Hypercalcemia and hypocalcemia Notes

NOTES NOTES HYPERCALCEMIA & HYPOCALCEMIA GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Calcium concentrations in the blood falling outside of the normal reference range ▪ Hypocalcemia: < 8.5mg/dL ▪ Hypercalcemia: > 10.5mg/dL SIGNS & SYMPTOMS ▪ Variations that are mild, or slow in onset, usually asymptomatic ▪ Hypercalcemia → less excitable neurons and associated symptoms across multiple systems ▪ Hypocalcemia → more excitable neurons and associated symptoms across multiple systems DIAGNOSIS LAB RESULTS ▪ Blood calcium levels ▪ Determination of underlying cause (blood tests for levels of) ▫ Parathyroid hormone, vitamin D, albumin, phosphorus, magnesium OTHER DIAGNOSTICS ECG ▪ Identify associated organ dysfunction TREATMENT MEDICATIONS Hypercalcemia ▪ Lower blood calcium levels ▫ Rehydrate, loop diuretics, glucocorticoids, bisphosphonates or calcitonin, dialysis Hypocalcemia ▪ Raise calcium levels ▫ Calcium gluconate ▫ Vitamin D supplementation 794 OSMOSIS.ORG

Chapter 111 Hypercalcemia & Hypocalcemia HYPERCALCEMIA osms.it/hypercalcemia PATHOLOGY & CAUSES ▪ High blood calcium (> 10.5mg/dL) ▪ True hypercalcemia due to elevation of free ionized calcium (not protein-bound, which is 40–45% of total calcium) CAUSES Excessive bone resorption ▪ Hyperparathyroidism ▫ Most common cause ▫ Increased osteoclastic bone resorption ▫ Overactive parathyroid → releases more parathyroid hormone → stimulates osteoclasts → osteoclasts break down bone → release calcium into blood ▪ Thyrotoxicosis ▫ Thyroid hormone mediated increase in bone reabsorption ▪ Malignant tumors ▫ Can secrete parathyroid hormonerelated protein (PTHrP) ▫ Can cause osteoblast cells to die ▫ Can also cause overstimulation of osteoclasts → lytic bone lesions ▫ Can directly invade bone ▪ Uncommon causes ▫ Immobilisation, Paget disease of bone, anti-oestrogen treatment, hypervitaminosis A (retinoic acid → dose dependent increase in bone resorption) ▫ Thiazide diuretics (increase calcium reabsorption in distal tubule of kidney) ▫ Lithium (increase calcium reabsorption from the loop of Henle, also interferes with normal hypercalcemic feedback on the parathyroid gland) ▫ Calcium carbonate supplementation ▪ Milk-alkali syndrome ▫ Extra calcium from diet, alkali found in antacids) ▫ Hypercalcemia, metabolic alkalosis, renal insufficiency Insufficient excretion ▪ Adrenal insufficiency (e.g. Addisonian crisis) ▪ Adrenal failure (e.g. rhabdomyolysis) False hypercalcemia / pseudohypercalcemia ▪ Hyperalbuminemia → ↑ albumin → ↑ protein-bound calcium → ↑ total calcium ▫ Free ionized calcium concentrations remain the same (hormonal regulation) ▫ Total calcium high, free ionized calcium normal ▫ Rare cause: dehydration COMPLICATIONS ▪ Calcium oxalate kidney stones (hypercalciuria, fluid loss) ▪ Osteoporosis (depletion of calcium stores in bone) ▪ Renal failure ▪ Cardiac arrhythmias ▪ Confusion, dementia, coma Excessive calcium absorption ▪ Excess vitamin D ▫ Stimulates active intestinal absorption, resorption from bone and increased renal reabsorption ▪ Diet or excessive supplementation ▫ When intake exceeds 2 grams daily, passive transport may also lead to hypercalcemia ▪ Medications OSMOSIS.ORG 795

