Familial hypocalciuric hypercalcemia differential diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ajay Gade MD[2]]

Overview

Familial hypocalciuric hypercalcemia must be differentiated from primary hyperparathyroidism to avoid unnecessary parathyroidectomy. Calcium creatinine clearance ratio is used to differentiate FHH from primary hyperparathyroidism, ratio < 0.01 suggestive of FHH and > 0.01 suggestive of primary hyperparathyroidism. This genetic test of the CaSR gene is the gold standard. If negative, genetic testing for mutation of G alpha 11 and AP2S1 can diagnose FHH2 and FHH3, respectively.

Differentiating Familial Hypocalciuric Hypercalcemia From Other Diseases

Familial hypocalciuric hypercalcemia should be differentiated from other causes of hypercalcemia. Causes of hypercalcemia include:

Parathyroid-related	Non-parathyroid related	Medication-induced	Other
Primary hyperparathyroidism Secondary hyperparathyroidism Tertiary hyperparathyroidism	Malignancy Humoral hypercalcemia of malignancy Osteolytic tumors Production of calcitriol by tumors Ectopic parathyroid hormone production	Thiazide diuretics Lithium	Nutritional Milk-alkali syndrome Vitamin D toxicity Granulomatous disease Sarcoidosis Surgical Immobilization

Differential diagnosis of Familial Hypocalciuric Hypercalcemia on the basis of hypercalcemia
Disorder		Mechanism of hypercalcemia	Clinical features	Laboratory findings				Imaging & diagnostic modalities
				PTH	Calcium	Phosphate	Other findings
Familial hypocalciuric hypercalcemia		This is a genetic disorder caused by mutation in calcium-sensing receptor gene.	This is a benign condition and does not require treatment.	Normal/↑	Normal/↑		--	Calcium/creatinine clearance ratio
Hyperparathyroidism	Primary hyperparathyroidism	Increase in secretion of parathyroid hormone (PTH) from a primary process in the parathyroid gland. Parathyroid hormone causes an increase in serum calcium.	Usually asymptomatic Hypercalcemia detected on routine biochemical panel	↑	↑	↓/Normal	Normal/↑ calcitriol	Findings of bone resorption: X-ray DEXA Preoperative localization of hyperfunctioning parathyroid gland: Non-Invasive Tc-99m sestamibi scintigraphy Neck ultrasound 4D-CT SPET(P-SPECT) PET MRI Invasive: Super sensitive venous sampling Selective arteriography Angiography Predicting post-operative success: Intraoperative parathyroid hormone monitoring
	Secondary hyperparathyroidism	Increase in secretion of parathyroid hormone (PTH) from a secondary process. Parathyroid hormone causes an increase in serum calcium.	May present with history of: Chronic renal failure Vitamin D deficiency	↑	↓/Normal	↑	--
	Tertiary hyperparathyroidism	Continuous elevation of parathyroid hormone (PTH) even after successful treatment of the secondary cause of elevated parathyroid hormone. Parathyroid hormone causes an increase in serum calcium.	Usually present with a history of: Kidney transplant Usually hyperplasia of all four parathyroid glands	↑	↑	↑	--
Malignancy	Humoral hypercalcemia of malignancy	Tumor cells secrete parathyroidhormone-related protein (PTHrP) which acts similarly to parathyroid hormone.	Most common cause of malignancy related hypercalcemia. Usually present in solid tumors	--	↑	↓/Normal	↑ PTHrP Normal/↑ calcitriol	Chest X-ray CT scan MRI
	Osteolytic tumors	Multiple myeloma produces osteolysis of bones causing hypercalcemia. Osteolytic metastasis can cause bone resorption causing hypercalcemia.	Most commonly present in multiple myeloma and breast cancer.	↓	↑	--	--	DXA X-ray Mammography Ultrasound ESR Serum protein electrophoresis
	Production of calcitriol	Some tumors have ectopic activity of 1-alpha-hydroxylase leading to increased production of calcitriol. Calcitriol is active form of vitamin D and causes hypercalcemia.	Most commonly present in lymphomas and in some ovarian germ cell tumors.	--	↑	--	↑ Calcitriol	CT scan MRI
	Ectopic parathyroid hormone	Some tumors leads to ectopic production of parathyroid hormone.	In rare instances, small cell carcinoma of lung may produce hypercalcemia by this process.	↑	↑	↓/Normal	Normal/↑ Calcitriol	Chest X-ray CT scan MRI
Medication induced	Lithium	Lithium lowers urinary calcium and causes hypercalcemia. Lithium has been reported to cause an increase in parathyroid hormones and enlargement of parathyroid gland after weeks to months of therapy.	History of mood disorder	↑	↑	--	--	Lithium levels
	Thiazide diuretics	Thiazide diuretics lowers urinary calcium excretion and causes hypercalcemia	History of cardiac disorder Rarely causes hypercalcemia	--	↑	--	--	--
Nutritional	Milk-alkali syndrome	Hypercalcemia caused by high intake of calcium carbonate	History of High milk intake Excess calcium intake for treating: Osteoporosis Dyspepsia May lead to metabolic alkalosis and renal insufficiency.	--	↑	--	--	Renal function test
	Vitamin D toxicity	Excess vitamin D causes increased absorption of calcium from intestine causing hypercalcemia.	History of: Excess intake vitamin D Excess milk fortified with vitamin D Topical application of vitamin D analogue calcipotriol	--	↑	--	↑ Vitamin D (calcidiol and/or calcitriol)	--
Granulomatous disease	Sarcoidosis	Hypercalcemia is caused by endogenous production of calcitriol by disease-activated macrophages.	History of: Cough Dyspnea Chest pain Tiredness or weakness Fever Weight loss	--	↑	--	↑ Calcitriol ↑ ACE levels	Chest X-ray Biopsy