Sections View Full Chapter Figures Tables Videos Full Chapter Figures Tables Videos Supplementary Content + Print Section ++ For further information, see CMDT Part 26-14: Hyperparathyroidism + Key Features Print Section ++ ++ Essentials of Diagnosis ++ Frequently detected incidentally by routine blood testing Kidney stones, polyuria, hypertension, constipation, mental changes Bone pain Parathyroid hormone (PTH), serum and urine calcium, and urine phosphate elevated Serum phosphate low to normal Alkaline phosphatase normal to elevated ++ General Considerations ++ Primary hyperparathyroidism PTH hypersecretion usually due to parathyroid adenoma, less commonly, to hyperplasia or carcinoma (rare) If age < 30 years, higher incidence of multiglandular disease (36%) and parathyroid carcinoma (5%) responsible for hyperparathyroidism Secondary or tertiary hyperparathyroidism Chronic kidney disease (CKD): hyperphosphatemia and diminished renal vitamin D production decrease serum ionized calcium, thus stimulating the parathyroids Renal osteodystrophy: bone disease of secondary hyperparathyroidism and CKD Multiple endocrine neoplasia (MEN) Hyperparathyroidism is familial in about 10% of cases; parathyroid hyperplasia may arise in MEN types 1, 2A, and 2B In MEN 1, multiglandular hyperparathyroidism is usually the initial manifestation and ultimately occurs in over 90% of affected individuals Hyperparathyroidism in MEN 2A is less frequent than in MEN 1 and is usually milder Hyperparathyroidism-jaw tumor syndrome is autosomal dominant and associated with recurrent parathyroid adenomas (5% malignant), benign jaw tumors and renal cysts ++ Demographics ++ Most common cause of hypercalcemia, with a prevalence of 1000–4000 cases per 1 million persons Occurs at all ages but most commonly in the seventh decade and in women (74%) Before age 45, the prevalence is similar in men and women More prevalent in blacks, followed by whites, then other races + Clinical Findings Print Section ++ ++ Symptoms and Signs ++ Frequently asymptomatic Symptoms include problems with “bones, stones, abdominal groans, psychic moans, fatigue overtones” Bone pain and arthralgias are common Severe, chronic hyperparathyroidism can cause diffuse demineralization, pathologic fractures, and cystic bone lesions throughout the skeleton, a condition known as osteitis fibrosa cystica Postmenopausal women are prone to asymptomatic vertebral fractures Mild hypercalcemia May be asymptomatic Some patients can have significant symptoms, particularly depression, constipation, and bone and joint pain Hypercalcemia in patients with hyperparathyroidism usually causes a variety of manifestations whose severity is not entirely predictable by the level of serum calcium or PTH Paresthesias, muscular weakness, and diminished deep tendon reflexes Malaise, fatigue, intellectual weariness, depression, increased sleep requirement, progressing to cognitive impairment, disorientation, psychosis, or stupor Hypertension; ECG findings of prolonged P-R interval, shortened Q-T interval, sensitivity to arrhythmic effects of digitalis, bradyarrhythmias, heart block, asystole Polyuria and polydipsia, caused by hypercalcemia-induced nephrogenic diabetes insipidus Anorexia, nausea, vomiting, abdominal pain, weight loss, constipation, and obstipation; pancreatitis (in 3%) Pruritus may be present Calcium may precipitate in the corneas ("band keratopathy"), in extravascular tissues, and small arteries, causing small vessel thrombosis and skin necrosis (calciphylaxis) ++ Differential Diagnosis ++ Artefactual hypercalcemia Hypercalcemia of malignancy Plasma cell myeloma Vitamin D intoxication Granulomatous diseases (sarcoidosis, tuberculosis) Familial benign hypocalciuric hypercalcemia Immobilization Hyperthyroidism Vitamin D deficiency (serum 25-OH vitamin D < 20 ng/mL) can cause high serum