THE PARATHYROID

PTH/Calcium Homeostasis

PTH Renal effects (steady state maintenance) Inhibition of phosphate transport Increased reabsorption of calcium Stimulation of 25(OH)D-1alpha-hydroxylase Bone effects (immediate control of blood Ca) Causes calcium bone release within minutes Chronic elevation increases bone remodeling and increased osteoclast-mediated bone resorption However, PTH administered intermittently has been shown to increase bone formation and this is a potential new therapy for osteoporosis

Disorders of the Parathyroid Glands Calcitonin is released by the “C” cells (parafollicular cells in the thyroid gland) in response to small increases in plasma ionic calcium. It acts on the kidney and bones to restore the level of calcium to just below a normal set point which in turn inhibits secretion of the hormone. Calcitonin is therefore the physiological antagonist of PTH. The two hormones act in concert to maintain normal concentration of calcium ion in the extracellular fluid

Classification of disease of parathyroid Hormone excess -primary primary hyperpara (adenoma, ca, hyperplasia) tertiary after prolong secondary -secondary secondary hyperpara (CRF) ,malabsorption, vit D deficincy

Hormone def- post surgical, autoimmune, inherted H hypersensitivity-hypercalcemic hypocalciuria H resistance-pseudohypoparathyroidism familial hypocalciuric hypercalc. --Parathyroid carcinoma

Primary HPT: Clinical Features Symptomatic: Osteitis fibrosa cystica Nephrolithiasis Pathologic fractures Neuromuscular disease Life-threatening hypercalcemia ?Peptic Ulcer Disease ?Asymptomatic: Fatigue Subjective muscle weakness Depression Increased thirst Polyuria Constipation Musculoskeletal aches and pains

X-rays: sub-periosteal resorption pepper pot skull rugger jersey spine cystic brown tumours

X-rays: sub-periosteal resorption pepper pot skull rugger jersey spine cystic brown tumours

Diagnosis *High s. Ca, high PTH *Serum phosphate is usually low but may be normal. *Hypercalcaemia is common *blood alkaline phosphatase (of bone origin) *urinary hydroxyproline concentrations elevated *Nephrogenous CAMP is elevated in about 80%

Pre-Operative Imaging High-resolution ultrasound Sensitivity 65-85% for adenoma; 30-90% for enlarged gland Results suboptimal in pts with multinodular thyroid disease, pts with short thick neck, ectopic glands (15-20%) May be useful in detecting sestamibi scan negative adenomas CT with contrast/thin section Sensitivity of 46-87% Good for ectopic glands in the chest MRI Sensitivity of 65-80% Good for ectopic glands Sestamibi 85-95% accurate in localizing adenoma in primary HPT Sestamibi-SPECT Sensitivity 60% for enlarged gland and 98% for solitary adenomas

Medical Management Asymptomatic patients may elect to be closely followed and managed medically A 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 levels—25% of patients had progressive disease including worsening hypercalcemia, hypercalciuria and reduction in bone mass—younger 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 Estrogen Bisphosphonates Studies have shown increase in lumbar spine and femoral neck mineral density Calcium/Vitamin D Surgery

Surgical Treatment Clinical indications for surgery in patients with primary hyperparathyroidism Significant symptoms of hypercalcemia Nephrolithiasis Decreased bone mass Serum Calcium > 12 mg/dl Age< 50 years Infeasibility of longterm follow up

Secondary Hyperparathyroidism Decreased 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 glands Retained phosphate also causes excessive production and secretion of PTH through lowering of ionized Ca2+ and by suppression of calcitriol production Reduced calcitriol production results both from decreased synthesis due to reduced kidney mass and from hyperphosphatemia.

