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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 dermatitis known as impetigo herpetiformis or pustular psoriasis is peculiar to hypocalcemia.

B. LABORATORY FINDINGS

Serum calcium is low, serum phosphate high, urinary calcium low, and alkaline phosphatase normal. Parathyroid hormone levels are low. Serum magnesium should be determined since hypomagnesemia frequently accompanies hypocalcemia and may exacerbate symptoms and decrease parathyroid function.

C. IMAGINGRadiographs or CT scans of the skull may show basal ganglia calcifications; the bones may be denser than normal. Cutaneous calcification may occur.

D. OTHER EXAMINATIONSSlit-lamp examination may show early posterior lenticular cataract formation. The ECG shows prolonged QT intervals and T wave abnormalities.The principles of management of hypo- and hypercalcemia

TREATMENT OF HYPOCALCEMIA

a. Acute HypocalcemiaPatients with tetany should receive intravenous calcium as calcium chloride (272 mg calcium per 10 mL), calcium gluconate (90 mg calcium per 10 mL), or calcium gluceptate (90 mg calcium per 10 mL). Approximately 200 mg of elemental calcium can be given over several minutes. The patient must be observed for stridor and the airway secured if necessary. Oral calcium and a rapidly acting preparation of vitamin D should be started. If necessary, calcium can be infused in doses of 4001000 mg/24 h until oral therapy has taken effect. Intravenous calcium is irritating to the veins. Caution must be exercised in patients taking digitalis, since they are predisposed to toxicity by infusion of calcium.

B. Chronic HypocalcemiaThe objective of chronic therapy is to keep the patient free of symptoms and to maintain a serum calcium of approximately 8.59.2 mgIdL. With lower serum calcium levels, the patient may not only experience symptoms but may be predisposed over time to cataracts. With serum calcium concentrations in the upper normal range, there may be marked hypercalciuria, which occurs because the hypocalciuric effect of PTH has been lost. This may predispose to nephrolithiasis, nephrocalcinosis, and chronic renal insufficiency. In addition, the patient with a borderline elevated calcium is at increased risk of overshooting the therapeutic goal, with symptomatic hypercalcemia.The mainstays of treatment are calcium and vitamin D. Oral calcium can be given in a dose of 1.53 g of elemental calcium per day. These large doses of calcium reduce the necessary dose of vitamin D and allow for rapid normalization of calcium if vitamin D intoxication subsequently occurs. Numerous preparations of Calcium are available.

A short-acting preparation of vittamin D (calcitriol) and the very long-acting preparations such as vitamin D2 (ergocalciferol) are available. By far the most inexpensive regimens are those that use ergocalciferol. In addition to economy, they have the advantage of rather easy maintenance in most patients. The disadvantage is that ergocalciferol can slowly accumulate and produce delayed and prolonged vitamin D intoxication. Caution must be exercised in the introduction of other drugs that influence calcium metabolism. For example, thiazide diuretics have a hypocalciuric effect. By reducing urinary calcium excretion in treated patients, whose other adaptive mechanisms, PTH and 1,25(OH)2D3, are n000perative and who are thus absolutely dependent on renal excretion of calcium to maintain the serum calcium level, thiazides may produce severe hypercalcemia. In a similar way, intercurrent illnesses that compromise renal function may produce dangerous hypercalcemia in the patient who is maintained on large doses of vitamin D. Short-acting preparations are less prone to some of these effects but may require more frequent titration and are much more expensive than vitamin D2.

HyperparathyroidismPrimary Hyperparathyroidism Normal feedback of Ca disturbed, causing increased production of PTHSecondary HyperparathyroidismDefect in mineral homeostasis leading to a compensatory increase in parathyroid gland functionTertiary HyperparathyroidismAfter prolonged compensatory stimulation, hyperplastic gland develops autonomous functionPrimary HyperparathyroidismEpidemiology25/100,000 50,000 new cases yearlyF > MIncidence increases w/ ageMost in > 50 years old