SIGNS & SYMPTOMS ▪ Many individuals asymptomatic ▪ Slow chronic onset, better tolerated ▪ Neurological ▫ Neurons less excitable ▫ Blurred vision, slow or absent reflexes ▫ Central nervous system: fatigue, anxiety, confusion, hallucinations, stupor ▪ Cardiovascular ▫ Arrhythmias, shortened QT interval, bradycardia, hypertension ▪ Musculoskeletal ▫ Generalized muscle weakness, bone pain, weak bones ▪ Gastrointestinal ▫ Anorexia, nausea and vomiting, constipation ▪ Renal ▫ Hypercalciuria, polyuria, polydipsia, kidney stones, distal renal tubular acidosis, nephrogenic diabetes insipidus, renal insufficiency DIAGNOSIS LAB RESULTS ▪ High calcium levels in blood > 10.5mg/dL ▪ Calcium levels must be corrected for albumin levels or measure free ionized calcium ▫ Albumin: may be ↑ in pseudohypercalcemia ▪ Parathyroid hormone: ↑ or ↓ ▪ PTH-related hypercalcemia: primary hyperparathyroidism and familial hyperparathyroidism ▪ Non-PTH-related hypercalcemia: primary malignancy, intoxication of vitamin D, granulomatosis ▪ PTH-related peptide: may ↑ in certain malignancies 796 OSMOSIS.ORG ▪ Vitamin D: may be ↑ in intoxication ▪ Phosphate: ↑ or ↓ depending if PTHdependent (high in renal insufficiency, hypoparathyroidism, low in vitamin D deficiency) ▪ Magnesium: hypercalcemia may ↓ Mg levels OTHER DIAGNOSTICS ECG ▪ Bradycardia ▪ Atrioventricular block ▪ Shortening of QT interval ▪ Osborn wave (positive deflection at junction between QRS complex and ST segment) TREATMENT MEDICATIONS ▪ Main goal: lower calcium levels in blood ▪ Rehydrate: increases urinary excretion of calcium ▪ Loop diuretics: inhibit calcium reabsorption, so more is excreted ▪ Glucocorticoids: decrease gastrointestinal calcium absorption ▪ Bisphosphonates or calcitonin: inhibit osteoclasts, prevent bone resorption ▪ Dialysis: if renal failure is present, consider hemodialysis or peritoneal dialysis MNEMONIC The effects of hypercalcemia Stones: renal or biliary calculi Bones: bone pain Groans: abdominal pain/ nausea Thrones: polyuria Psychiatric overtones: depression, anxiety, coma, insomnia

Chapter 111 Hypercalcemia & Hypocalcemia Figure 111.1 Illustration of the potential sequelae of hypercalcemia. HYPOCALCEMIA osms.it/hypocalcemia PATHOLOGY & CAUSES ▪ Low blood calcium (< 8.5mg/dL) CAUSES Less calcium entering blood ▪ Most common cause ▪ Low vitamin D: deficient diet, malabsorption, cirrhosis, lack of sunlight, chronic renal failure ▪ Hypoparathyroidism: low levels or low activity of parathyroid hormone ▫ Hypomagnesemia (Mg serum concentration < 1mg/dL) can facilitate parathyroid hormone resistance via suppressing secretion ▪ Pseudohypoparathyroidism type 1A: kidney unresponsive to parathyroid hormone ▫ Pseudohypoparathyroidism: end-organ parathyroid hormone resistance ▪ Inhibition of bone resorption (uncommon) ▫ Medications such as bisphosphonates, calcitonin and denosumab ▫ Often occurs in setting of vitamin D deficiency, hypoparathyroidism and parathyroid hormone resistance Too much calcium leaving blood ▪ Kidney failure: nephron doesn’t effectively reabsorb calcium ▪ Tissue injury: burns, rhabdomyolysis, tumor lysis syndrome ▪ Acute pancreatitis: free fatty acids bind to ionized calcium ▪ Inflammatory processes (eg. sepsis and severe illness) ▫ Up to 90% of critically-ill individuals, or those that have had major surgery develop hypocalcemia ▪ Too many blood transfusions → additives bind to ionised calcium → additives in blood (citrate, ethylenediaminetetraacetic acid (EDTA) chelate (bind) to calcium → complexed calcium, an inactive molecule ▪ Hyperphosphatemia: results in calcium being deposited in bone and extraskeletal tissue ▪ Calcium complex formation: formation of complexes → reduced availability of ionized OSMOSIS.ORG 797

