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Primary Hyperparathyroidism Megha Poddar, PGY5 January 2015 Objectives • To Review: • Differential diagnosis of hypercalcemia • Pathophysiology of hyperparathyroidism • Clinical Presentation • Diagnosis • Treatments Hypercalcemia is a common metabolic abnormality seen in approximately 5% of hospitalized individuals. The Canadian Journal of Diagnosis / February 2006/Aliya Khan Primary Hyperparathyoidism – Epidemiology • PHPT - most common cause of hypercalcemia in the outpatient clinical setting • Prevalence ranges from 1 to 4 per 1000 people • Female-to-Male ratio: 2:1 to 3:1 • Incidence increases with age • Postmenopausal women have an incidence 5x higher than the general population Canadian Family Physician February 2011 vol. 57 no. 2 184-189 The Parathyroid Glands • History: • The parathyroid glands were first discovered in the Indian Rhinoceros by Richard Owen in 1850. • The glands were first discovered in humans by Ivar Viktor Sandström, a Swedish medical student, in 1880. • It was the last major organ to be recognized in humans. Parathyroid Gland: Ectopic locations are seen in 4- 16% - the parathyroid glands might also be found in the carotid sheath, anterior mediastinum, and intrathyroidal tissue. Atlas of Microscopic Anatomy: Section 15 - Endocrine Glands 115-AAC trypsin-like protease 90-AAC 84-AAC Packaged PTH is an 84-amino acid polypeptide (chain) derived from a prohormone The biosynthetic process is estimated to take less than one hour. BASIC BIOLOGY OF MINERAL METABOLISM, F. Richard Bringhurst Parathyroid hormone: 84 amino acid peptide Recognized by PTH-1 receptor and then acts on target organs to effect calcium homeostasis 70% metabolized by the liver and 20% by kidneys; Half life of 2 minutes Functions of PTH • Chief cells – produce PTH • PTH = Main regulator of calcium homeostasis in the body • Ionised calcium – tightly regulated for optimum function of cell signalling, neural function, muscular function, and bone metabolism • PTH responds to changes in circulating ionised calcium via the calcium-sensing receptor (CaSR) located on the surface of the chief cells Parathyroid Hormone Receptors • PTH acts by binding to its receptor(PTH1R and PTH2R) • Both are members of the G Protein coupled receptor family of transmembrane proteins • PTH-1R receptor binds PTH and PTHrP with equal affinity. • Regulates calcium homeostasis through activation of adenylate cyclase and phospholipase C • mostly expressed in bone and kidney • PTH2R selectively binds PTH only. • PTH2R expressed heavily in the brain, pancreas, endothelium Uptodate: Parathyroid Hormone and Action Calcium sensing receptors • CaSR expressed in parathyroid, thyroid C cells and kidney. • Activation of the CaSR by increased extracellular Ca2+ inhibits parathyroid hormone (PTH) secretion, stimulates calcitonin secretion, and promotes urinary Ca2+ excretion, and thereby maintains the extracellular Ca2+ at the normal level PTH/Calcium Homeostasis Causes of Hyperparathyroidism Primary Secondary- In response to hypocalcemia Tertiary •Parathyroid Adenoma, Hyperplasia, Carcinoma •Renal Failure -Impaired calcitriol production -Hyperphosphatemia •Autonomous hypersecretion of parathyroid hormone -chronic secondary hyperparathyroidism -After renal transplantation •MEN 1 or MEN 2a •Familial hypocalciuric hypercalcemia •Hyperparathyroid-jaw tumor (HPT-JT) syndrome •Decreased calcium -Low oral intake -Vit D deficiency -Malabsoption -renal calcium loss – lasix •Familial isolated hyperparathyroidism (FIHPT) •Inhibition of bone resorption -Bisphophonates -Hungry Bone Syndrome Primary Hyperparathyroidism (PHPT) • Etiology: • Single gland adenoma: 75-85% • Multigland adenoma • 2 glands: 2-12% • 3 glands: <1-2% • 4 or > glands: 1-15% • Parathyroid carcinoma: 1% Lancet 2009; 374: 145–58 Lower pole adenomas are more common than are upper pole adenomas; sizes range from 1 cm to 3 cm and weights from 0·3 g to 5 g; may be more than 25g. Parathyroid adenoma Largest reported weighted 