurring in the lower back, pelvis and legs
      • Worse on weight bearing leading to characteristic flat-footed, spring-less, waddling gait
    • Pseudofractures - often seen where major arteries cross bones
    • Milkman’s syndrome - multiple symmetric pseudofractures in osteomalacia patients
  • Osteoblasts are usually flattened and sparse
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