Ca, parathyroid and metabolic bone disorders

Question 1

Primary hyperparathyroidism

Answer 1

Excess PTH due to a disorder of the parathyroid gland itself

• most common cause of outpatient hypercalcemia
• 1/1000, peak in 5-6th decades
• female:male = 4:1

Pathology

• 85% single adenoma
• 10% hyperplasia – sporadic, MEN1, MEN2, hereditary jaw tumor hyperparathyroidism
• 5% ectopic production
• 1% cancer

Question 2

Primary hyperparathyroidism - Signs + symptoms

Answer 2

Range from none to life threatening depending on the degree of elevation of ionized calcium and duration of hypercalcemia

o Usually see clinical manifestations when ca >12 mg/dL (normal 8.5-10.5)
o Asymptomatic – most
o Bones –> osteoporosis, pain, fracture
o Stones –> kidney stones, polyuria, azotemia
o Moans –> neuromuscular = muscle weakness + fatigue; joints = chondrocalcinosis
o Groans –> GI = constipation, anorexia, vomiting
o Psychological overtones –> mild = depression, severe = obtundation + coma
o Other –> short QT on ECG; eye = band keratopathy (calcium deposits around the eye)

Question 3

Autosomal dominant primary hyperparathyroidism

Answer 3

Hyperplasia –> multiple glands affected

• MEN1 or 2
• MEN1 usually presents with hyper PTH

Question 4

Diagnosis of primary hyperparathyroidism

Answer 4

Required for diagnosis

• Elevated serum Ca
• Elevated or inappropriately normal PTH (should be low when high ca)
• Elevated or normal urine calcium - never low

Also may be associated but not required for diagnosis

• Elevated calcitriol
• Low normal or low serum phorphorous
• Mild hyperchloremic metabolic acidosis

Question 5

Treatment of primary hyperparathyroidism

Answer 5

Asymptomatic/mild - observation

Symptomatic
- Surgery - generally take measurements of iPTH before and after surgery to assure cure
•Sestamibi scan (for localization), US + –> minimally invasive surgery
•Sestamibi scan, US neg –> 4 gland exploration
- Poor surgical candidates  treat medically with scinacalcet (sensipar)

Question 6

Familial hypocalciuric hypercalcemia

Answer 6

o Calcium sensing receptor mutation - autosomal dominant, rare
o Parathyroid glands constantly sensing lack of calcium so continuously release PTH
o Looks exactly like primary hyperparathyroidism except for urine calcium is really low
o Diagnosed by abnormally low Ca/Cr clearance ratio
o Does not require treatment - doesn’t cause symptoms

Question 7

Non-PTH mediated hypercalcemia

Answer 7

PTH suppressed in response to high calcium, indicating normal parathyroid feedback respose

1,25 vit D mediated
o Vit D intoxication
o Granulomatous diseases - e.g. sarcoidosis
o Some lymphomas have 1-hydroxylase function

PTHrP mediated
o Cancer - most common cause of inpatient symptomatic hypercalcemia

Other
o Milk alkali syndrome (seen rarely in patients with mild renal insufficiency and excessive intake of calcium containing antacids) 
o Immobilization 
o Rhabdomyolysis  recovery phase 
o Multiple myeloma  cytokine mediated

Question 8

Treatment of hypercalcemia

Answer 8

Treat underlying cause
o Primary hyperparathyroidism -surgery
o Cancer - surgery, chemo, radiation
o Granulomatous disease - glucocorticoids

Acute treatment while awaiting diagnosis
o Saline - delivering a salt load to the kidneys helps to excrete additional calcium
o Loop diuretics - inhibit calcium reabsorption from the kidneys
o IV bisphosphonates - BEST; zoledronic acid, inhibits bone breakdown and correct hyperCa
o Calcitonin 4 IU/kg q12 hours - effective initially but loses effectiveness

Question 9

Secondary hyperparathyroidism

Answer 9

Diagnosis = normal or low calcium + elevated PTH
o Usually due to whole body lack of calcium or excess phosphate

Most common cause = chronic kidney disease, vit D deficiency, hypercalciuria

Complications
o Bone loss – consistently high PTH = bone breakdown
o Vascular calcification –accelerates coronary artery disease + peripheral vascular disease

