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
- 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
- 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
- Bone tenderness
- Osteoblasts are usually flattened and sparse