EtiologyUnknown causeSingle gland adenomatous diseaseMultiglandular disease exogenous stimulusOverexpression of PRAD1 oncogene controlls cell cycleIonizing radiation exposureClinical PresentationNephrolithiasisBone DiseasePeptic Ulcer DiseasePsychiatric disordersMuscle weaknessConstipationPolyuriaPancreatitisMyalgiaArthralgia302121570322815454HypercalcemiaI.Parathyroid-related-Primary hyperparathyroidism-Lithium therapy-Familial hypocalciuric hypercalcemiaII. Malignancy-related-Solid tumor with metastases (breast)-Solid tumor with humoral mediation of hypercalcemia (lung, kidney)-Hematologic malignancies (multiple myeloma, lymphoma, leukemia)III. Vitamin D-related-Vitamin D intoxication- 1,25(OH)2D; sarcoidosis and other granulomatous diseases-Idiopathic hypercalcemia of infancyIV. Associated with high bone turnover-Hyperthyroidism-Immobilization-Thiazides-Vitamin A intoxicationV. Associated with renal failure-Severe secondary hyperparathyroidism-Aluminum intoxication-Milk-alkali syndrome**Primary hyperparathyroidism and cancer account for 90% of cases of hypercalcemia38Familial Hypocalciuric HypercalcemiaThis benign condition can be easily mistaken for mild hyperparathyroidism. It is an autosomal dominant inherited disorder characterized by hypocalciuria (usually < 50 mg/24 h), variable hypermagnesemia, and normal or minimally elevated levels of PTH. These patients do not normalize their hypercalcemia after subtotal parathyroid removal and should not be subjected to surgery. The condition has an excellent prognosis and is easily diagnosed with family history and urinary calcium clearance determination.

39Secondary HyperparathyroidismDecreased GFR leads to reduced inorganic phosphate excretion and consequent phosphate retention Retained phosphate has a direct stimulatory effect on PTH synthesis and on cellular mass of the parathyroid glandsRetained phosphate also causes excessive production and secretion of PTH through lowering of ionized Ca2+ and by suppression of calcitriol productionReduced calcitriol production results both from decreased synthesis due to reduced kidney mass and from hyperphosphatemia. Low calcitriol levels, in turn, lead to hyperparathyroidism via both direct and indirect mechanisms. Calcitriol is known to have a direct suppressive effect on PTH transcription and therefore reduced calcitriol in CRD causes elevated levels of PTHReduced calcitriol leads to impaired Ca2+ absorption from the GI tract, thereby leading to hypocalcemia, which then increases PTH secretion and production. 40Secondary HPTClinical presentationUsually asymptomaticDiagnosisElevated PTH in the setting of low or normal serum calcium is diagnosticIf phosphorous is elevated, cause is renalIf phosphorous is low, other causes of vit D deficiency should be soughtPreventionVit D replacementPhosphorus binders [Sevelamer]TreatmentMedicalCalcimimetic agentsSurgicalConsidered in cases of refractory severe hypercalcemia, severe bone disease, severe pruritis, calciphylaxis, severe myopathy

41Tertiary HyperparathyroidismTertiary hyperparathyroidism develops in patients with long-standing secondary hyperparathyroidism, which stimulates the growth of an autonomous adenoma. A clue to the diagnosis of tertiary hyperparathyroidism is intractable hypercalcemia and/or an inability to control osteomalacia despite vitamin D therapy.

Surgical Referral- calcium- phosphate product > 70- severe bone disease and pain -intractable pruritus- extensive soft tissue calcification with tumoral calcinosis -calciphylaxis

42Lab AbnormalitiesPrimary HPTIncreased serum calciumPhosphorus in low normal rangeUrinary calcium elevatedSecondary HPT (renal etiology)Low or normal serum calciumHigh phosphorusTertiary HPT (renal etiology)High calcium and phosphorus43Bone DiseaseOsteitis fibrosa cysticaIn early descripts of disease, many had severe bone disease (50-90%), but now 5-15%Subperiosteal resorption pathognomonic of hyperparathyroidism

Familial SyndromesMEN I MEN IIAFamilial Hypocalciuric HypercalcemiaHyperparathyroidism-jaw tumor syndromeFibro-osseous jaw tumorsRenal cystsSolid renal tumors Familial isolated hyperparathyroidism

