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Disorders of Calcium Metabolism: Hypercalcemia Dr. BHUMIKA KATOCH (F5) REVIEW, Ca++ metabolism: PTH, Vitamin D and Calcium homeostasis 1. Calcium and phosphorus 2. Bone Vitamin D Parathyroid Hormone Calcitonin 3. 4. 5. Extracellular Calcium • Three definable fractions of calcium in serum: – Ionized calcium 50% – Protein-bound calcium 41% • 90% bound to albumin – Calcium complexed to serum constituents 9% • Citrate and phosphate Calcium turnover Renal Excretion • The kidneys account for the bulk of regulated calcium excretion • Three distinct locations along the renal tubule are involved • The regulation of calcium excretion at each of the three renal sites is different Renal Excretion • Proximal convoluted tubule – Accounts for 70% of calcium reabsorption – Mainly paracellular pathway Renal Excretion • Proximal convoluted tubule • Thick ascending limb of loop of Henle 20 % of calcium reabsorption Calcium sensing receptor (CaSR) FHH, FBH (familial benign/hypocalciuric hypercalcemia) Caskey F J , Pickett T M Nephrol. Dial. Transplant. 2005;20:1752-1755 Renal Excretion • Proximal convoluted tubule • Thick ascending limb • Distal convoluted tubule – PTH regulation – 8% of calcium reabsorption 20-8 PTH, Vitamin D and Calcium homeostasis 1. Calcium and phosphorus 2. Bone 3. Vitamin D Parathyroid Hormone Calcitonin 4. 5. 20-9 Calcium Regulation: Bone Exchange • Bone is dynamic and is constantly remodeled • Calcium is exchanged between blood and bone daily (roughly 400 mg/day); 10% of skeleton per year • Ongoing remodeling allows bone to store and release calcium as needed to help maintain homeostasis Normal bone remodeling cycle GI: ◦ Nausea, vomiting, abdominal pain ◦ Constipation Renal: ◦ Polyuria, dehydration ◦ Renal failure ◦ Nephrolithiasis Neurological ◦ Fatigue ◦ Confusion ◦ Depression ◦ Stupor, coma Skeletal ◦ Bone pain and tenderness ◦ Spontaneous fracture (compression fx’s) Hyperparathyroidism/Hypercalcemia – signs/symptoms Neuromuscular ◦ Muscle weakness, hypotonia Cardiovascular ◦ Hypertension ◦ Short QT interval Primary hyperparathyroidism (PHPT) Malignancy Others Primary ◦ Adenoma (90%) ◦ Multiple gland enlargement (10%) MEN 1 MEN 2A Familial hyperparathyroidism ◦ Carcinoma (<1%) ◦ Familial benign hypercalcemia (FBH) Secondary (normo- or hypocalcemic) ◦ Renal failure ◦ Vitamin D deficiency Primary hyperparathyroidism • Affects approximately 100,000 patients a year. • Prevalence: 0.1 to 0.3% of the general population. • More common in women (1:500) than in men (1:2000). • Patients with single adenoma (~90%): minimally invasive surgery Sestamibi imaging ~90% sensitive, ~98% specific Minimally invasive = incision length < 2.5 cm Intraoperative PTH testing confirms biochemical cure PTHrP - mediated ◦ Breast carcinoma ◦ Squamous carcinoma (lung, head & neck, esophagus) ◦ Renal carcinoma Cytokine/osteoclast activating factor mediated ◦ Myeloma (lymphoma, leukemia) Tumor production of calcitriol ◦ Lymphoma Drugs: ◦ ◦ ◦ ◦ ◦ Vitamin D Calcium carbonate (milk alkali syndrome) Lithium Thiazide diuretics Vitamin A Sarcoidosis, other granulomatous disorders Hyperthyroidism Hypercalcemia - Treatment – NS bolus to restore volume; then 100 – 200 ml/hr – Bisphosphonates (onset 24-48 hrs) – Calcitonin 4 – 8 IU q6-8 hrs (onset immediate, resistance develops in 24-48 hrs) – [Mg and K prn] REGULATION OF RENAL 1α-HYDROXYLASE PRODUCTION Stimulates Inhibits PTH Low calcium Low phosphate Calcitonin 1,25(OH)2D3 High calcium High phosphate Summary: vitamin D action • Main action of 1,25-(OH)2-D is to stimulate absorption of Ca2+ (and phosphate) from the intestine. also: • acts on osteoblasts to increase RANKL and thus activate osteoclasts to increase Ca++ resorbtion. • is necessary for proper bone formation. Parathyroid Hormone Calcium regulates PTH secretion via a CaSR PTH and calcium+phosphate homeostasis Calcitonin • Decreases plasma Ca2+ and phosphate concentrations, mainly by decreasing bone resorption. • Synthesized and secreted by the parafollicular cells (aka C cells) of the thyroid gland. • Release stimulated by hypercalcemia and inhibited by hypocalcemia Slide credit: Dale Buchanan Hales Ph.D. Calcitonin effects • Calcitonin rapidly inhibits osteoclast activity o causes inhibition of osteoclast motility, alterations in cell morphology and osteoclast inactivation. • Kidneys o inhibits calcium reabsorption (increases excretion) o also increases phosphorus excretion • Role in calcium homeostasis unclear Hormone Effect on bones Effect on gut Effect on kidneys Parathyroid hormone increase Ca++, decrease PO4 levels in blood Promotes resorption Indirect effects via increase in calcitriol from 1hydroxylation Promotes Ca++ reabsorption and PO4 excretion, activates 1hydroxylation Calcitriol (RANKL→bone (vitamin D) Ca++, PO4 levels resportion) increase in blood Increases Ca++ and PO4 absorption No direct effects Calcitonin No direct effects Promotes Ca++ and PO4 excretion Inhibits resorption Hypocalcemia: clinical signs • • • • • Paresthesias Tetany (carpopedal spasm) Trousseau’s, Chvostek’s signs Seizures Chronic: cataracts, basal ganglia Ca Trousseau’s sign Hypocalcemia: causes • Hypoparathyroidism – Surgical (thyroid, parathyroid surgery) – Autoimmune – Magnesium deficiency • PTH resistance (pseudohypoparathyroism) • Vitamin D deficiency • Vitamin D resistance • Other: renal failure, pancreatitis, tumor lysis