Disorders of Calcium & Bone Flashcards
What are biochemical tests used in a Child with serum Ca < 2.2 mmol/l?
SERUM
- Calcium [Ca]
- Phosphate [P]
- Magnesium [Mg]: Always measure serum magnesium in hypocalcaemia child. The low serum magnesium can impair PTH secretion and can lead to restance of the action of PTH (bone & kidney)
- Parathyroid hormone [PTH]
- 25-hydroxyvitamin D [25OHD]
- 1,25-dihydroxvitamin D [1,25(OH)2D]
URINE
- Calcium/Creatinine ratio
How is Srum Calcium Concentration regulated by PTH?
- Low calcium is sensed by the calcium sensing receptor in the parathyroid cell
- PTH leads to increased calcium reabsorption in kidneys and phosphate excretion
- PTH also activates 1α Hydroxylase which leads to calcitriol activation from 25 hydroxyvitamin D. The Calcitriol leads to increased dietary calcium absorption and phosphate absorption
- This leads to maintenance of the serum calcium and this acts on the calcium sensing receptor which leads calcium absorption. Activation of PTH is then switched off.
What are symptoms of Hypocalcaemia?
- Tingling sensation around the mouth & digits
- Muscle cramps
- Tetany
- Focal or Generalised Fits
- Laryngospasm & stridor
- Apnoea
- Cardiac Rhythm disturbance
What are causes of Low Serum Calcium?
- Lab Error
- Low Albumin
- Is serum Magnesium Normal
- Familial Hypocalcaemic Hypercalciuria
- Hypoparathyroidism
- Pseudo-hypoparathyroidism
- Severe Vitamin D Deficiency or Vitamin D Dependent Rickets Type 1 or 2
What are biochemical results for Hypoparathyroidism?
- PTH [Low/Undetectable]
- 25-hydroxyvitamin D [Normal]
- 1,25-dihydroxvitamin D [Low/Normal]
- Calcium [LOW]
- Phosphate [High]
What are biochemical results for Pseudo-hypoparathyroidism?
- PTH [High/Very High]
- 25-hydroxyvitamin D [Normal]
- 1,25-dihydroxvitamin D [Low/Normal]
- Calcium [LOW]
- Phosphate [High]
What are biochemical results for Early vitamin D deficiency?
- 25(OH)D ↓
- Ca [Low normal]
- PTH ↑
- P ↓
- 1,25(OH)2D ↑
- ALP ↑
What are biochemical results for Severe vitamin D deficiency?
- 25(OH)D ↓ ↓
- Ca ↓
- PTH ↑ ↑
- P ↓ ↓
- 1,25-(OH)2D ↓
- ALP ↑ ↑
What are biochemical results for Transient PTH resistance?
- Ca ↓
- P ↑
- 25(OH)D ↓↓
How does Neonatal Hypocalcaemia develop?
EARLY: Usually transient - by day 3-4 of life
- Infants of diabetic mothers
- Perinatal asphyxia
- Severe pre-eclampsia
LATE: Occurs after day 5 of life
- Oral phosphate load, e.g feeding of unmodified Cows milk
- Infants of hyperparathyroid mother
- Severe Vitamin D deficient mothers
- Hypomagnesaemia
- Osteopetrosis
What are genetic causes of impaired synthesis or secretion of PTH?
- DiGeorge Syndrome
- Genetic mutations interfering with the production of PTH (autosomal dominant, autosomal recessive)
- HDR Syndrome (hypoparathyroidism, deafness, renal anomaly) - GATA 3 mutation
- Sanjad-Sakati or Kenny-Caffey syndromes - TBCE mutation
- Mutations of the calcium-sensing receptor (CaSR) and related proteins (autosomal dominant hypocalcemia)
- Mutations interfering with parathyroid gland development (X-linked), GCM1 mutation
- Mitochondrial disorders (eg, MELAS Syndrome, Kearns Sayre syndrome, mitochondrial trifunctional protein deficiency)
What are autoimmune causes of Impaired synthesis or secretion of PTH?
- Autoimmune polyglandular syndrome type 1 (APS1)
- Parathyroid or thyroid gland surgery
- Infiltration of parathyroid gland (eg, iron overload)
How is Severe symptomatic treatment of hypocalcaemia managed?
- IV 10% Calcium Gluconate @ 0.11 mmol/kg (0.5 mls/kg – max 20 mls) over 10 minutes
- Continuous IV infusion of Calcium Gluconate @ 0.1 mmol/kg (Max 8.8 mmols) over 24 hours
- Oral Calcium Supplements @ 0.2 mmol/kg (Max 10 mmols or 400 mg Ca) 4 x a day
How is Hypo & Pseudohypoparathyroidism treated?
