Parathyroid disorders

Dr. Muhammad Nadeem Akbar Khan

Assoc. Prof. Chem. Pathology IIMCT Hospital Rawalpindi Sept 6, 2013

Learning Objectives

Describe the Epidemiology, Etiology, Pathogenesis and clinical features of hyperparathyroidism. Name different types of hyperparathyroidisms and their Lab findings. Briefly describe etiology, clinical features and lab findings of different types of hypoparathyroidism. Briefly discuss:

Familial Hyocalciuric Hypercalcemia Pseudohypoparathyroidism

Functional anatomy of Parathyroid Glands

The parathyroids consist of 4 glands, lie in close proximity to the upper and lower poles of each Thyroid lobe Each gland is composed of chief cells, oxyphil cells, fibrous stroma and variable amounts of fat Chief cells respond directly to changes in calcium concentration via a G-protein-coupled cell surface receptor(the ca sensing receptors) located on the cell surface When serum ionized ca levels fall, PTH secretion rises

ANATOMY OF PARATHYROID GLAND

6x4x1 mm

Parathyroid hormone.contd
PTH is a single-chain polypeptide of 84 amino acids The effects of PTH are initiated by binding of PTH to PTH receptors in the target tissues (type 1) The PTH receptor is a seven-transmembrane Gprotein-coupled receptor Hormone binding leads to activation of stimulatory Gprotein Leads to generation of c-AMP

Biological effects of PTH

1.Skeletal actions of PTH PTH acts on bone to mobilize Calcium from readily available skeletal stores (immediate effect) Later it stimulates Calcium and phosphate release by bone resorption

3. Synthesis of calcitriol [1,25 (OH)2 D]

Stimulates the synthesis of 1-alpha hydroxylase in proximal tubules leading to conversion of Calcidiol (25 OHD) to active Calcitriol [1,25 (OH)2 D],which in turn enhances Ca absorption from gut 4. Intestines Indirect effect of PTH Produces calcitriol which leads to intestinal absorption of calcium and phosphorus

2. Renal actions of PTH PTH acts on distal tubules to stimulate calcium absorption at DCT It inhibits proximal reabsorption of Phosphate

*Net result of these activities is an increase in the level of free Ca, which in turn, inhibits further PTH
secretion in a classic feedback loop

Effect of High PTH on Bone

More than 99% of total body Ca is in bone. Prolonged exposure of bone to high levels of PTH is associated with increased osteoclastic activity and new bone formation. But the net effect is to cause bone loss with mobilization of Ca into the ECF. In contrast, pulsatile release of PTH causes net bone gain, an effect used therapeutically in the treatment of osteoprosis

Biological effects of PTH

Plasma Ca++

Kidney

Plasma PTH

Bones

1,25 DHCC (1 hydroxylase)

Renal Ca++ Absorption

Negative

Gut Ca++ Absorption

Plasma Ca++

Calcium-PTH interactions
The PTH responds to hypocalcemia
Serum ionized calcium concentration be maintained within a very narrow range Seconds to minutes- exocytosis of PTH Minutes to 1 hour- reduction in intracellular PTH degraded Hours to days- increase in PTH gene expression Days to weeks- proliferation of parathyroid cells

Hyperparathyroidism
A clinical syndrome causing signs and symptoms that result from PTH, PTH induced bone resorption and hypercalcemia Three types of hyperparathyroidism - Primary - Secondary - Tertiary (less common)

Primary Hyperparathyroidism
A common endocrine disorder and is usually due to autonomous, spontaneous overproduction of PTH An important cause of hypercalcemia Epidemiology Overall incidence is 42 in 100,000 Prevalence is 1:1000 Female to male ratio is 3:1 Disease of the adults, 90% patients are over 50yrs of age

Etiology and Pathogenesis

Primary hyperparathyroidism is caused by

..parathyroid adenoma (which can vary in diameters from few mm to several cm): 80%

Inversion of a proto-oncogene Parathyroid adenoma 1 (PRAD1) leads to over expression of Cyclin D 1 protein , forcing the cells of parathyroid gland to proliferate

