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  1. 2. Hypercalcemia Ahmed Elshebiny University of Menoufyia
  2. 3. Case : History <ul><li>A 41-year-old woman was brought by her husband to the emergency department with a history of 72 hours of epigastric pain, nausea, repeated vomiting, and altered mental status. Her blood calcium was found to be 18.9 mg per deciliter (4.7 mmol per liter). </li></ul><ul><li>Alcoholic, peptic ulcer, analgesics for back pain </li></ul>
  3. 4. Examination <ul><li>On physical examination, </li></ul><ul><li>the blood pressure was 160/90 mm Hg, </li></ul><ul><li>the heart rate 100 beats per minute, and </li></ul><ul><li>the temperature 37.4°C. </li></ul><ul><li>The patient was disoriented and intermittently writhing in pain. </li></ul><ul><li>Her skin turgor was poor, and her oral mucosa was dry. </li></ul><ul><li>The cardiac examination was significant only for tachycardia, and </li></ul><ul><li>the pulmonary examination was normal. </li></ul><ul><li>There was epigastric tenderness on palpation but no rebound tenderness. </li></ul><ul><li>The patient was responsive to simple commands and was not tremulous. </li></ul><ul><li>There were no other significant neurologic findings. </li></ul>
  4. 5. Investigations
  5. 6. Specific investigations <ul><li>Intact parathyroid= undetectable </li></ul><ul><li>25 hydroxy vitamin D = normal </li></ul><ul><li>PTH related protein= normal </li></ul><ul><li>Calcium fall with hydration only </li></ul><ul><li>Computed tomography (CT) of the neck revealed no parathyroid masses. CT of the chest was normal. Abdominal CT showed an edematous pancreas with surrounding infiltration of the mesenteric fat, a finding consistent with acute pancreatitis. No bone lesions were noted on the chest or abdominal CT scans. </li></ul>
  6. 7. Diagnosis <ul><li>In response to further questioning, the patient reported that during the days before admission she had consumed the contents of entire containers of Tums and a preparation containing sodium bicarbonate (Alka-Seltzer, Bayer) because of the severe abdominal pain. She did not consume any other medications or supplements. </li></ul><ul><li>This history, together with the laboratory-test results, establishes the &quot;milk alkali syndrome&quot; as the primary diagnosis </li></ul>
  7. 8. Milk Alkali Syndrome <ul><li>The pathogenesis of the milk alkali syndrome involves a reduction in the ability of the kidney to excrete excess calcium. </li></ul><ul><li>This reduction is secondary to a decrease in the glomerular filtration rate (due to renal vasoconstriction and hypovolemia) and to a significant increase in tubular reabsorption of calcium (secondary to metabolic alkalosis). </li></ul><ul><li>The plasma PTH level decreases with the rise in the serum calcium level. </li></ul><ul><li>Thus, the constellation of excess oral intake of calcium and milk, plus impaired renal function, may result in PTH suppression, hypercalcemia, and hyperphosphatemia. </li></ul><ul><li>In cases of chronic ingestion of excessive alkaline calcium preparations and milk, metastatic calcifications and occasionally nephrocalcinosis may occur, 7 whereas such complications are not expected with acute milk alkali syndrome, as in the present case. </li></ul>
  8. 9. Calcium <ul><li>Plays a role inside (intracellular) and outside (extarcellular) cells </li></ul><ul><li>Functions of calcium </li></ul><ul><ul><ul><ul><li>Muscle contraction </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Nerve conduction </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Coagulation </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Enzyme and electrolyte regulation </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Hormone release and exocytosis </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Cell division </li></ul></ul></ul></ul><ul><li>Calcium enters extra-cellular fluid from intestine and bone </li></ul><ul><li>Calcium is excreted through kidneys </li></ul><ul><li>Calcium is tightly controlled by hormones (PTH, Calcitriol, calcitonin) </li></ul><ul><li>Human body contains 1100 g calcium </li></ul>
  9. 13. Hypercalcemia <ul><li>For hypercalcemia to develop, the normal calcium regulation system must be overwhelmed by an excess of PTH, Calcitriol, some other serum factor that can mimic these hormones, or a huge calcium load. </li></ul><ul><li>Between 20 and 40% of patients with cancer develop hypercalcemia at some point in their disease </li></ul><ul><li>the most common serious electrolyte presenting in adults with malignancies </li></ul><ul><li>primary hyperparathyroidism is considerably higher in women. </li></ul><ul><li>Hyperparathyroidism and malignancy increases with age </li></ul><ul><li>Breast cancer is one of the most common malignancies responsible for hypercalcemia. </li></ul>
  10. 14. PTH dependent hypercalcemia <ul><li>Primary hyperpara( adenoma commonly) </li></ul><ul><li>Tertiary hyperparathyroidism </li></ul><ul><li>FHH </li></ul><ul><li>MEN syndromes </li></ul><ul><li>Lithium therapy </li></ul>
