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There are three types of hyperparathyroidism and should be differentiated between each other. Hyperparathyroidism should be differeniated from other causes of hypercalcemia. Causes of hypercalcemia include:

• Parathyroid related
  • Primary hyperparathyroidism
    • Typical primary hyperparathyroidism
    • Familial hypocalciuric hypercalcemia
  • Secondary hyperparathyroidism
  • Tertiary hyperparathyroidism
• Non-parathyroid related
  • Malignancy
    • Para-neoplastic syndrome: Parathyroid hormone related peptide
    • Hypercalcemia due to bone destruction
  • Medication induced
    • Thiazide diuretics
    • Lithium
  • Nutritional
    • Milk alkali syndrome
    • Vitamin D toxicity
  • Granulomatous disease
    • Sarcoidosis
  • Surgical
    • Immobilization

Hypercalcemia

Related to Parathyroid gland

Unrelated to parathyroid gland

Primary hyperparathyroidism

Secondary hyperparathyroidism

Tertiary hyperparathyroidism

Typical primary hyperparathyroidism

Familial hypocalciuric hypercalcemia

Malignancy

Medication induced

Nutritional

Granulomatous disease

Surgical

Para-neoplastic syndrome: Parathyroid hormone related peptide

Metaplasia: Hypercalcemia due to bone destruction

Thiazide diuretics

Lithium

Milk alkali syndrome

Vitamin D toxicity

Sarcoidosis

Immobilization

Differential diagnosis

Differential diagnosis of hyperparathyroidism on the basis of hypercalcemia
Disorder		Mechanism of hypercalcemia	Clinical features	Laboratory findings	Imaging & diagnostic modalities
Hyperparathyroidism	Primary hyperparathyroidism	Increase in secretion of parathyroid hormone (PTH) from a primary process in parathyroid gland. Parathyroid hormone causes increase in serum calcium.	Usually asymptomatic Hypercalcemia detected on routine biochemical panel	↑ PTH ↑ Calcium ↓/N Phosphate N/↑ calcitriol	Findings of bone resorption: X-ray DXA 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 increase in serum calcium.	May present with history of: Chronic renal failure Vitamin D deficiency	↑ PTH ↓/N Calcium ↑ Phosphate
	Tertiary hyperparathyroidism	Continuous elevation of parathyroid hormone (PTH) even after successful treatment of the secondary cause of elevated parathyroid hormone. Parathyroid hormone causes increase in serum calcium.	Usually present with history of: Kidney transplant Usually hyperplasia of all four parathyroid glands	↑ PTH ↑ Calcium ↑ Phosphate
Familial hypocalciuric hypercalcemia		style="background: #DCDCDC;" This is a genetic disorder caused my mutation in calcium-sensing receptor gene.	style="background: #DCDCDC;" This is a benign condition and does not require treatment.	style="background: #DCDCDC;" N/↑ PTH N/↑ Calcium	style="background: #DCDCDC;" Calcium/creatinine clearance ratio
Malignancy	Humoral hypercalcemia of malignancy	Tumor cells secretes parathyroid hormone related protein (PTHrP) which has similar action as parathyroid hormone.	Most common cause of malignancy related hypercalcemia. Usually present in solid tumors	↑ PTHrP ↑ Calcium ↓/N Phosphate N/↑ 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.	↓ PTH ↑ Calcium	DXA X-ray Mammography Ultrasound ESR Serum protein electrophoresis
	Production of calcitirol	Some tumors has 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.	↑ Calcium ↑ 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.	↑ PTH ↑ Calcium ↓/N Phosphate N/↑ 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 if parathyroid gland after weeks to months of therapy.	History of mood disorder	↑ PTH ↑ Calcium	Lithium levels
	Thiazide diuretics	Thiazide diuretics lowers urinary calcium excretion and causes hypercalcemia	History of cardiac disorder Rarely causes hypercalcemia	↑ Calcium	--
Nutritional	Milk-alkali syndrome	Hypercalcemia is be 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.	↑ Calcium	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 analogue calcipotriol	↑ Calcium ↑ Vitamin D (calcidiol and/or calcitriol)	--
Granulomatous disease	Sarcoidosis	Hypercalcemia is causes by endogeous production of calcitriol by disease-activated macrophages.	History of: Cough Dyspnea Chest pain Tiredness or weakness Fever Weight loss	↑ Calcium ↑ Calcitriol ↑ ACE levels	Chest X-ray Biopsy