Snapshot A 55-year-old woman presents to the clinic for an annual well-exam. She has no major complaints besides some constipation over the past week that she attributes to her change in diet. She denies any chest pain, fever, weight changes, abdominal pain, or palpitations. A routine laboratory exam demonstrates hypercalcemia. Introduction Clinical definition disorder characterized by the over secretion of parathyroid hormone (PTH) by 1 or more of the parathyroid glands can be of primary, secondary, or tertiary causes Associated conditions multiple endocrine neoplasia (MEN) 1 and 2A (primary hyperparathyroidism) chronic renal disease (secondary and tertiary hyperparathyroidism) renal osteodystrophy (secondary or tertiary hyperparathyroidism) Serum Ca2+Serum PhosphasteSerum PTHPrimary↑↓↑SecondaryNormal/↓↑↑Tertiary↑↑↑ Epidemiology Demographics occurs in 0.1% of the population and 90% of cases result from a single adenoma Risk factors severe, prolonged calcium or vitamin D deficiency menopause neck radiation lithium use ETIOLOGY Pathogenesis PTH leads to activation of osteoclasts leading to increased Ca2+ and phosphate reabsorption at the bone increased reabsorption of Ca2+ in the distal convoluted tubule at the kidney stimulation of kidney 1α-hydroxylase in the proximal convoluted tubule to increase calcitriol production primary hyperparathyroidism most commonly results from parathyroid adenoma or hyperplasia associated with osteitis fibrosa cystica high osteoclast activity at bone resulting in cystic bone spaces with brown fibrous tissue commonly occurs at the jaw secondary hyperparathyroidism secondary parathyroid hyperplasia as a result of low Ca2+ absorption and/or high phosphate levels often in association with chronic renal disease (e.g., hyperphosphatemia and hypovitaminosis D leading to hypocalcemia) other conditions include severe calcium or vitamin D deficiency tertiary hyperparathyroidism dysregulation of parathyroid glands following chronic renal disease will secrete PTH regardless of Ca2+ levels Presentation Symptoms asymptomatic (most common) weakness kidney stones (“stones”) bone pain (“bones”) constipation (“groans”) abdominal/flank pain depression (“psychiatric overtones”) uncommon cause of secondary hypertension Physical exam hypertension imaging Bone mineral density test dual energy X-ray absorptiometry (DEXA) is the most common test to measure bone mineral density allows for measurement skeletal involvement and guides management Computed tomography (CT) abdominal CT may be indicated to determine if kidney stones or other abnormalities are present Radiograph cystic bone spaces (“salt and pepper”) most common at the skull loss of phalange bone mass with increased concavity Sestamibi parathyroid scan allows for visualization of the parathyroid glands indicated if surgery is expected Studies Diagnostic testing diagnostic approach patients often present asymptomatically and the disease is often discovered through either routine blood tests or tests order for another condition studies serum calcium test best initial test primary hyperparathyroidism hypercalcemia secondary/tertiary hyperparathyroidism hypocalcemia/normocalcemia serum PTH best initial test levels will be elevated in all forms of hyperparathyroidism 24-hour urinary calcium routinely measured in patients to assess risk of renal complications hypercalciuria/normocalciuria serum 25-hydroxyvitamin D helps in differentiating from FHH guides management genetic testing may be indicated in patients suspected of MEN 1 or MEN 2A Differential Paraneoplastic syndrome (e.g., squamous cell cancer of the lung) distinguishing factors serum PTH levels will be low due to negative feedback Familial hypocalciuric hypercalcemia (FHH) distinguishing factors urine calcium will be low Treatment Acute hypercalcemia IV fluids loop diuretics Asymptomatic patients first-line observation with follow-up second-line surgical intervention indicated in select patients with abnormal studies indicating skeletal and renal damage Symptomatic patients (e.g., nephrolithiasis) first-line parathyroid surgery is the only definitive therapy complications include post-operative hypocalcemia (e.g., numbness, tingling, and muscle cramps) treat with IV calcium gluconate second-line cinacalcet indicated in patients who are unable to have surgery decreases PTH levels by sensitizing Ca2+ sening receptors at the parathyroid gland Complications Peptic ulcer disease ↑ gastrin production stimulated by ↑ Ca2+ Acute pancreatitis ↑ lipase activity stimulated by ↑ Ca2+ CNS dysfunction anxiety, confusion, and coma result of metastatic calcification of the brain