- Aim to keep serum Ca between 2.0 to 2.2 mmol/l
- Oral Calcium supplements
- Active preparations of Vitamin D: Alfacalcidiol @ 50 ng/kg (Max ~2µg/day)
- Monitoring: Urine Ca/Cr (<0.7), Renal Ultrasound Scan-yearly
What are symptoms of Hypercalcaemia?
- Gastrointestinal symptoms: Nausea, anorexia, vomiting & weight loss
- Renal symptoms: Nephrogenic diabetes like picture – dehydration. Nephrocalcinosis.
- CNS & Musculoskeletal symptoms: Lethargy & muscle weakness. Older children may present with psychiatric symptoms.
- Cardiac effects: Hypertension. Short QT interval
What are causes of High PTH related Hypercalcaemia?
-
Neonatal Severe Primary Hyperparathyroidism (AR inactivating mutations of the CaSR)
- Decreased urinary calcium
-
Parathyroid adenoma (Sporadic, Familial (MEN, hyperparathyroid jaw sd)
- Increased urinary calcium
- Parathyroid carcinoma
What are causes of Normal PTH related Hypercalcaemia?
Familial Hypocalciuric Hypercalcaemia – inactivating mutations of CaSR
- Decreased Urinary Calcium
What are causes of Low PTH related Hypercalcaemia?
- Williams syndrome
- Idiopathic hypercalcaemia of infancy
- Vitamin D toxicity
- Increased 1,25(OH)D2 synthesis
- Subcutaneous fat necrosis
-
Sarcoidosis, tuberculosis
- Increased urinary calcium
- Increased calcium absorption
- Increased 1,25(OH)D2 synthesis
How is Hypercalcaemia managed?
- Hyperhydration
- Low Calcium & Vitamin D free diet
- Corticosteroids
- Pamidronate infusion (x2)
- Bisphosphonates
- Cinacalcet
- Parathroidectomy
- Monitoring Urine Ca/Cr (<0.56) and renal ultrasound scan
What is Osteogenesis Imperfecta?
- OI is a condition of extreme fragility of the bones causing recurrent low-trauma fractures
- OI is the most common cause of primary osteoporosis
- Osteoporosis is defined as reduced bone mass for body size and presence of significant fractures
What are features of Type 1 Collagen?
- Predominant collagen in bones
- Type 1 collagen is formed by two α 1 chains and one α 2 chain
- α 1 chain is coded by COL1A1 gene, α 2 chains are coded by COL1A2 gene
- Mutations in the gene leads to OI
What is the classification system of Osteogenesis Imperfecta?
Sillence Classification
What is the Sillence Classification of Osteogenesis Imperfecta?
- Type I: Mild with blue/grey sclera (autosomal dominant)
- Type II: Usually lethal (autosomal dominant)
- Type III: multiple fractures with deformities of limbs & spine
-
Type IV: Intermediate between types I & III (autosomal dominant)
- Iva: Normal teeth
- IVb: Dentinogenesis Imperfecta
What are Signs and Symptoms of Osteogenesis Imperfecta?
- Thin & smooth skin
- Blue/grey sclera
- Wormian bones
- Dentinogenesis imperfecta
- Presenile deafness
What is the investigation for Oesteogenesis Imperfecta?
- No definitive biochemical or imaging marker for OI
- X-ray
- Bone Mineral Density Scans
- MUTATIONS IN GENES CODING FOR TYPE I COLLAGEN: Molecular biology tests to look for mutations in COL1A1 and COL1A2 genes responsible for production of Type 1 collagen
What does the X-ray show for Osteogenesis Imperfecta?
- Generalised osteoporosis of axial and appendicular skeleton
- Milder forms - Thin, slender bones with thin cortices
- Severe forms - Broad, shortened long bones with multiple fractures complicated by hyperplastic callous formation
- Skull X-ray for Wormian bones
- Vertebral X-ray for crush fractures
How do Bisphosphonates act?
Bisphosphonates are taken up by osteoclasts and cause apoptosis
- Net effect: Reduced bone resorption and an increase in bone mineral density
- Bisphosphonates, synthetic analogues of inorganic pyrophosphate, potently inhibit skeletal resorption by suppressing the recruitment and activity of osteoclasts and shortening their life span
What are side effects of Bisphosphonates?
- Acute phase reaction at the first IV infusion (influenza-like symptoms); Rx with paracetamol or ibuprofen
- Hypocalcaemia (uncommon problem) after ~ 72 hrs from infusion
- Bone pain: ↓ with subsequent use
- Transient iritis and/or uveitis (uncommon)