120g Largest number was 8 Lancet 2009; 374: 145–58 Causes • Exact cause of primary hyperparathyroidism is unknown • Ionizing radiation maybe associated • Irradiation for acne -?2·3-fold increase • Survivors of an atomic bomb - 4-fold increase • A dose response was recorded in people receiving external-beam radiotherapy for benign disease before their 16th birthday • Present doses of radioactive iodine for thyrotoxicosis do not increase the incidence of primary hyperparathyroidism Lancet 2009; 374: 145–58 Rare Familial Disorders • Multiple endocrine neoplasia (MEN) type 1 –MEN1 gene mutation (Parathyroid, pituitary, pancreatic) • MEN type 2A syndromes –RET gene mutation (Parathyroid, Pheo, MTC) • Familial hypocalciuric hypercalcemia (FHH)- autosomal dominantinactivating mutation of the CaSR gene • Familial hyperparathyroidism–jaw tumour syndrome- HRPT2 gene; Autosomal dominant • Familial isolated hyperparathyroidism FHH PHPT Mechanism (CaSR gene on Chr 3) – PTH Adenoma, Hyperplasia, makes PTHR less sensitive to carcinoma calcium - higher serum calcium level is required to reduce PTH secretion Fhx + Autosomial Dominant + rare syndromes PTH Mildly high in 15-20% High normal – high Urine Calcium /Magnesium Low Normal – high FECa ; sensitivity 85%, specificity 88%, PPV 85% <1% >1% Symptoms - +/- Management Conservation Parathyroidectomy Plasma albumin-adjusted calcium (mmol/L) 2.55-3.5 2.55-4.5 Age/sex <40; women = male >50; mainly women Clinical Presentation of PHPT • Possible presentations: • Asymptomatic Incidental hypercalcemia – 70-80% • In most patients, mean serum calcium < 0.25 mmol/L above the ULN range • Normocalcemic hyperparathyroidism • Usually present for evaluation of low BMD, osteoporosis, or fragility fractures • Symptomatic hypercalcemia Symptoms of Hypercalcemia • Stones • Bones • Groans • Psychiatric Moans Renal Manifestations • Nephrolithiasis 15-20% • Nephrocalcinosis • Polyuria • Renal insufficiency • Acute hypercalcaemic crisis with nephrogenic diabetes insipidus and dehydration seen when calcium greater than 3·0 mmol/L Psychic Moans: • Neuropsychiatric: lethargy, decreased cognitive and social function, depressed mood, psychosis, and coma in those with severe hypercalcemia. • Neuromuscular: weakness and myalgia • Prolonged HPTH causes direct neuropathy with abnormal nerve conduction velocities Gastrointestinal Manifestations Commonly constipation, nausea, vomiting, anorexia • Uncommon, but serious: PUD or Acute pancreatitis • Mechanism: • • PTH stimulates gastrin secretion (PUD), decreases peristalsis, and increases the calcium- phosphate product with calcium-phosphate deposition and obstruction in pancreatic ducts Uptodate: Clinical manifestations of primary hyperparathyroidism Bone Manifestations • • • • Bony pain Low bone mineral density – most at cortical sites Fragility fractures Rarely PHPT bone disease – osteitis fibrosa cystica- <5 percent of patients • Proximal muscle weakness due to type II muscle fibre atrophy can be seen in association with severe bone disease (osteitis fibrosa cystica). Uptodate: Clinical manifestations of primary hyperparathyroidism subperiosteal resorption Osteitis fibrosa cystica • Very rare; occurs only in severe cases – carcinoma • Characterized clinically by bone pain • Radiographically by subperiosteal bone resorption on the radial aspect of the middle phalanges, tapering of the distal clavicles, a "salt and pepper" appearance of the skull, bone cysts, and brown tumors of the long bones Uptodate: Clinical manifestations of primary hyperparathyroidism Cardiovascular: - Shortened QT interval HTN – hypercalcemia causes vasoconstriction Arrhythmias in severe hypercalcemia Deposition of calcium on valves, in coronaries, and myocardium Other Manifestations • Arthralgia, synovitis, arthritis • HPT associated with increased crystal deposition from calcium phosphate, calcium pyrophosphate (pseudogout), and uric acid (gout) • Band Keratopathy – Calcium phosphate precipitation in medial and limbic margins of cornea Symptoms • The