  11. 15. PTH independent hypercalcemia <ul><li>Malignancy related </li></ul><ul><li>Vitamin D related( Granulomas, infections, toxcicity, williams syndrome) </li></ul><ul><li>Other endocrine( hyperthyroidism, pheochromocytoma, adrenal insufficiency, islet cell tumor) </li></ul><ul><li>Miscellaneous( immobilization, milk alkali, other medications) </li></ul>
  12. 16. Hypercalcemia of Hyperparathyroid <ul><li>Primary: Usually adenoma </li></ul><ul><li>Secondary </li></ul><ul><li>tertiary </li></ul><ul><li>Hypophosphatemia and elevated urine calcium </li></ul><ul><li>Surgery </li></ul><ul><li>Complications of surgery </li></ul>
  13. 17. PTH and calcium measurment <ul><li>PTH assay </li></ul><ul><li>PTH related protein </li></ul><ul><li>Total calcium </li></ul><ul><li>Ionized calcium </li></ul>
  14. 18. FHH <ul><li>Autosomal dominant, </li></ul><ul><li>usually mild elevation </li></ul><ul><li>Shift of the set point </li></ul><ul><li>Urine calcim is low </li></ul><ul><li>Previous history of normal calcium rules out FHH </li></ul>
  15. 19. Hypercalcemia of Malignancy <ul><li>Secretion of PTH related peptide </li></ul><ul><li>Osteoclastic activation </li></ul><ul><li>Secretion of vitamin D </li></ul><ul><li>Unknown mechanisms </li></ul><ul><li>Common with( Breast cancer with bone metastasis, lung cancer, multiple myeloma, Hodgikins, pancreatic islet tumors, cholangiocarcinoma and adenocarcinomas) </li></ul>
  16. 20. Symptoms <ul><li>Depends on the underlying disease and rate of increase in serum calcium </li></ul><ul><li>Mild elevations in calcium levels usually have few or no symptoms </li></ul><ul><li>Manifestations include </li></ul><ul><ul><ul><ul><li>Nausea, vomiting, abd pain, stones, constipation, pancreatitis, ulcer </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Polyuria, polydepsia, nocturia </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Weakness and vague muscle and Joint aches </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Altered mental state, lethargy, depression, Headache , confusion </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Coma </li></ul></ul></ul></ul><ul><li>Hypercalcemia of malignancy </li></ul><ul><li>Hypercalcemia of Hyperparathroid </li></ul>
  17. 21. Examination <ul><li>Mental state </li></ul><ul><li>Pulse and blood pressure </li></ul><ul><li>Abdomen </li></ul><ul><li>Reflexes and muscle power </li></ul><ul><li>Hydration </li></ul><ul><li>Malignancy </li></ul><ul><li>Other specific disease </li></ul><ul><li>Band keratopathy </li></ul>
  18. 22. ECG <ul><li>Short Q-T </li></ul><ul><li>Prolonged P-R </li></ul><ul><li>At high levels …. Wide QRS </li></ul><ul><li>Flat or inverted T </li></ul><ul><li>Variable degrees of Heart block </li></ul><ul><li>N.B. Digoxin effects are amplified </li></ul>
  19. 23. Phosphate and Chloride <ul><li>Serum phosphate levels tend to be low or normal in primary hyperparathyroidism and hypercalcemia of malignancy. </li></ul><ul><li>Phospate levels are elevated in hypercalcemia secondary to vitamin D–related disorders or thyrotoxicosis. </li></ul><ul><li>Serum chloride levels usually are higher than 102 mEq/L in hyperparathyroidism and less than this value in other forms of hypercalcemia. </li></ul>
  20. 24. Investigations and DD
  21. 25. Vitamin D metabolism
  22. 26. Treatment <ul><li>Hydration </li></ul><ul><li>Loop diuretics (avoid thiazide) </li></ul><ul><li>Biphosphonates and other medications </li></ul><ul><li>Dialysis </li></ul><ul><li>Surgery </li></ul><ul><li>Chemo or radiotherapy for malignancy </li></ul>
  23. 27. Medications used to treat Hypercalcemia Medications used to treat Hypercalcemia Bisphosphonates Calcitonin Gallium nitrate (Ganite) Plicamycin Glucocorticoids Phosphate Cinacalcite Pamidronate Zolidronic acid Etidronate
  24. 28. Acute management <ul><li>Rehdrate + or - lasix </li></ul><ul><li>Bisphosphonate </li></ul><ul><li>Other Medicate </li></ul><ul><li>Calcitonin </li></ul><ul><li>May be phosphate </li></ul>
  25. 29. Chronic management <ul><li>Indications of surgery in hyperparathyroidism </li></ul><ul><li>Biphosphonates </li></ul><ul><li>Cortisone in myeloma </li></ul><ul><li>Cortisone in granulomas and /or hydroxy chloroquine or ketokonazole </li></ul><ul><li>Cinacalcet </li></ul>
  26. 30. Take home points <ul><li>Majority of hypercalcemias are caused by hyperparathyroid or malignancy but others other sought when the diagnosis is not clear </li></ul><ul><li>Symptoms are usually subtle </li></ul><ul><li>Severer hypercalcemia(stones , bones, moans and groans) </li></ul><ul><li>History + PTH levels are the essentials for diagnosis </li></ul><ul><li>Acute management focuses on hydration the other medications </li></ul><ul><li>Chroni management focuses on the underlying aetiology </li></ul>
  27. 31. References <ul><li>Washington subspecialty consult: Endocrinology 2009 </li></ul><ul><li>Kumar and Klark’s Medicine 2009 </li></ul><ul><li>E-medicine online text book – emergency medicine/ and Nephrology </li></ul><ul><li>Nejm CASES, 2008 </li></ul>
  28. 32. THANK YOU