..parathyroid hyperplasia: 15% ..parathyroid carcinoma: 1-2%

Etiology and pathogenesis

Primary hyperparathyroidism also occurs in familial MEN syndromes, when hyperplasia or multiple adenomas of all four parathyroid glands rather than a solitary adenoma are more likely Genetic syndromes associated with familial primary hyperparathyroidism include : inactivated Pituitary adenoma (60%) Pancreatic endocrine tumor (75%) Parathyroid neoplasia (90%)

..MEN 1: Tumor suppressor gene on short arm of chromosome 11 is

..MEN 2a: activating mutations in the tyrosine receptor on chromosome 10

Medullary thyroid cancer (100%) Adrenal Medulla (Pheochromocytoma) (50%) Parathyroid neoplasia (10-40%)

..Isolated familial hyperparathyroidism(FHH):

parathyroid calcium sensing receptor gene on chromosome 3q

mutations in

Autosomal dominant disorder caused by decreased sensitivity of parathyroid to EC Calcium

Clinical Course

Asymptomatic Hyperparathyroidism
identified after routine chemistry profilehigh ionized serum Ca

Other causes of hypercalcemia e.g., malignancy should be excluded by appropriate clinical and lab investigations .

Serum PTH levels

In Primary hyperthyroidism, levels are inappropriately elevated for the level of serum calcium low to undetectable PTH levels in hypercalcemia because of nonparathyroid disease. In primary hyperparathyroidism Hypercalcaemia, Hypophosphatemia, and increased urinary excretion of Ca and PO4 Secondary renal disease may lead to PO4 retention with normal serum PO4

Serum and Urine Ca and PO4

Clinical Course
Symptomatic Primary Hperparathythyroidism
Combined effects of increased PTH secretion and Hypercalcemia Hyperpparathyroidism: nephrolithiasis and bone disease Hypercalcemia: fatigue, weakness and constipation Classic phrase of these features is renal stones, painful bones, abdominal groans and psychic moans

Bones Renal G.I.T

Bone pain, Fractures, arthralgias Stones, polyuria Pain, duodenal ulcer, pancreatitis

Neurological
Cardiac

Depression, apathy
Hypertension, heart block

Hypercalcemia:Causes
Important

Malignancy is the most common cause of clinically apparent hypercalcaemia Primary hyperparathyroidism is a more common cause of asymptomatic elevated blood calcium

Radiological Features

skeletal X-rays are hyperparathyroidism In advanced disease observed

usually

normal

in

mild

charecteristic

changes

are

in early stages demineralization, with subperiosteal erosions and terminal resorption in the phalanges A pepper-pot appearance may be seen on lateral x-rays of the skull Reduced bone mineral density, resulting in either osteopenia or osteoporosis, is now the most common skeletal manifestation of hyperparathyroidism and it requires assessment by DEXA scan

HYPERPARATHYROIDISM PLAIN FILMS

NORMAL X-RAY HAND

BONE RESORPTION ACRO-OSTEOLYSIS

HYPERPARATHYROIDISM PLAIN FILMS

BILATERAL RENAL CALCULI

Familial Hypocalciuric Hypercalcemia(FHH)

Autosomal dominant inherited disorder, caused by an inactivating mutation in one of the alleles of calcium sensing receptor gene, which reduces the ability of the parathyroid gland to sense ionized ca conc. So, higher than normal ca levels are required to suppress PTH secretion The typical presentation is mild hypercalcemia with PTH conc. that are inappropriately at the upper end of normal range or are slightly elevated. Ca sensing receptors in the renal tubules are also effected and this leads to increased renal tubular reabsorption of ca and hypocalciuria. Hypercalcemia is always asymptomatic and complications do not occur Main risk of FHH is being subjected to an unnecessary and ineffective parathyroidectomy if misdiagnosed as primary hyperthyroidism Diagnosis of FHH can be confirmed by screening family members for hypercalcemia and it is also possible to perform genetic testing No treatment is necessary