classic features of hypercalcemia are very uncommon initial complaints in the Western world • Most patients in developed countries have asymptosymatic forms of PHPT or nonspecific symptoms such as fatigue, mild depression, or cognitive impairment. Diagnosis • Repeat calcium to confirm, correct for low Albumin • Ionized Calcium: adds little if you have a normal albumin and no acid base problems • ?Useful if normocalcemic primary hyperparathyroidism – in one series 16/60 patients had a raised ionized calcium, but normal serum calcium • Check PTH – rule in PHPT if frankly elevated PTH concentration or normal PTH level with hypercalcemia • Supporting findings: low P04,high Cl, high urine pH (>6), high ALP • Address DDX hyperparathyroidism and hypercalcemia • Multiple endocrine neoplasia (MEN) type 1 –MEN1 gene mutation • -MEN type 2A syndromes –RET gene mutation • -Familial hypocalciuric hypercalcemia (FHH) • Familial hyperparathyroidism–jaw tumour syndrome- HRPT2 gene; Autosomal dominant • -Familial isolated hyperparathyroidism • Teritiary HPT • Medications • Two most common causes are Primary HPT and Cancer- related hypercalcemia (PTH related protein mediated, or directly via bony lesions) How do PTHrP and PTH differ? • PTHrP has 3 protein forms: 139, 141, 173 amino acids • First 139 AA are the most common among all 3 forms • 8 of first 13N-terminal AA are same as intact PTH (1-84), therefore PTHrP and PTH can stimulate the same receptors • But, different effects on 1,25(OH)2D • Continuous secretion of PTHrP by tumors downregulates receptors that stimulate 1 alpha hydroxylase decreased enzyme decreased 1,25(OH)2D • Higher levels of Calcium may also decrease 1,25(OH)2D Differences between PTHrP and PTH Intact PTH Primary High HPT PTHrP Low malignancy PTHrP 1,25 VitD Calcium Low High High High Low High Two drugs deserve special consideration when evaluating a patient for hyperparathyroidism: • Thiazide: • Reduce urinary calcium excretion and cause mild hypercalcemia [upto 2.9 mmol/L]) – therefore may unmask the HPT • Lithium • Decreases parathyroid gland sensitivity to calcium, shifting the calcium-PTH curve to the right; has an action downstream of the calcium-sensing receptor, but the exact locus is still unknown. • If possible; trial of discontinuation: calcium more likely to normalize if the duration of lithium use short, eg, less than a few years, but less likely if it had been longer, eg, more than 10 years. Uptodate: Diagnosis and differential diagnosis of primary hyperparathyroidism Approach • PHPT: elevated intact PTH or at the high end of the normal range in the setting of elevated total calcium • Repeat measurements (usually 2- 3), check PO4 (low-normal), ALP (high) • Further laboratory testing is to rule out other causes of hypercalcemia. • Distinguish FHH from PHTP– 24h urine and FECa • Correct levels of 25(OH)D if present may cause a false positive • Renal function tests r/o secondary causes • Consider genetic testing if Fhx of MEN syndrome Localize • Localization: technetium 99m–labeled sestamibi scanning, ultrasound, CT, MRI, and PET. Used to aid surgery. **Imaging should not be used to establish the diagnosis of PHPT or to screen patients for surgical referral** • Gold standard: a four gland parathyroid exploration • However, a more focused, minimally invasive approach to parathyroid surgery is being adopted at many centers to facilitate unilateral exploration and minimally invasive surgery in those with probable single gland disease Sestamibi scintigraphy • Sestamibi scintigraphy — Technetium-99mmethoxyisobutylisonitrile (99mTc-sestamibi or MIBI) • 99mTc-sestamibi is taken up by the mitochondria in thyroid and parathyroid tissue; however, the radiotracer is retained by the mitochondria-rich oxyphil cells in parathyroid glands longer than in thyroid tissue • Planar images obtained after injection of 99mTc-sestamibi and again at 2hours to identify foci of retained radiotracer activity consistent with hyperfunctioning parathyroid