Disorders of Calcium Metabolism: Hypercalcemia Dr. BHUMIKA KATOCH (F5)

Calcium and phosphorus Bone Vitamin D Parathyroid Hormone Calcitonin REVIEW, Ca++ metabolism: PTH, Vitamin D and Calcium homeostasis Calcium and phosphorus Bone Vitamin D Parathyroid Hormone Calcitonin

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 FHH, FBH (familial benign/hypocalciuric hypercalcemia) 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 Distal convoluted tubule PTH regulation Proximal convoluted tubule Thick ascending limb Distal convoluted tubule PTH regulation 8% of calcium reabsorption 20-8

Calcium and phosphorus Bone Vitamin D Parathyroid Hormone Calcitonin PTH, Vitamin D and Calcium homeostasis Calcium and phosphorus Bone Vitamin D Parathyroid Hormone Calcitonin 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

Hypercalcemia/hyperparathyroidism: clinical signs 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

Hypercalcemia: major causes Primary hyperparathyroidism (PHPT) Malignancy Others

Hyperparathyroidism: causes 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

Malignant hypercalcemia: major causes 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

Hypercalcemia: other causes 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 PTH Low calcium Low phosphate Calcitonin Inhibits 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 causes inhibition of osteoclast motility, alterations in cell morphology and osteoclast inactivation. Kidneys inhibits calcium reabsorption (increases excretion) also increases phosphorus excretion Role in calcium homeostasis unclear

Parathyroid hormone increase Ca++, decrease PO4 levels in blood 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 1-hydroxylation Promotes Ca++ reabsorption and PO4 excretion, activates 1-hydroxylation Calcitriol (vitamin D) Ca++, PO4 levels increase in blood (RANKL→bone resportion) Increases Ca++ and PO4 absorption No direct effects Calcitonin Inhibits resorption Promotes Ca++ and PO4 excretion

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