Hyperparathyroidism

Prof

Mohameed Mashahit

Fayoum University

Objectives

• To Review:

• The parathyroid glands

• 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

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 prohormone

The 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

master 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 , blood coagulation . etc

• 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

• 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

•HYPERPARATHYROIDISM

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 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

1- Parathyroid adenoma or carcinoma

• 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 120g

Largest 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

• Present doses of radioactive iodine for thyrotoxicosis

do not increase the incidence of primary

hyperparathyroidism

Lancet 2009; 374: 145–58

2- 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

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

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

Diagnosis

• Repeat calcium to confirm, correct for low Albumin

• Ionized Calcium: may be more helpful in some conditions

• 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 , as frusimide and lithium

• Two most common causes are Primary HPT and Cancer-

related hypercalcemia (PTH related protein mediated,

or directly via bony lesions)

Differences between PTHrP and PTH

Intact

PTH

PTHrP 1,25 VitD Calcium

Primary

HPT

High Low High High

PTHrP

malignancy

Low High Low High

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

Sestamibi scintigraphy

• 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 2 hours to identify foci of

retained radiotracer activity consistent with

hyperfunctioning parathyroid tissue.

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 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

Silverberg, NEJM 1999

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)

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

Mollerup CL. Risk of renal stone events in primary hyperparathyroidism before and after parathyroid

surgery: controlled retrospective follow up study. Bmj, 325: 807, 2002.

Medical Management for

those NOT candidates for

parathyroidectomy

DRUGS USED

• CALCIMIMETICS

• HRT

• SERMS

• BISPHOSPHONATES

Calcimimetics

• Drugs that mimics calcium circulating in the blood so can trick the parathyroid gland to release less parathormone .

• FDA approved for CKD and cancer . Mainly ..

• Some doctors prescribe it for primary PHPT if surgery is not feasible

• Sensipar ( cinacalcet )

• The most common side effects are bone and muscle aches , diarrhea , respiratory tract infection

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,

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.

Summary

• Primary hyperparathyroidism is one of the 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 AND RECENTLY CACIMIMETICS

Thank you

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

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

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.