calcium for cellular processes ▫ Foscarnet, drug for treatment of refractory herpes and cytomegalovirus ▫ Fluoride poisoning, causes hypocalcemia partially due to formation of fluorapatite False hypocalcemia / pseudohypocalcemia ▪ Hypoalbuminemia (low albumin): loss of bound calcium ▫ Hormonal regulation means free ionized calcium concentrations stay essentially the same ▫ Less overall calcium due to less bound calcium, but free ionized calcium levels remain the same COMPLICATIONS ▪ Osteopenia, osteoporosis, cardiovascular collapse, vasogenic shock (calcium required in vascular smooth muscle contraction), cardiac arrhythmias, seizures, tetany, basal ganglia calcification, parkinsonism, hemiballismus, choreoathetosis Figure 111.2 Trousseau’s sign of latent tetany. SIGNS & SYMPTOMS ▪ Neurological → neurons hyperexcitable ▫ Involuntary contraction of muscles ▫ Chvostek’s sign (facial muscles twitch after facial nerve lightly finger tapped 1cm/0.39in below zygomatic process) ▫ Trousseau’s sign (blood pressure cuff occludes brachial artery → pressure makes nerve fire → muscle spasm makes wrist and metacarpophalangeal 798 OSMOSIS.ORG joints flex) ▫ Muscle cramps ▫ Abdominal pain ▫ Perioral tingling (tingling around mouth) ▫ Paresthesias (abnormal sensation felt on skin, eg. tingling, tickling, prickling, numbness, burning) ▫ Carpopedal spasm (spasmodic contraction of muscles in hands, feet, ankles, wrists) ▫ Hyperactive deep tendon reflexes ▫ Seizures (extreme cases) ▪ Cardiovascular: decrease in rate, strength of contractions ▫ Hypotension ▫ Heart failure ▫ Arrhythmias DIAGNOSIS LAB RESULTS ▪ Low level of calcium in blood (< 8.5mg/dL) ▪ Calcium levels must be corrected for albumin levels or measure free ionized calcium ▫ Albumin may be low in pseudohypocalcemia ▪ PTH-related hypocalcemia ▫ ↓ : hypoparathyroidism ▫ ↑ : kidney disease, vitamin D deficiency, pseudohypoparathyroidism ▪ Non-PTH-related hypocalcemia: hypomagnesemia ▪ Autosomal dominant hypocalcemia: mutation in calcium-sensing receptor gene ▪ PTH ▫ ↑ in kidney disease, vitamin D deficiency, pseudohypoparathyroidism ▫ ↓ in hypoparathyroidism ▪ Vitamin D ▫ Hypocalcemia may be caused by ↓ vitamin D (which ↑ PTH secretion) ▪ Phosphate ▫ ↑ in hypoparathyroidism (in absence of kidney disease) or pseudohypoparathyoidism (PTH resistance) ▫ ↓ in secondary hyperparathyroidism

Chapter 111 Hypercalcemia & Hypocalcemia ▫ Normal in setting of hypocalcemia: hypomagnesemia/mild vitamin D deficiency ▪ Magnesium: ↓ levels can cause hypocalcemia OTHER DIAGNOSTICS ECG ▪ Prolonged QT segment ▪ Prolonged ST segment ▪ Arrhythmias (torsades de pointes, atrial fibrillation) TREATMENT MEDICATIONS ▪ Main goal: normalize calcium levels ▫ Calcium gluconate ▫ Vitamin D supplementation Figure 111.3 Hypocalcemia can can cause tetany, seen here in the face of this individual. OSMOSIS.ORG 799