Disorders of Parathyroid gland and Calcium levels
Dr. Shweta Agarwal MD (Medicine) Associate Professor, Department of Medicine, Career Institute of Medical Sciences & Hospital, Lucknow Outline of lecture
• Introduction – parathyroid gland and hormone • Regulation of PTH levels • Regulation of serum calcium levels • Calcitonin • Hypocalcemia – – Acute – Chronic – hypoparathyroidism and other causes
• Hypercalcemia – hyperparathyroidism and other causes – will be discussed in next lecture Introduction • 4 parathyroid glands posterior to thyroid gland • Parathyroid hormone - – 84-amino-acid single-chain peptide – primary regulator of calcium physiology • PTH acts directly on – Bone - induces calcium resorption – Kidney – stimulates • calcium reabsorption
• synthesis of 1,25-dihydroxyvitamin D [1,25(OH)2D] - stimulates GI calcium absorption. • Renal actions of the hormone are exerted at multiple sites and include – inhibition of phosphate transport (proximal tubule) – increased reabsorption of calcium (distal tubule) – stimulation of the renal 25(OH)D-1-hydroxylase • Hormone preserves calcium concentration in blood at the cost of bone destruction. Regulation of PTH levels
• Serum PTH levels are tightly regulated by a negative feedback loop. • Hypocalcemia (calcium-deficient diets) leads to increased secretion of PTH. • High calcium increases and low calcium inhibits the proteolytic destruction of hormone stores • Severe intracellular magnesium deficiency impairs PTH secretion Regulation of serum calcium levels
• Immediate control of blood calcium is due to PTH effects on – bone – renal calcium clearance. • Maintenance of steady-state calcium balance results from the effects of 1,25(OH)2D on calcium absorption Calcitonin • Hypocalcemic peptide hormone that acts as an antagonist to PTH. • Acts as tumor marker in sporadic and hereditary cases of medullary carcinoma • Used as pharmacologic agent to suppress bone resorption in Paget's disease and osteoporosis and in the treatment of hypercalcemia of malignancy • Acts by inhibition of osteoclast-mediated bone resorption and stimulation of renal calcium clearance • Thyroid is the major source of the hormone, and the cells involved in calcitonin synthesis arise from neural crest tissue HYPOCALCEMIA Acute hypocalcemia
• usually does not require specific tt. • Transient hypocalcemia - severe sepsis, burns, acute renal failure, and extensive transfusions with citrated blood; medications such as protamine, heparin, and glucagon • severe sepsis may have a decrease in ionized calcium (true hypocalcemia) • other severely ill, hypoalbuminemia is the primary cause of hypocalcemia • acute pancreatitis – hypocalcemia persists during the acute inflammation Chronic hypocalcemia • usually symptomatic and requires treatment. • Neuromuscular and neurologic manifestations – muscle spasms, carpopedal spasm, facial grimacing – in extreme cases, laryngeal spasm and convulsions • Respiratory arrest may occur • Increased intracranial pressure in some; often associated with papilledema • Mental changes include irritability, depression, and psychosis • QT interval on the ECG is prolonged (shortened in hypercalcemia) • Arrhythmias occur, digitalis effectiveness may be reduced • Intestinal cramps and chronic malabsorption may occur • Chvostek's or Trousseau's sign can be used to confirm latent tetany. • Chvostek's sign - twitching of the facial muscles in response to tapping over the area of the facial nerve about 2cm anterior to external auditory meatus • Trousseau's sign - carpopedal spasm caused by inflating the blood-pressure cuff to a level above systolic pressure for 3 minutes. Classification of Hypocalcemia PTH Absent • Hereditary hypoparathyroidism • Acquired hypoparathyroidism • Hypomagnesemia PTH Ineffective • Chronic renal failure • Active vitamin D lacking – Dietary intake or sunlight – Defective metabolism: Anticonvulsant therapy ; Vitamin D–dependent rickets type I • Active vitamin D ineffective – Intestinal malabsorption – Vitamin D–dependent rickets type II • Pseudohypoparathyroidism PTH Overwhelmed • Severe, acute hyperphosphatemia – Tumor lysis – Acute renal failure – Rhabdomyolysis • Osteitis fibrosa after parathyroidectomy Hypoparathyroidism – clinical features
• Hereditary hypoparathyroidism – – onset is more gradual, often associated with other developmental defects. – Basal ganglia calcification and extrapyramidal syndromes are more common and earlier in onset – alopecia and candidiasis – present when associated with autoimmune polyglandular failure • Both hereditary and acquired hypoparathyroidism - – Extraosseous calcification – extrapyramidal manifestations such as choreoathetotic movements and dystonia. – Papilledema and raised intracranial pressure – chronic changes in fingernails and hair – lenticular cataracts Hereditary hypoparathyroidism
• May be – – Isolated - Idiopathic hypoparathyroidism – Associated with other endocrine/ dermatological manifestations • DiGeorge syndrome – defective development of thymus and parathyroid gland. • HDR – hypoparathyroidism, deafness, renal dysplasia – Autosomal dominant Acquired hypoparathyroidism
