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hyperparathyroidism

Etiology: 1) primary hyperparathyroidism a) most common cause of hypercalcemia in ambulatory patients [17] b) hyperfunctioning solitary parathyroid adenoma (80%) d) parathyroid carcinoma d) multiple endocrine neoplasia-1 (MEN1) - hyperparathyoidism is the most common manifestation of MEN1 e) multiple endocrine neoplasia-2A (MEN2A) f) hypercalcemia in ambulatory patient taking thiazide diuretic [17] 2) secondary hyperparathyroidism a) renal failure is associated with a high phosphorus & low calcium & stimulates PTH production b) diminished Ca+2 absorption stimulates PTH secretion - vitamin D deficiency - malabsorption syndromes 3) tertiary hyperparathyroidism a) in renal failure, PTH secretion may become independent of serum Ca+2 b) ectopic secretion of PTH by non-parathyroid tumors (rare) 4) risk factor - low calcium diet may induce production of PTH, thus promote formation of parathyroid adenomas [9] Epidemiology: 1) 2-4 times more common in women than men 2) increased incidence after age 50 3) incidence of 30/100,000 in USA 4) most common cause of hypercalcemia in outpatients Genetics: - familial forms associated with mutations in parafibromin gene History: - psychiatric disease, lithium carbonate use - thiazide diuretic use - calcium supplementation, vitamin D supplementation Clinical manifestations: 1) often asymptomatic, detected during routine laboratory screening 2) general: weakness, fatigue 3) musculoskeletal: a) bone tenderness/pain b) arthralgia/ joint effusion c) soft tissue calcification d) osteitis fibrosa cystica (uncommon) e) osteopenia, osteoporosis 4) neurologic: memory impairment, confusion, depression 5) GI: nausea/vomiting, peptic ulcer, constipation 6) GU: renal colic (nephrolithiasis), polyuria 7) abdominal pain 8) hypertension 9) corneal bands 10) pseudogout (calcium pyrophosphate dihydrate deposition) 11) 'stones, bones & moans' a mneumonic developed in the 1930's by Fuller Albright 12) symptoms do not correlate with degree of hypercalcemia [8] Laboratory: 1) hypercalcemia: serum calcium is generally < 12 mg/dL 2) increased serum ionized calcium (unnecessary if serum albumin is normal) [20] 3) elevated intact parathyroid hormone (fasting) (< 5X normal) - may be inappropriately normal in patient with hypercalcemia - upper 1/2 of reference interval [3] 4) mild to moderate decrease in serum phosphate 5) serum chloride: chloride:phosphate ratio is generally > 33:1 (need to use same units for chloride & phosphorus) 6) non anion gap metabolic acidosis 7) azotemia may be observed 8) urinalysis (24-hour urine calcium)* a) increased urinary excretion of Ca+2 & phosphate (24 hour urinary Ca+2 > 4 mg/kg or > 200 mg/day is significant) b) increased biochemical markers of bone turnover 1] osteocalcin 2] collagen-cross-linked peptides 3] alkaline phosphatase derived from bone c) diminished urinary excretion of Ca+2 suggests 1] vitamin D deficiency 2] malabsorption syndrome 3] familial hypocalciuric hypercalcemia 9) serum 25-hydroxyvitamin D3 (all patients) [3] - 50% of patients with primary hyperparathyroidism have coexisting vitamin D deficiency - target serum 25-hydroxyvitamin D3: > 30 ng/dL [3] 10) serum 1,25 dihydroxyvitamin D level may be high * rule out secondary causes of secondary hyperparathyroidism including familial hypocalciuric hypercalcemia, idiopathic hypercalciuria & absorptive hypercalciuria before diagnosing hyperparathyroidism [3] Radiology: 1) routine radiographs rarely helpful unless symptomatic a) chondrocalcinosis b) subperiosteal bone resorption of the digits & sternoclavicular joints c) osteitis fibrosa cystica (bone cysts) d) renal calcifications e) pathologic fractures f) osteolytic "brown tumor" (rare) 2) bone density measurement a) osteoporosis generally manifests at cortical sites b) assessment of the distal forearm or hip better than the lumbar spine - include distal 3rd of radius [17,18] 3) imaging procedures to localize the parathyroid glands a) if indications for parathyroidectomy (see Management: below b) ultrasound (lacks