Secondary HPT Clinical presentation Usually asymptomatic Diagnosis Elevated PTH in the setting of low or normal serum calcium is diagnostic If phosphorous is elevated, cause is renal If phosphorous is low, other causes of vit D deficiency should be sought Prevention Vit D replacement Phosphorus binders [Sevelamer] Treatment Medical Calcimimetic agents Surgical Considered in cases of refractory severe hypercalcemia, severe bone disease, severe pruritis, calciphylaxis, severe myopathy

Hypoparathyroidism Clinical Features: Neuromuscular Parathesia Tetany Convulsion Signs of latent tetany Chvostek sign Trousseau sign Extrapyramidal signs (due to basal ganglia calcification) Other clinical manifestation Posterio lenticular cataract Cardiac manifestation: Prolonged QT interval in the ECG Refractory heart failure with cardiomegally 3.Dental 4.malabsorption

CALCIUM HEMOSTASIS

Hypercalcemia I.Parathyroid-related -Primary hyperparathyroidism -Lithium therapy -Familial hypocalciuric hypercalcemia II. 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 infancy IV. Associated with high bone turnover -Hyperthyroidism -Immobilization -Thiazides -Vitamin A intoxication V. Associated with renal failure -Severe secondary hyperparathyroidism -Aluminum intoxication -Milk-alkali syndrome **Primary hyperparathyroidism and cancer account for 90% of cases of hypercalcemia

Differential Diagnosis Causes of Hypercalcemia Parathyroid - related Vitamin D – related Primary hyperparathyroidism Solitary adenomas Multiple endocrine neoplasia Lithium therapy Familial hypocalciuric hypercalcemia Vitamin D intoxication 1,25(OH)2D; sarcoidosis and other granulomatous diseases Idiopathic hypercalcemia or infancy

Differential Diagnosis Causes of Hypercalcemia Associated with high bone turnover Malignancy - related Solid tumor with metastases(breast) Solid tumor with humoral mediation of hypercalcemia (lung kidney) Hematologic malignancies (multiple myeloma, lymphoma, leukemia) Hyperthyroidism Immobilization Thiazides Vitamin A intoxication Assocated with Renal Failure: Severe secondary hyperparathyroidism Aluminum intoxication Milk alkali syndrome

Etiologies of Hypocalcemia Decreased GI Absorption Poor dietary intake of calcium Impaired absorption of calcium Vitamin D deficiency Poor dietary intake of vitamin D Malabsorption syndromes Decreased conversion of vit. D to calcitriol Liver failure Renal failure Low PTH Hyperphosphatemia Decreased Bone Resorption/Increased Mineralization PTH resistance Vitamin D deficiency / low calcitriol Hungry bones syndrome Osteoblastic metastases Increased Urinary Excretion Low PTH s/p thyroidectomy s/p I131 treatment Autoimmune hypoparathyroidism PTH resistance Vitamin D deficiency / low calcitriol

HyPOCALCEMIA Disease CAL Ca+ Ph PTH Alkalosis - low - -or high Vit D def low low low high CRF low low high high Hypopara low low high low Psudohypo low low high high Pancreatitis low low low high Hypoalbumin low - - -

Pharmacologic options of hypercalcemia Normal Saline 2-4 L IV daily for 1-3 days Enhances filtration and excretion of CA++. Indication: Ca > 14 mg/dl, moderate Calcium with symptoms Caution: may exacerbate heart failure in elderly patients. Lowers Calcium by 1-3 mg/dl

Pharmacologic options Furosemide 10-20 mg IV as necessary Inhibits calcium resorption in distal renal tubule. Indication: following aggressive hydration Caution: hypokalemia, dehydration if used before intravascular volume is restored

Pharmacologic options Bisphosphonates Pamidronate Zoledronic acid Inhibits osteoclast action and bone resporption Indication: hypercalcemia of malignancy

Management of hypocalcemia Dependent on the underlying cause and severity Administration of calcium alone is only transiently effective Mild asymptomatic cases: Often adequate to increase dietary calcium by 1000 mg/day Symptomatic: Treat immediately (Ca gluconate 20% 20cc in 20 min). Consider activated Vit D Respiratory alkalosis (treat accordingly)

Osteoporosis - Idiopathic osteoporosis - normal investigations - In old patients we have to role out malignancy and multiple myeloma - Younger patients must be fully investigated - Several causes may be involved - Osteoporosis can be associated with osteomalacia

Osteoporosis Symptoms & Signs - Bony aches - Easy fractures spine - lower radius - femoral neck - Rib fracture , chest pain - Normal biochemistry

Osteoporosis X-rays - Decrease bone density - Wedging or biconcave vertebrae - Thin cortex and deformities - Dexa Scan - Biopsy

Osteoporosis Treatment - Treat underlying cause - Idiopathic , extremely difficult - Calcium and vitamin D - Fluoride and triple therapy - Calcitonin , Diphosphonate - Treat fractures