Treatment – depends on the cause

Question 10

Tertiary hyperparathyroidism

Answer 10

Same as primary but follows previous secondary hyperparathyroidism, usually in CKD
• Pathology changes from hyperplasia (in secondary hyperparathyroidism) to development of monoclonal tumor (adenoma) with autonomy
• Diagnosis
– elevated ca
– elevated PTH or inappropriately normal PTH (should be low when increased ca)

Question 11

Etiology and diagnosis of hypoparathyroidism

Answer 11

Etiology
o Post-operative - thyroidectomy, head/neck surgery
o Autoimmune - polyglandular failure syndrome type 1 = AIRE gene
o Calcium sensing receptor mutation (CASR) = autosomal dominant; activation mutation of calcium sensing receptor - 50% of cases
o Familial isolated
o Congenital absence - e.g. Digeorge syndrome

Diagnosis

• low serum ca
• high phosphate
• low PTH or inappropriately normal PTH (should be elevated if low ca)

Question 12

Signs and symptoms of hypocalcemia

Answer 12

Depend on how low the ca is and for how long
o Tetany – hallmark of hypocalcemia = neuromuscular irritability
—> Circumoral/extremity paresthesias, cramps = seizures, laryngospasm
—> Chvostek sign = tap along facial nerve and see ipsilateral twitching of the mouth
—> Trousseau sign = carpal spasm after elevating BT cuff over systolic BP for 2 minutes
o Mental status – fatigue, anxiety, depression, psychosis
o Intracranial – calcification of basal ganglia, papilledema
o Cardiovascular – prolonged QT, heart failure
o Ocular – cataracts
o Dental – when present in early development, dental hypoplasia, defective enamel

Question 13

Pseudohypoparathyroidism

Answer 13

End organ resistance to PTH

Diagnosis = low serum Ca, elevated phosphate + PTH

Albright hereditary osteodystrophy = hereditary form, autosomal dominant
o Short stature + short 4th/5th metacarpals
o Wide spaced nipples + mental retardataion

Question 14

Vit D disorders

• diagnosis
• causes
• symptoms

Answer 14

Diagnosis = normal or decreased calcium and phosphate + decreased 25(OH)D
– Must be severe to cause hypocalcemia
–Causes
• Lack of dietary intake
• Inadequate sun, fat malabsorption (vit D is fat soluble)
• Anticonvulsants  increase vit D catabolism
• Obesity  vit D is stored in fat
– Mild deficiency  very common
• Normal levels ~30
– Symptoms - if mild = none; if severe = bone pain, fracture
• In childhood  if persistent, bones are soft = rickets

Question 15

Vit D resistance

Answer 15

Hereditary vit D dependent Rickets

• Type 1 - due to 1-apha hydroxylase deficiency
— Responds to treatment with 1,25 vit D

• Type 2 - due to mutations in 1,25 receptor causing true resistance to all it D
—Associated with alopecia

Question 16

Treatment of hypocalcemia

Answer 16

Hypocalcemic crisis
• Symptoms = tetany, laryngospasm, seizures
• Treatment = IV calcium infusion + calcitriol

Mild hypocalcemia = no symptoms, mild circumoral numbness
• Treatment = oral calcium + vit D

Question 17

Developmental bone disorders

Answer 17

Lack of signal transduction = osteoporosis pseudoglioma syndrome
• Mutation in LRP5 –> activates wnt pathway to stimulate bone formation
• Results in childhood osteoporosis + congenital blindness

Defect in extracellular proteins = osteogenesis imperfecta
• Mutation in type 1 collagen genes
• Results in osteoporosis of variable severeity +/- blue sclerae

Question 18

Rickets due to hypophosphatemia

Answer 18

Just as important as calcium to keep the bones hard/mineralized
- Renal phosphate wasting
• Hereditary rickets - e.g. X linked hypophosphatemic rickets
• Fanconi syndrome - renal wasting of phosphate, glucose, amino acids, associated with renal failure
• Oncogenic osteomalacia (FGF23) = benign mesenchymal tumor produces FGF23