Kuliah paratiroid 1

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Dr. Pandji Mulyono,SpPD,KEMD,FINASIMPARATHYROID DISEASEThe parathyroids are 4 small glands - 3 x 6 mm with a total weight of about 0.4 g. They are located behind the thyroid gland, one at each end of the upper and lower poles, usually in the capsule that covers the lobes of the thyroid

AnatomyArterial supply usually from inferior thyroid artSuperior glands usually imbedded in fat on posterior surface of middle or upper portion of thyroid lobeLower glands near the lower pole of thyroid glandIn 1-5% pts, inferior gland in deep mediastinum

Histology

50/50 parenchymal cells, stromal fatChief cells secrete PTHWaterclear cells Oxyphil cellsPTH function

Synthesis, regulatory mechanism and secretion of PTH

Pre pro-PTH (115 amino acids) pro-PTH (90 amino acids) PTHThe biosynthesis and secretion of PTH is regulated by the plasma Ca2+ concentration:Acute Ca2+ plasma concentration PTH mRNA rate of PTH synthesis and secretion. PTH exists in storage vesicles, however most of the pro-PTH (80-90 %) synthesized is quickly degraded before it enters the storage vesicle, especially when Ca2+ in the parathyroid cells are high.PTH is secreted when Ca2+ in the parathyroid cells is low. Cathepsin B (a proteolytic enzyme) cleaves PTH into 2 fragments: PTH 1-36 and PTH 37-84. PTH 37-84 is not further degraded, however PTH 1-36 is rapidly and progressively cleaved into dipeptides and tripeptides. Most of the proteolysis of PTH occurs within the gland, but once PTH is secreted, is degraded in other tissue especially the liver by similar mechanism Ca2+ plasma concentration blocks production of PTH

Mechanism of action and Biologic effect of PTH on calcium and phosphate metabolismMechanism of action of PTHPTH binds to the cell surface receptor in the target cells stimulates the synthesis of cAMP.The action of PTH on bone and kidney are mediated through its G-protein linked receptor coupled to cAMP formation and increased protein phosphorylation.The intestinal action of PTH is indirect, mediated through the enhanced renal synthesis of active vitamin D

Biologic effect of PTH on calcium & phosphate concentrationPTH increases plasma Ca2+ concentration by:stimulating Ca2+ resorption from the bone and the kidneyincreasing dietary absorption of Ca2+ from the intestinePTH stimulates bone resorption, renal Ca reabsorption, and intestinal Ca absorption increased blood calcium level. PTH increases phosphate absorption from the bone, and in the intestine, but markedly increases phosphate excretion by the kidneys leading to decreased blood phosphate level.

Function of bone mineral; bone cells and bone remodeling Function of bone mineral: to strengthen a tough organic matrix of the bone. The crystalline salts (major: hydroxyapatite) deposited in the organic matrix of bone are composed principally of calcium and phosphate.Bone cells consist of osteoblast and osteoclast. Bone is continually being deposited by osteoblast, and absorbed where osteoclasts are active.Bone remodeling functions to adjust bone strength and shape in proportion to the degree of bone stress; and to maintain the normal toughness of boneFactors that contribute to the calcium metabolismCalcitonin: tends to decrease plasma calcium concentration and in general has effects opposite to those of PTH. intestinal absorption: increased if blood calcium level is decreased, regulated by PTH and vitamin D.Vitamin D: promote intestinal calcium absorption, decreases renal calcium excretion and bone absorption leading to increased blood calcium level.

PTH plays a major role in regulating the activation of vitamine D:High PTH stimulates the production of 1,25 dihydroxycholecalciferol (the active form of vit. D = calcitriol) by the kidney, which in turn enhance the transfer of intestinal Ca2+ to the blood.Low PTH induces formation of inactive 24,25 dihydroxycholecalciferol {24,25(OH)2D}.In bone, PTH and calcitriol act synergistically to promote bone resorption. In the kidney, PTH and calcitriol inhibit calcium excretion by stimulating calcium reabsorption in the distal renal tubules11Gain, maintenance and loss of bone Bone is deposited in proportion to the compressional load that the bone must carry. For instance, the bones of athletes become considerably heavier than those of non-athletes.Normally, except in growing bones, the rates of bone deposition and absorption are equal to each other so that the total mass of bone remains constant.Bone is also being continually absorbed in the presence of osteoclasts which are normally active on less than 1 per cent of the bone surfaces of an adult. Bone remodeling: the action of two types of bone cells:Osteoblasts: synthesize collagen fibrils that form the bulk of bones organic matrix where hydroxyapatite {Ca5(PO4)3OH} is laid down it is inhibited by PTHOsteoclasts : participate in bone resorption it is stimulated by PTH