sensitivity) c) computed tomography d) magnetic resonance imaging (MRI) e) choline PET-CT is the best preoperative imaging modality for localization of primary hyperparathyroidism [16] f) thallium scan or technetium-99m sestamibi scan [4] g) angiography h) selective venous catheterization with intact PTH measurement to localize parathyroid gland Complications: 1) nephrolithiasis 2) hypertension 3) osteoporosis (bone fractures) 4) band keratopathy Differential diagnosis: (see also hypercalcemia) 1) primary vs secondary vs tertiary hyperparathyroidism 2) hypercalcemia of malignancy 3) familial hypocalciuric hypercalcemia a) generally normal PTH, but may be elevated b) low urinary calcium 4) granulomatous disease may be associated with hypercalcemia with suppressed serum PTH a) tuberculosis b) sarcoidosis Management: === medical management === 1) criteria [6] a) contraindications to surgery (surgery generally treatment of choice) b) serum Ca+2 < 11.5 mg/dL c) compliance with regular follow-up d) bone density should be normal e) no evidence of renal insufficiency f) frail elderly 2) semiannual follow-up a) blood pressure b) serum calcium c) bone mass 3) avoid dehydration, immobilization & thiazide diuretics 5) bisphosphonates 1st line therapy if osteoporosis or meets FRAX criteria for treatment [3] a) may temporarily mitigate effects of excess PTH on bone loss b) prolonged efficacy has not been demonstrated c) increases bone mineral density, but also increases risk of hip fracture in primary hyperparathyroidism relative to observation (RR=1.5) [15] 6) postmenopausal women a) estrogen therapy b) selective estrogen receptor modulators (SERMs) c) progestins 7) cinacalcet (Sensipar) for patients who decline surgery & not at risk for fracture - expensive, mulitple drug interactions 8) treat vitamin D deficiency [3] - target serum 25-hydroxyvitamin D3 > 30 ng/dL - calcitriol for secondary hyperparathyroidism due to chronic renal failure [3] 9) treat hyperphosphatemia in patients with chronic renal failure (1st line) [19] - sevelamer rather than calcium carbonate [19] === parathyroidectomy === 1) treatment of choice [5,6] - underutilized in the elderly 2) indications (or logic, any of the following) a) age < 50 years b) serum calcium > 11.0 mg/dL; > 11.5 mg/dL [17] - >= 1 mg/dL higher than upper limit of normal [3,17] c) osteoporosis - T-score <= -2.5 at hip, lumbar spine, or distal radius d) minimal trauma fracture [3,10] e) nephrolithiasis f) 24-hour urine calcium > 400 mg g) elevated serum creatinine - creatinine clearance < 60 mL/min h) GERD or peptic ulcer disease i) significant bone, renal, GI or neuromuscular symptoms [3] j) previous episodes of hypercalcemic crisis 3) preserves bone density in patients with mild hyperparathyroidism [7] 4) minimally invasive surgery [4] a) may be treatment of choice if imaging suggests solitary adenoma b) excision of adenoma through a small unilateral incision with the patient under local cervical block anesthesia c) may be combined with rapid serum PTH assays 1] intraoperatively assess success of surgery 2] serum PTH levels diminish within minutes after excision of PTH-secreting adenoma 5) otherwise,surgical exploration requires identification of all 4 parathyroid glands 6) in 4 gland hyperplasia (MEN syndromes), 3 glands are removed & portions of the 4th are implanted in the forearm 7) glands may be aberrant in location, especially within the thyroid or mediastinal in location 8) initial success of surgery is about 90% 9) complications of surgery a) vocal cord paralysis (recurrent laryngeal nerve) b) hypocalcemia 1] inadvertant removal of all 4 parathyroid glands 2] hungry bone syndrome c) hematoma formation 10) surgical follow-up a) hypocalcemia & tetany b) flare-ups of gout & pseudogout c) decreased renal function d) monitor serum calcium e) recurrent hyperparathyroidism implies previously undiagnosed hyperplasia or carcinoma 11) repeat surgeries difficult due to scar tissue & higher likihood of ectopic thyroid tissue === familial form === 1) periodic monitoring of family members 2) genetic screening for MEN syndromes is available

