Primary Hyperparathyroidism

Megha Poddar, PGY5January 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

PTH is an 84-amino acid polypeptide (chain) derived from a prohormoneThe biosynthetic process is estimated to take less than one hour. BASIC BIOLOGY OF MINERAL METABOLISM, F. Richard Bringhurst

Packaged

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

•MEN 1 or MEN 2a

•Familial hypocalciuric hypercalcemia

•Hyperparathyroid-jaw tumor (HPT-JT) syndrome

•Familial isolated hyperparathyroidism (FIHPT)

•Renal Failure-Impaired calcitriol production-Hyperphosphatemia

•Decreased calcium -Low oral intake-Vit D deficiency-Malabsoption -renal calcium loss – lasix

•Inhibition of bone resorption-Bisphophonates-Hungry Bone Syndrome

•Autonomous hypersecretion of parathyroid hormone -chronic secondary hyperparathyroidism-After renal transplantation

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

Lancet 2009; 374: 145–58

Largest reported weighted 120gLargest number was 8

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 dominant- inactivating 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) – makes PTHR less sensitive to calcium - higher serum calcium level is required to reduce PTH secretion

PTH Adenoma, Hyperplasia, carcinoma

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

PTHrP 1,25 VitD

Calcium

Primary HPT

High Low High High

PTHrP malignancy

Low 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-99m-

methoxyisobutylisonitrile (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 Studies- It 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

121 patients83% asymptomatic17% symptomatic

Surgery (50%)49 Asymptomatic12 symptomatic

No surgery 50%52 Aysmptomatic8 symptomatic

Normalization of markers & increased BMD in 100%

Disease progression100% in Symptomatic

Stable Disease73% Aysmptomatic

A 10-Year Prospective Study of Primary Hyperparathyroidism with or without Parathyroid SurgeryShonni 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).

Silverberg, NEJM 1999

8% after 1yr (P=0.05) 12% after 10 years (P=0.03)6% after 1 year (P=0.002) 14 % after 10 years (P=0.002)

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,

placebo-controlled trial.

1.3% ± 0.4%; P = 0.004

5.2% ± 1.4%; P = 0.002

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

3.6%

6.6%

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).

Khan A A et al. JCEM 2004;89:3319-3325

©2004 by Endocrine Society

LUMBAR4.92%6.85%

TOTAL HIP4.01%

FEMORAL One third distal radius

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

Canadian Family Physician February 2011 vol. 57 no. 2 184-189

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