The various parathyroid disorders, the causes of hypoparathyroisism

A.HypoparathyroidismSurgicalIdiopathicNeonatalFamilialDeposition of metals (Fe, Cu and Al)PostradiationInfiltrativeFunctional (in hypomagnesemia

b. Resistance to PTH actionPseudohypoparathyroidism

c. Primary hyperparathyroidismSporadicAssociated with MEN 1 or MEN 2AFamilialAfter renal transplantation

d. Variant forms of hyperparathyroidismFamilial benign hypocalciuric hypercalcemiaLithium therapyTertiaty hyperparathyroidism in chronic renal failure

Etiology of hypo- and hyperpathyroidism

Hypoparathyroidism is most commonly seen following thyroidectomy, when it is usually transient but may be permanent Hypoparathyroidism may also be seen in Di- Georges syndrome, along with congenital cardiac and facial anomalies Parathyroid deficiency may also be the result of damage from heavy metals such as copper (Wilsons disease) or iron (hemochromatosis, transfusion hemosiderosis), granulomas, sporadic autoimmunity, Riedels thyroiditis, tumors, or infection. Causes of hypocalcemia

1. Hypoparathyroidism2. Resistance to PTH actionPseudohypoparathyroidismRenal insufficiencyMedications that block osteodastic bone resorption PlicamycinCalcitoninBisphosphonates3. Failure to produce 1,25(OH)aD normally Vitamin D deficiencyHereditaty vitamin D -dependent rickets, type 1 (renal 25- OH-vitamin D 1 -hydroxylase deficiency)4. Resistance to 1 ,25(OH)2D actionHereditary vitamin 0-dependent rickets, type 2 (defectiveVDR

5. Acute complexation or deposition of calcium Acute hyperphosphatemiaCrush injury With myonecrosisRapid tumor lysisParenteral phosphate administrationExcessive enteral phosphateOral (phosphate-containing antacids) Phosphate-containing enemas6. Acute pancreatitis7. rated blood transfusion8. Rapid, excessive skeletal mineralization Hungry bones syndromeOsteoblastic metastasisVitamin D therapy for vitamin D deficiency

Ad 1. HypoparathyroidismHypoparathyroidism may be: surgical, autoimmune, familial, or idiopathic. The signs and symptoms are those of chronic hypocalcemiaBiochemically, the hallmarks of hypoparathyroidism are; hypocalcemia, hyperphosphatemia (because the phosphaturic effect of PTH is lost), and an inappropriately low or undetectable PTH levelClinical Features

Most of the symptoms and signs of hypocalcemia occur because

of increase neuromuscular excitability (tetany, paresthesias, seizures, organic brain syndrome)

or because of deposition of calcium in soft tissues (cataract, calcification of basal ganglia).

SYMTOM AND SIGN OF HYPOCALCEMIASYMTOM vometing diarhea nervousness weakness paresthesia muscle stiffnes and muscle cramps headaches abdominal pain 21Sign

Tetany/sceizure/muscle spasmPeripheral neurogic finding - CHVOSTKS SIGN - TROUSSEAUS SIGN Irritability,confussion,hallucination,dementia hair loss cataract papil edemaA. Neuromuscular manifestation

Clinically, the hallmark of severe hypocalcemia is tetany the classic muscular component of tetany is carpopedal spasm. These involuntary muscle contractions are painful. Although the hands are most typically involved, tetany can involve other muscle groups, including life-threatening spasm of laryngeal musdes23Lesser degrees of neuromuscular excitability (eg, serum calcium 79 mg/clL) produce latent tetany, which can be elicited by testing for Chvosteks and Trousseaus signs Chvosteks sign is elicited by rapping the facial nerve about 2 cm anterior to the earlobe, just below the zygoma. The response is a contraction of facial muscles ranging from twitching of the angle of the mouth to hemifacial contractions. The specificity of the test is low; about 25% of normal individuals have a mild Chvostek sign. Trousseaus sign is elicited by inflating a blood pressure cuff to about 20 mm Hg above systolic pressure for 3 minutes. A positive response is carpal spasm. Trousseaus sign is more specific than Chvosteks, but 14% of normals have positive Trousseau signs

Other central nervous system effects of hypocalcemia include pseudtumor cerebri, papilledema, confusion, lassitude, and organic brain syndrome.

B. Other manifestation of hypocalcemia

1. Cardiac effectsRepolarization is delayed, with prolongation of the QT interval. Excitation-contraction coupling may be impaired, and refractory congestive heart failure is sometimes observed, particularly in patients with underlying cardiac disease.2. Ophthalmologic effectsSubcapsular cataract is common in chronic hypocalcemia, and its severity is correlated with the duration and level of hypocalcemia3. Dermatologic effectsThe skin is often dry and flaky and the nails brittle. A de