Related

hypercalcemia hypoparathyroidism multiple endocrine neoplasia (MEN)

Specific

osteitis fibrosa cystica; von Recklinghausen's disease of bone primary hyperparathyroidism secondary hyperparathyroidism tertiary hyperparathyroidism

General

bone disease; osteopathia parathyroid disease sign/symptom

Database Correlations

OMIM correlations MORBIDMAP 607393

References

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  4. Journal Watch 22(12):98, 2002 Monchik JM et al Minimally invasive parathyroid surgery in 103 patients with local/regional anesthesia, without exclusion criteria. Surgery 131:502, 2002 PMID: 12019402
  5. Journal Watch 23(22):179, 2003 Vestergaard P & Mosekilde I, BMJ 327:530, 2003 http://bmj.com/cgi/content/full/327/7414/530 PMID: 12958111
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  7. Ambrogini E, Cetani F, Cianferotti L, Vignali E, Banti C, Viccica G, Oppo A, Miccoli P, Berti P, Bilezikian JP, Pinchera A, Marcocci C. Surgery or surveillance for mild asymptomatic primary hyperparathyroidism: a prospective, randomized clinical trial. J Clin Endocrinol Metab. 2007 Aug;92(8):3114-21. Epub 2007 May 29. PMID: 17535997
  8. Bargren AE et al. Can biochemical abnormalities predict symptomatology in patients with primary hyperparathyroidism? J Am Coll Surg 2011 Sep; 213:410. PMID: 21723154
  9. Paik JM et al Calcium intake and risk of primary hyperparathyroidism in women: prospective cohort study BMJ 2012;345:e6390 PMID: 23080543 http://www.bmj.com/content/345/bmj.e6390
  10. Bilezikian JP, Khan AA, Potts JT et al Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the third international workshop. J Clin Endocrinol Metab. 2009 Feb;94(2):335-9. PMID: 19193908
  11. Sprague SM, Coyne D. Control of secondary hyperparathyroidism by vitamin D receptor agonists in chronic kidney disease. Clin J Am Soc Nephrol. 2010 Mar;5(3):512-8. PMID: 20133492
  12. Wu B, Haigh PI, Hwang R, Ituarte PH, Liu IL, Hahn TJ, Yeh MW. Underutilization of parathyroidectomy in elderly patients with primary hyperparathyroidism. J Clin Endocrinol Metab. 2010 Sep;95(9):4324-30 PMID: 20610600
  13. Bilezikian JP, Brandi ML, Eastell R et al Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Fourth International Workshop. J Clin Endocrinol Metab. 2014 Oct;99(10):3561-9. PMID: 25162665
  14. NIDDK: Hyperparathyroidism http://www.niddk.nih.gov/health/endo/pubs/hyper/hyper.htm - OMAR: Diagnosis and Management of Asymptomatic Primary Hyperparathyroidism, Consensus Statement http://consensus.nih.gov/cons/082/082_intro.htm - The American Association of Clinical Endocrinologists and the American Association of Endocrine Surgeons position statement on the diagnosis and management of primary hyperparathyroidism. Endocr Pract. 2005; 11(1):49 PMID: 16033736
  15. Yeh MW, Zhou H, Adams AL et al The Relationship of Parathyroidectomy and Bisphosphonates With Fracture Risk in Primary Hyperparathyroidism: An Observational Study. Ann Intern Med. Published online 5 April 2016 PMID: 27043778 http://annals.org/article.aspx?articleid=2511009
  16. Lee SW, Shim SR, Jeong SY et al Direct Comparison of Preoperative Imaging Modalities for Localization of Primary Hyperparathyroidism. A Systematic Review and Network Meta-analysis. JAMA Otolaryngol Head Neck Surg. 2021;147(8):692-706. PMID: 34081083 PMCID: PMC8176390 (available on 2022-06-03) https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/2780789
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  21. Information for Patients about Primary Hyperparathyroidism http://www.osteo.org/newfile.asp?doc=p112i&doctitle=Primary+Hyperparathyroidism&doctype=HTML+Fact+Sheet