PTH with normal serum calcium High-dose corticosteroid therapy in patients taking thiazide diuretics Hypercalcemia due to other conditions (eg, milk-alkali syndrome) + Diagnosis Print Section ++ ++ Laboratory Tests ++ In hyperparathyroidism, hallmark finding is serum adjusted total calcium > 10.5 mg/dL Elevated or high-normal PTH confirms the diagnosis; immunoradiometric assay (IRMA) for PTH is most specific and sensitive Serum phosphate is often < 2.5 mg/dL Serum phosphate is high in secondary hyperparathyroidism (CKD) Serum ionized calcium levels are elevated (above 1.36 mmol/L) Urine calcium excretion is high or normal (100–300 mg/day (25–75 mmol/day), but low for the degree of hypercalcemia Urine phosphate is high despite low to low normal serum phosphate Serum alkaline phosphatase is elevated only if bone disease present A serum calcium:phosphate (Ca/P) ratio above 2.5 (mg/dL) or above 2.17 (mmol/L) helps confirm the diagnosis of primary hyperparathyroidism Plasma chloride and uric acid may be elevated Screen for familial benign hypocalciuric hypercalcemia with 24-h urine for calcium and creatinine. Discontinue thiazide diuretics prior to urine collection ++ Imaging Studies ++ Ultrasound of the neck Should be performed with a high-resolution transducer (5–15 MHz) and should scan the neck from the mandible to the superior mediastinum in an effort to locate ectopic parathyroid adenomas Has a sensitivity of 79% for single adenomas but only 35% for multiglandular disease Sestamibi scintigraphy can help locate parathyroid adenomas preoperatively CT and MRI are not usually required prior to a first neck surgery However, 4-dimensional CT has been developed and is useful for preoperative imaging in patients who have had prior neck surgery and in those with ectopic glands MRI may also be useful for repeat neck operations and when ectopic parathyroid glands are suspected; it does not deliver radiation and shows better soft tissue contrast than CT Noncontrast-enhanced CT scanning of the kidneys is recommended for all patients to determine whether calcium-containing stones are present 18F-flurocholine PET/MRI Useful scan for patients with primary hyperparathyroidism and negative or discordant localization imaging on neck ultrasound and sestamibi scanning A small study showed the sensitivity of this scan to be 90% with a 100% positive predictive value Bone radiographs Usually normal and not required However, may show demineralization, subperiosteal bone resorption, loss of lamina dura of the teeth, cysts throughout skeleton, mottling of skull, or pathologic fractures Articular cartilage calcification (chondrocalcinosis) is sometimes found In renal osteodystrophy, bone radiographs may show Ectopic calcifications around joints or soft tissue Osteopenia Osteitis fibrosa Osteosclerosis Bone densitometry of wrist, hip, and spine may reveal low bone mineral density ++ Diagnostic Studies ++ Recommendations for genetic testing Documented primary hyperparathyroidism Age younger than age 40 Presence of multiglandular disease Family history of hyperparathyroidism + Treatment Print Section ++ ++ Medications ++ Bisphosphonates Pamidronate, 30–90 mg (in 0.9% saline) intravenously over 2–4 hours Zoledronate, 5 mg intravenously over 15–20 minutes; it is quite effective but also very expensive Oral bisphosphonates, such as alendronate, are not effective for treating the hypercalcemia or hypercalciuria of hyperparathyroidism However, oral alendronate has been shown to improve bone mineral density in the lumbar spine and hip (not distal radius) and may be used for asymptomatic patients with hyperparathyroidism who have a low bone mineral density Cinacalcet hydrochloride (calcium sensing receptor activator [CaSR]) Given to patients with severe hypercalcemia due to parathyroid carcinoma Initial dose is 30 mg twice daily orally