Causes • Inadvertent surgical removal of parathyroid glands – surgery for hyperthyroidism/ hyperparathyroidism (commonest) • radiation-induced damage subsequent to radioiodine therapy of hyperthyroidism • Glandular damage in patients with hemochromatosis or hemosiderosis after repeated blood transfusions. • Infection may involve one or more of the parathyroids - rarely cause hypoparathyroidism when all four glands are involved • Transient hypoparathyroidism is frequent following surgery for hyperparathyroidism; normal parathyroid function may return due to hyperplasia or recovery of remaining tissue Hypoparathyroidism: Treatment
• Replacement with – Vitamin D - 40,000–120,000 U/d (1–3 mg/d) OR
– 1,25(OH)2D3 (calcitriol) - 0.5–1.0 g (better due to reduced conversion of vitamin D to 1,25(OH)2D) • Combined with calcium - 1 g (elemental) • Thiazides + Low-sodium diet are used to reduce hypercalciuria Hypomagnesemia
• Severe hypomagnesemia (<0.4 mmol/L; <0.8 meq/L) is associated with hypocalcemia • Two causes of the hypocalcemia— – impaired PTH secretion – reduced responsiveness to PTH • Serum phosphate levels are often not elevated, in contrast to that in acquired or idiopathic hypoparathyroidism • Repletion of magnesium cures the condition • Repletion should be parenteral • Renal magnesium wasting - Magnesium may have to be given chronically to prevent recurrence. Chronic Renal Failure
• Renal Osteodystrophy – characterised by - – calcium deficiency – secondary hyperparathyroidism – bone disease • Causative factors – – Phosphate retention – leads to • extraosseous deposition of calcium and phosphate • impairment of the bone-resorbing action of PTH • reduction in 1,25(OH)2D production by remaining renal tissue
– impaired production of 1,25(OH)2D - impairment of intestinal absorption of calcium Therapy - CRF
• Restriction of phosphate in the diet • Avoidance of aluminum-containing phosphate-binding antacids to prevent the problem of aluminum intoxication • Adequate calcium intake by mouth, usually 1– 2 g/d • Calcitriol supplement - 0.25–1.0 g/d Vitamin D Deficiency Due to • Inadequate Diet and/or • Sunlight Hepatocellular dysfunction – low 25(OH)D levels Bowel ds – malabsorption of Vit D and its metabolites
PTH hypersecretion compensates for the tendency for the blood calcium to fall but also induces renal phosphate wasting and results in osteomalacia Treatment involves adequate replacement with vitamin D and calcium Defective Vitamin D Metabolism
A - Anticonvulsant Therapy • increases the conversion of vitamin D to inactive compounds and/or • causes resistance to its action B - Vitamin D–Dependent Rickets Type I • less severe and can be reversed with vitamin D or active metabolite, 1,25(OH)2D3 • Autosomal recessive • Clinical features include hypocalcemia, often with tetany or convulsions, hypophosphatemia, secondary hyperparathyroidism, and osteomalacia, often associated with skeletal deformities and increased alkaline phosphatase. • Treatment - physiologic replacement doses of 1,25(OH)2D3 C - Vitamin D–dependent rickets type II • results from end-organ resistance to the active metabolite 1,25(OH)2D3 • mutations in the gene for the vitamin D receptor • Clinical features include hypocalcemia, hypophosphatemia, secondary hyperparathyroidism, and rickets but also partial or total alopecia
• Plasma levels of 1,25(OH)2D are at least three times normal Pseudohypoparathyroidism
• hereditary disorder • deficient end-organ response to PTH • Parathyroid hyperplasia - elevation of PTH levels • Low calcium, high phosphate • PHP Ia is associated with Albright's hereditary osteodystrophy (AHO) - short stature, round face, skeletal anomalies (brachydactyly), and heterotopic calcification • Amorphous deposits of calcium and phosphate in the basal ganglia • short fourth and fifth metacarpals and metatarsals • Treatment - similar to that of hypoparathyroidism; doses of vitamin D and calcium are usually lower PTH overwhelmed • Loss of calcium from the ECF is so severe that PTH cannot compensate – eg. acute pancreatitis and severe, acute hyperphosphatemia • Extensive tissue damage or cell destruction leads to – increased release of phosphate from muscle and – impaired ability to excrete phosphorus because of renal failure • causes moderate to severe hyperphosphatemia which causes calcium loss from the blood and mild to moderate hypocalcemia • Other causes of hyperphosphatemia – – hypothermia – massive hepatic failure – hematologic malignancies - because of • high cell turnover of malignancy or • cell destruction by chemotherapy • Treatment - – lowering of blood phosphate by the administration of phosphate-binding antacids or dialysis – calcium replacement – only if hypocalcemia is severe and symptomatic as it tends to increase extraosseous calcium deposition and aggravate tissue damage Osteitis Fibrosis after Parathyroidectomy • Severe hypocalcemia after parathyroid surgery is rare • Osteitis fibrosa cystica - infrequent manifestation of hyperparathyroidism. • When osteitis fibrosa cystica is severe, bone mineral deficits can be large. • After parathyroidectomy, hypocalcemia can persist for days if calcium replacement is inadequate. • Treatment may require parenteral administration of calcium; addition of calcitriol and oral calcium supplementation is sometimes needed for weeks to a month or two until bone defects are filled Suggested reading
• Diseases of the Parathyroid Gland and Other Hyper- and Hypocalcemic Disorders; Harrison’s Principles of Internal Medicine.
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