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STIGMATA OF MEN ILipomasCollagenomasAngiofibromas46Renal ComplicationsGenerally the most severe clinical manifestationsMany have frequency, polyuria, polydipsiaUsually present w/ nephrolithiasis (20-30%)Calcium phosphate or Calcium oxalateNephrocalcinosis (in 5-10%) calcification w/in parenchyma of kidneysSevere renal damageHypertension secondary to renal impairmentGastrointestinal ManifestationsPeptic Ulcer disease Pancreatitis Cholelithiasis 25-35%Emotional DisturbancesHypercalcemia of any cause assoc w/ neurologic or psychiatric disturbancesDepression, anxiety, psychosis, comaSevere disturbances not usually correctable by parathyroidectomy

Articular and Soft TissueChondrocalcinosis and Pseudogout 3-7%Deposits of Calcium pyrophosphate in articular cartilages and menisciVascular and Cardiac calcificationsNeuromuscular complicationsMuscular weakness, fatigueMore commonly in proximal musclesSensory abnormalities also possible

Laboratory DiagnosisElevated Serum Ca and PTHMust measure Ionized Ca (subtle cases of hyperPTH will have normal Serum Ca)50% will have hypophosphatemia Elevated Alkaline Phosphatase in 10-40%Hyperchloremic metabolic acidosis Low Mg in 5-10%High Urinary Ca in almost all casesHyperparathyroid crisisMost pts w/ hyperparathyroidism chronically ill w/ renal and skeletal abnormalitiesRarely can become acutely illRapidly developing weakness, N/V, weight loss, fatigue, drowsiness, confusion, AzotemiaUncontrolled PTH production, hyperCa, polyuria, dehydration, reduced renal function, worsening hyperCaHyperparathyroid CrisisDefinitive therapy - resection Must reverse hyperCa firstDiuresis - Saline hydration then Lasix to excrete CaCalcitonin - rapid affect, inhibits bone resorptionSteroids - take up to a weekMithramycin - rapidly inhibiting bone resorption

TreatmentOnly Curative treatment - ParathyroidectomyWho should have surgery? Many found incidentally, assx

Surgical CandidacySymptomatic primary HPTNIH Consensus Development Panel 2002 Revised Guidelines [if any of the following are met]Serum calcium greater than 1mg/dL above the upper limit of the reference range24 hour urine calcium greater than 400 mgCreatinine clearance reduced by more than 30% compared with age-matched subjectsBone density at the lumbar spine, hip, or distal radius more than 2.5 SD below peak bone massAge under 50Patients for whom medical surveillance is not desirable or possible

creatinine clearance (mL/min) = ((urine creatinine in mg/dL) * (urine volume in mL)) / ((plasma creatinine in mg/dL) * (time period in minutes))56Other Considerations in Surgical ReferralNeuropsychological abnormalitiesSeveral studies document improvement in HRQL after parathroidectomyStudies on neurobehavioral abnormalities have reported less consistent results with parathyroidectomyCardiovascular abnormalitiesSymptomatic patients suffer from increased cardiovascular mortality before and after treatmentAsymptomatic primary HPT is associated with LVH; some studies suggest this is reversible with parathyroidectomyPrimary HPT patients have increased calcifications of mitral and aortic valvePerimenopausal womenAsymptomatic primary HPT associated with increased bone turnover, reduced bone mineral density and higher risk for fractures

57Medical ManagementAsymptomatic patients may elect to be closely followed and managed medicallyA recent study of pts with asymptomatic primary HPT showed that the majority of pts followed for ten years did not demonstrate an increase in serum calcium or PTH levels25% of patients had progressive disease including worsening hypercalcemia, hypercalciuria and reduction in bone massyounger patients more likely to have progression of disease Patients opting not to have surgery should have a serum calcium level drawn every 6 months and should have annual bone densiometry at all three sites

58Medical Management Primary HPTEstrogenDose required is highSERMsReduction in serum calcium and markers of bone turnover after 4 weeksBisphosphonatesStudies have shown increase in lumbar spine and femoral neck mineral densityCalcium/Vitamin DCalcimimetic agents (Cinacalcet)Under investigation for primary HPT59