Vitamin%20d%20deficiency Diagnosis

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

Clinical Presentation:

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

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

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

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

• 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

• 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