Dose is increased progressively to 60 mg twice daily, then 90 mg twice daily, then to a maximum of 90 mg every 6–8 hours Usually well tolerated but may cause nausea and vomiting, which are usually transient Etelcalcetide (CaSR) Activates the parathyroid glands' CaSR Reduces hypercalcemia in dialysis patients Given intravenously at the end of hemodialysis sessions, thereby avoiding the gastrointestinal side effects of cinacalcet Vitamin D replacement, 800–2000 units daily for patients with vitamin D deficiency Calcitriol Used in secondary and tertiary hyperparathyroidism associated with azotemia Given orally or intravenously after dialysis, suppresses parathyroid hyperplasia of CKD For patients with near-normal serum calcium levels, it is given orally in starting at doses of 0.25 mcg on alternate days or daily Doxercalciferol Used in secondary or tertiary hyperparathyroidism associated with azotemia Administer intravenously three times weekly during hemodialysis to patients with secondary hyperparathyroidism due to CKD Starting dose: 4 mcg three times weekly to maximum dose of 18 mcg three times weekly Alternatively, administered orally three times weekly at dialysis, starting with 10 mcg at each dialysis to a maximum of 60 mcg/wk Denosumab Used in severe hypercalcemia due to parathyroid carcinoma Dose of 120 mcg subcutaneously monthly may be effective However, high doses increase the risk of jaw osteonecrosis and serious infections Paricalcitol Used in secondary or tertiary hyperparathyroidism associated with azotemia Administer intravenously during dialysis three times weekly in starting doses of 0.04–0.1 mcg/kg body weight to a maximum dose of 0.24 mcg/kg three times weekly Estrogen replacement, reduces hypercalcemia slightly in postmenopausal women with hyperparathyroidism Oral raloxifene 60 mg/day May be given to postmenopausal women with hyperparathyroidism Reduces serum calcium an average of 0.4 mg/dL (0.1 mmol/L), while having an anti-estrogenic effect on breast tissue β-Blockers, such as propranolol, may prevent adverse cardiac effects of hypercalcemia ++ Surgery ++ Parathyroidectomy is indicated for patients with symptomatic hyperparathyroidism, nephrolithiasis, or bone disease Consider parathyroidectomy for asymptomatic patients if Serum calcium 1 mg/dL (0.25 mmol/L) above upper limit of normal if urine calcium excretion > 50 mg/24 h (off thiazide diuretics) Urine calcium > 400 mg/24 h (> 10 mmol/day) Creatinine clearance < 60 mL/min Nephrolithiasis or nephrocalcinosis Cortical bone density (wrist, hip) indicating osteoporosis (T score < –2.5) or previous fragility bone fracture Age < 50 years Difficulty ensuring medical follow-up Pregnancy (second trimester) Minimally invasive parathyroid surgery usually sufficient if adenoma identified preoperatively Subtotal parathyroidectomy (3½ glands removed) is done for patients with resistant parathyroid hyperplasia ++ Therapeutic Procedures ++ Patients with mild, asymptomatic hyperparathyroidism are advised to Keep active Drink adequate fluids Avoid immobilization Avoid thiazides, large doses of vitamin A, calcium-containing antacids or supplements + Outcome Print Section ++ ++ Follow-Up ++ In mild, asymptomatic hyperparathyroidism, check Serum calcium and albumin twice yearly Kidney function and urine calcium once yearly Bone density (distal radius) every 2 years Postoperatively Keep patients hospitalized overnight Monitor serum calcium and PTH Oral calcium and calcitriol, 0.25 mg/day orally for 2 weeks, helps prevent tetany Treat symptomatic hypocalcemia with oral calcium carbonate and calcitriol, 0.25–1.0 mcg once daily orally Secondary hyperparathyroidism occurs in ∼12% and is treated with calcium and vitamin D, usually for 3–6 months Hyperthyroidism immediately following parathyroid surgery may require short-term propranolol ++ Complications ++ Pathologic long bone fractures Urinary tract infection due to obstruction by stones Confusion, acute kidney injury, and soft tissue calcinosis from rapidly rising serum calcium Renal osteodystrophy from hyperphosphatemia Peptic ulcer disease Pancreatitis Pseudogout before or after surgery Disseminated calcification in skin, soft tissues, and arteries (calciphylaxis) can result in gangrene, arrhythmias, and respiratory failure Nephrolithiasis, hyperemesis, pancreatitis, muscle weakness, cognitive changes, and hypercalcemic crisis seen in some pregnant women About 80% of fetuses experience complications of maternal hyperparathyroidism, including Fetal demise Preterm delivery Low birth weight Postpartum neonatal tetany Permanent hypoparathyroidism ++ Prognosis ++ Asymptomatic mild hypercalcemia Remains stable with follow-up However, worsening hypercalcemia, hypercalciuria and reductions in cortical bone mineral density may develop in one-third of patients Must be monitored and treated with oral hydration and mobilization Resection of sporadic parathyroid adenoma generally results in cure Despite severe cyst formation or fracture, bones heal if parathyroid tumor removed Occurrence of pancreatitis increases mortality rate Significant kidney damage may progress even after adenoma removal Parathyroid carcinoma Associated with 5- and 10-year survival rates of 78% and 49%, respectively A better prognosis is associated with clear surgical margins and no detectable metastases postoperatively Positive surgical margins or metastases predict a very poor 5-year survival Prognosis is also poorer for nonfunctioning parathyroid carcinoma and those tumors that carry a CDC73 mutation, loss of fibromin, or loss of CaSR expression Repeat surgical debulking procedures may improve survival Aggressive medical management can also prolong life ++ When to Refer ++ Refer to parathyroid surgeon for parathyroidectomy ++ When to Admit ++ Patients with severe hypercalcemia for intravenous hydration + References Print Section ++ + +Babwah F et al. Normocalcaemic primary hyperparathyroidism: a pragmatic approach. J Clin Pathol. 2018 Apr;71(4):291–7. [PubMed: 29437827] + +Bilezikian JP et al. Hyperparathyroidism. Lancet. 2018 Jan 13;391(10116):168–78. [PubMed: 28923463] + +Block GA et al. Effect of etelcalcetide vs cinacalcet on serum parathyroid hormone in patients receiving hemodialysis with secondary hyperparathyroidism: a randomized clinical trial. JAMA. 2017 Jan 10;317(2):156–64. [PubMed: 28097356] + +Cetani F et al. Update on parathyroid carcinoma. J Endocrinol Invest. 2016 Jun;39(6):595–606. [PubMed: 27001435] + +Hirsch D et al. Pregnancy outcomes in women with primary hyperparathyroidism. J Clin Endocrinol Metab. 2015 May;100(5):2115–22. [PubMed: 25751112] + +Khan AA et al. Primary hyperparathyroidism: review and recommendations on evaluation, diagnosis, and management. A Canadian and international consensus. Osteoporos Int. 2017 Jan;28(1):1–19. [PubMed: 27613721] + +Madeo B et al. Serum calcium to phosphorous (Ca/P) ratio is a simple, inexpensive, and accurate tool in the diagnosis of primary hyperparathyroidism. JBMR Plus. 2017 Nov 2;2(2):109–17. [PubMed: 30283895] + +Marx SJ. Calcimimetic use in familial hypocalciuric hypercalcemia – a perspective in endocrinology. J Clin Endocrinol Metab. 2017 Nov;102(11):3933–6. [PubMed: 28945857] + +Marx SJ. Familial hypocalciuric hypercalcemia as an atypical form of primary hyperparathyroidism. J Bone Miner Res. 2018 Jan;33(1):27–31. [PubMed: 29115694] + +Stephen AE et al. Indications for Surgical management of hyperparathyroidism: a review. JAMA Surg. 2017 Sep 1;152(9):878–82. [PubMed: 28658490] + +Wilhelm SM et al. The American Association of Endocrine Surgeons guidelines for definitive management of primary hyperparathyroidism. JAMA Surg. 2016 Oct 1;151(10):959–68. [PubMed: 27532368]