Laboratory findings: Primary

Hyperparathyroidism
Hypercalcemia is universal Serum phosphorus is low normal (<1.0 mmol/L) or low (<0.60 mmol/L) PTH is elevated or high normal Alkaline phosphatase may be increased Mild hyperchloremic metabolic acidosis

Secondary Hyperparathyroidism

Caused by any condition associated with a chronic depression in the serum Ca level because low serum Ca leads to compensatory over activity of parathyroid glands. Renal failure is by far the most common cause of secondary hyperparathyroidism Other diseases:

Inadequate dietary intake of Ca, Steatorrhoea, and Vit D deficiency, may also cause this disorder

 In CRF reduced GFR leads to reduced inorganic phosphate excretion and consequent hyperphosphatemia Retained phosphate 1. has a direct stimulatory effect on PTH synthesis 2. Also causes lowering of ionized Ca++ and suppression of 1,25(OH)D production 3. Low calcitriol [1,25(OH)D] levels lead to hyperparathyroidism: Calcitriol have a direct suppressive effect on PTH transcription and therefore reduced Calcitriol in CRD causes elevated levels of PTH 4. Impaired Ca ++ absorption from the GI tract, thereby leading to hypocalcemia, increases PTH secretion and production

Mechanism of Hyperparathyroidism in CRF

Clinical features

Usually dominated by those associated with CRF Bone abnormalities(renal osteodystrophy) and other changes associated with PTH excess are in general less severe

Tertiary Hyperparathyroidism
Develops in minority of patients with long-standing secondary hyperparathyroidism commonly seen in advanced CKD. In these patients, continous stimulation of parathyroids over a prolonged period of time results in adenoma formation and autonomous PTH secretion, with resultant hypercalcemia. A clue to the diagnosis of tertiary hyperparathyroidism is intractable hypercalcemia and/or an inability to control osteomalacia despite vitamin D therapy

Lab evaluation of hyperparathyroidism

Ca PO4 PTH (Calcidiol) (Calcitriol) 25-(OH) Vit D 1,25-(OH) 2Vit D

Primary

N N N

Secondary Tertiary

Hypoparathyroidism
Etiology
a. Surgical hypoparathyroidism Most common cause is neck surgery e.g. total thyroidectomy
b. Idiopathic hypoparathyroidism Age of onset is 2-10 years Female preponderance Circulating parathyroid Ab common c. Familial hypoparathyroidism Autosomal dominant Mutation in PTH gene leads to defective PTH d. Autoimmune hypoparathyroidism
Prominent component of autoimmune polyglandular syndrome Associated with primary adrenal insufficiency, mucocutaneous candidiasis Age of onset 5-9 years

e. Di Georges syndrome f. Congenital aplasia of the parathyroids g. Iron deposition in the glands h. Copper deposition i. Aluminium deposition j. Infiltration with metastatic carcinoma k. Magnesium depletion

Hypoparathyroidism
Acute Hypocalcemia: Parathyroidectomy PTH undetectable at 8 hours Normalizes by 30 hours Calcium nadir at 2000 hours, normal in 2-3 days Medications: I-131, Cimetidine, Cisplatin, Digoxin, Ampho-B Hypomagnesemia Hypermagnesemia

Hereditary Hypoparathyroidism
DiGeorges syndrome agenesis Pseudohypoparathyroidism end-organ resistance to PTH.
Serum PTH levels are normal or elevated. Inability of PTH to generate urinary cyclic AMP

Short stature, round facies, obesity, mild MR, dental abscesses,

short digits, ectopic calcification Pseudopseudohypoparathyroidism: Variant of Pseudohypoparathyroidism No Hypocalcemia or raised PTH

HYPOPARATHYROIDISM

Lab evaluation of hypoparathyroidism

Ca PO4 P T H Calcidiol [25-(OH) Vit D] Calcitriol [1, 25-(OH) Vit D]

Hypoparathyroidism

N N

Pseudohypoparathyroi dism

Renal disease

Thank you!
Questions?