hypercalcemia / hyperparathyroidism

Question 1

Causes of hypercalcemia

Answer 1

PTH-mediated
Primary hyperparathyroidism (sporadic)
Familial

• MEN-I and -IIa
• FHH
• Familial isolated hyperparathyroidism

Tertiary hyperparathyroidism (renal failure)
PTH-independent
Hypercalcemia of malignancy

• PTHrp
• Activation of extrarenal 1 alpha-hydroxylase (increased calcitriol)
• Osteolytic bone metastases and local cytokines

Vitamin D intoxication
Chronic granulomatous disorders
Activation of extrarenal 1 alpha-hydroxylase (increased calcitriol)
Medications
Thiazide diuretics
Lithium
Teriparatide
Excessive Vitamin A
Theophylline toxicity
Miscellaneous
Hyperthyroidism
Acromegaly
Pheochromocytoma
Adrenal insufficiency
Immobilization
Parenteral nutrition
Milk alkali syndrome

Question 2

DIAGNOSIS
Measurement of serum calcium
Measurement of PTH

Answer 2

Measurement of serum calcium

• Total Ca X 2 times
• ionized calcium - may be a useful adjunct to diagnosis is in patients with normocalcemic primary hyperparathyroidism. In one series, 12 of 60 patients had a raised serum concentration of ionized calcium in the presence of a normal total serum calcium concentration

Measurement of PTH

Question 3

Causes of secondary hyperparathyroidism

Answer 3

Renal failure

• Impaired calcitriol production
• Hyperphosphatemia

Decreased calcium intake
Calcium malabsorption

• Vitamin D deficiency
• Bariatric surgery
• Celiac disease
• Pancreatic disease (fat malabsorption)

Renal calcium loss

• Idiopathic hypercalciuria
• Loop diuretics

Inhibiton of bone resorption

• Bisphosphonates
• Hungry bone syndrome

Question 4

TESTS TO CONFIRM PRIMARY HYPERPARATHYROIDISM

• Measurement of urinary calcium excretion
• Vitamin D metabolites

Answer 4

FECa:

Ca/Cr clearance ratio = [24 hour Urine Ca x serum Cr] ÷ [serum Ca x 24 hour Urine Cr]

<0.01 in a vitamin D replete individual is highly suggestive of FHH rather than hyperparathyroidism (ratio usually >0.02).

Approximately 40 % of patients with PHPT are hypercalciuric, and most of the remaining patients have normal values. If calcium excretion is low < 200 mg/day (5.0 mmol/day), familial hypocalciuric hypercalcemia (FHH, see above) or hyperparathyroidism with concomitant vitamin D deficiency are possibilities; about 75 percent of affected persons with FHH excrete less than 100 mg of calcium in urine daily.z`

Measurement of vitamin D metabolites is also useful in the following circumstances:

●To differentiate hypervitaminosis D from primary hyperparathyroidism, we typically measure both 1,25-dihydroxyvitamin D and 25(OH)D. (See “Diagnostic approach to hypercalcemia”.)
●To differentiate FHH from mild primary hyperparathyroidism with concomitant vitamin D deficiency in individuals with elevated serum PTH and calcium and normal or low 24-hour urinary calcium excretion, we typically measure 25(OH)D. In the latter patients, urinary calcium excretion increases with vitamin D repletion, thereby distinguishing it from FHH.
●To differentiate secondary hyperparathyroidism due to vitamin D deficiency from normocalcemic primary hyperparathyroidism in patients with elevated PTH and normal serum calcium concentrations, we typically measure 25(OH)D, which is low in the former and normal in the latter.