tissue. Uptodate: Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism Imaging StudiesIt has an accuracy rate of 50% to 70% • High false negative rate: parathyroid hyperplasia, multiple parathyroid adenomas, by CCB that interfere with the take up of the isotope by parathyroid cells • Other gland characteristics that can increase the likelihood of a negative scan include small size, superior position, and a paucity of oxyphil cells • a single-focus positive imaging result does not reliably exclude the presence of multiglandular parathyroid disease • Thyroid disease requiring surgery significantly increases both the false positive and false negative rate Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism PHPT Localization • Biochemically confirmed PHPT and non-localizing imaging studies – need bilateral exploration by ENT surgeon. • In such patients: a single adenoma more common(62 to 77%); however, multiglandular disease is also common (20 to 38 %). • For re-operation (5-10% of patients): negative sestamibi and ultrasound results usually lead to use of CT and/or MRI. If these studies are also non-localizing, then invasive studies such as arteriography or selective venous sampling can be performed. • Reoperation with negative imaging: high failure rate (up to 50 %) and nonoperative medical management should be considered Uptodate: Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism Management Acute Management of Hypercalcemia • Avoid thiazides, lithium, volume depletion, prolonged bed rest, or inactivity, and high calcium diet (>1g/day) • Rehydration!!! • Calcitonin +/- cinacalcet can also be of value in the short term to maintain a reduction of calcium • If surgery planned within a few days, AVOID IV bisphosphonates because post op hypocalcemia risk Parathyroidectomy • Definitive therapy • Surgical techniques: total open parathyroidectomy or a minimally invasive procedure with or without the use of intraoperative PTH assays • Only a subgroup of people with asymptomatic PHTP benefit from surgery Guidelines for parathyroid surgery in patients with asymptomatic PHPT Results after Surgery • Calcium, phosphate, and urine calcium return to normal quickly • PTH levels fall by 50% within the first 10-15 min • Indicators of bone resorption (c-telo) normalise quicker than formation (ALP). Bone turnover returns to normal within 6 – 12 months • Osteoblast > osteoclast activity, resulting in a substantial improvement in bone mineral density – greatest at hip and spine A 10-Year Prospective Study of Primary Hyperparathyroidism with or without Parathyroid Surgery Shonni J. Silverberg, N Engl J Med 1999; 341:1249-1255 Methods: 10 year prospective study in 121 patietns with PHPT 30 men and 91 women (age range, 20 to 79 years). 121 patients 83% asymptomatic 17% symptomatic Surgery (50%) 49 Asymptomatic 12 symptomatic Normalization of markers & increased BMD in 100% No surgery 50% 52 Aysmptomatic 8 symptomatic Disease progression Stable Disease 100% in Symptomatic 73% Aysmptomatic 8% after 1yr (P=0.05) 12% after 10 years (P=0.03) 6% after 1 year (P=0.00 2) 14 % after 10 years (P=0.00 2) Silverberg, NEJM 1999 Will surgery decrease future fractures? • Retrospective cohort study of 1569 patients with PHPT(452 of whom had had a parathyroidectomy): • Reported a significant increase in 10-year fracture-free survival, mainly hip fractures after parathyroidectomy (59% vs 73%) • Parathyroidectomy decreased the 10-year hip fracture rate by 8% (P = .001) and the upper extremity fracture rate by 3% (P = .02) VanderWalde LH. The effect of parathyroidectomy on bone fracture risk in patients with primary hyperparathyroidism. Arch Surg 2006; 141: 885–89. Mollerup CL. Risk of renal stone events in primary hyperparathyroidism before and after parathyroid surgery: controlled retrospective follow up study. Bmj, 325: 807, 2002. Cardiac/Renal Outcomes • Cardiac Outcomes: • Longterm hypertension control not improved • Left ventricular hypertrophy decreases after surgery in some • slower the progression of aortic and mitral valve calcification • Renal Outcomes: • Kidney stones are reduced in frequency amongst those with a history of kidney stones Neurological and neuropsychiatric outcomes • No consistent significant change in symptoms (fatigue, weakness, lassitude, anxiety, depression) • In an uncontrolled open prospective study of 74 patients, a significant improvement in SF-36 scores was noted 1 year after parathyroidectomy in five (asymptomatic) and seven (symptomatic). • A prospective study of 191 patients with mild asymptomatic primary hyperparathyroidism who were randomised to medical observation or surgical intervention has not shown any benefit of operative treatment on SF-36 or psychological symptoms after 2 years www.thelancet.com Vol 374 July 11, 2009 Medical Management for those NOT candidates for parathyroidectomy Medical Management • Focused on goals: • Improving BMD as most are postmenopausal women – HRT, SERMS, Bisphosphonates HRT: • significant reduction in calcium (0·1–0·3 mmol/L) • 4–8% increase in BMD at trabecular and cortical sites Orr-Walker BJ. Effects of hormone replacement therapy on bone mineral density in postmenopausal women with primary hyperparathyroidism: four-year follow-up and comparison with healthy postmenopausal women. Arch Intern Med 2000; 160: 2161–66. 42 Postmenopausal women with mild PHPT, a 2-yr randomized, placebocontrolled trial. 1.3% ± 0.4%; P = 0.004 3.6% 5.2% ± 1.4%; P = 0.002 6.6% Grey AB. 1996 Effect of hormone replacement therapy on bone mineral density in postmenopausal women with mild primary hyperparathyroidism. A randomized, controlled trial. Ann Intern Med 125:360 –368 SERMS • A small, placebo-controlled, randomized trial reported the effects of raloxifene (60 mg/d) on serum calcium and phosphorus over 2 months in postmenopausal women with PHPT • calcium declined significantly by 2 months in the raloxifene-treated women. No changes in PTH, but a significant decline in the levels of urinary NTX and serum osteocalcin • Case series: BMD decline at both spine and hip sites in three subjects were arrested by the introduction of treatment with raloxifene (60 or 120 mg/d). J Clin Endocrinol Metab, February 2009, 94(2):373–381 Bisphosphonates • Pamidronate in patients with mild PHPT- Infusions (30 mg) 10 patients in a randomized crossover study and were effective in reducing serum calcium from 2.72 to 2.49 mmol/liter after 1 wk. • Short-term treatment with risedronate was effective in lowering serum calcium in individuals with mild PHPT; no long term study • Alendronate most extensively evaluated in individuals with PHPT. • Data from the RCT have consistently shown that alendronate decreases bone turnover and increases BMD at the lumbar spine and proximal femur in PHPT. Effect of alendronate on lumbar spine (A), total hip (B), femoral neck (C), and one third distal radius (D) BMD. *, Significantly higher than baseline (P < 0.001); †, significantly higher than baseline (P < 0.05). LUMBAR 4.92% 6.85% TOTAL HIP 4.01% FEMORAL One third distal radius Khan A A et al. JCEM 2004;89:3319-3325 ©2004 by Endocrine Society Medical Treatment Points to Remember: • Alendronate decreases bone turnover and increase BMD in PHPT (level I evidence) • Hormone replacement therapy (HRT) also improved BMD in postmenopausal women with mild PHPT (level I evidence) • It is not known whether these treatments also reduce fracture risk. • Raloxifene, SERM, decreases bone turnover in postmenopausal women with PHPT, but more research is needed to evaluate its effects on BMD (level I evidence). • Ensure Vit D is replete • Do not limit calcium intake Summary • Primary hyperparathyroidism is the third most common endocrine disorder • Asymptomatic disease is common, and severe disease with renal stones and metabolic bone disease arises less frequently. • Primary hyperparathyroidism can be cured by parathyroidectomy for those with symptomatic hypercalcemia and a subgroup of asymptomatic patients • Medical options for treating the skeletal complications of PHPT include bisphosphonates, HRT, and raloxifene