Hypercalcemia atee

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  • 1. Dr Nur Karyatee bt Kassim Mpath 4th yr
  • 2. Hypercalcaemia
  • 3.  Common condition ◦ Prevalence of <2 % in the general population ◦ 4% in the hospital population  Malignancy  commonest cause in hospital patients  Primary hyperparathyroidism  commonest in general population  Pathophysiology Occurs when calcium influx into the ECF from the intestine and/or bone exceeds renal calcium excretory capacity.
  • 4.  Hypercalcemia is defined as total serum calcium > 10.2 mg/dl(>2.5 mmol/L ) or ionized serum calcium > 5.6 mg/dl ( >1.4 m mol/L )  Severe hypercalemia is defined as total serum calcium > 14 mg/dl (> 3.5 mmol/L)  Hypercalcemic crises is present when severe neurological symptoms or cardiac arrhythmias are present in a patient with a serum calcium > 14 mg/dl (> 3.5 mmol/L).
  • 5. • Concentration in ECF maintained within narrow limit (2.2 – 2.6 mmol/L) by a control of hormones: a)Parathyroid hormone (PTH) b)Calcitriol (1,25-dihydroxycholecalciferol) c)Calcitonin- minor role  Principle organ systems : a)Gut b)Bone c)Kidneys
  • 6.  Bone ◦ Inhibits osteoblasts ◦ Accelerates osteoclastic bone resorption  Kidneys ◦ Increases renal tubular reabsorption of Ca ◦ Increases PO4 excretion ◦ Increases calcitriol activity (1-hydroxylation)  indirectly raises [Ca]  Gut ◦ Does not directly affect GIT absorption of Ca ◦ Effects are mediated indirectly through regulation of synthesis of calcitriol
  • 7. Gut (Principal target) Increases absorption of Ca and PO4 Bone Enhances bone resorption
  • 8.  32- amino acid hormone  Produced  Parafollicular C cells of thyroid  Weak inhibitor of osteoclasts  Opposes PTH effects of kidneys ◦ Promotes Ca and PO4 excretion  Its exact physiological role in human is uncertain ◦ Has few long term effects on serum Ca
  • 9. COMMON • Hyperparathyroidism • Primary • Tertiary • Malignant disease • Solid organ tumour • Haematological LESS COMMON  Thyrotoxicosis  Vit D intoxication  Thiazide diuretics  F. hypercalciuric hypercalcaemia  Sarcoidosis UNCOMMON  Milk-alkali syndrome  Immobilization  Lithium  Tuberculosis  Acute adrenal failure  Diuretic phase of ARF  Idiopathic hypercalcaemia of infancy
  • 10. Most common  Hypercalcaemia of malignancy ◦ Solid tumours ◦ Haematological malignancies  Primary Hyperparathyroidism (PHPT) Less common  Adrenal insufficiency  Vitamin D intoxication  Drug treatment  Chronic Renal Failure  Endocrine ◦ Thyrotoxicosis  Sarcoidosis  Immobilisation
  • 11.  30% of pts with Ca will develop hyperCa  Pathophysiology 1. Local osteolytic hyperCa due to direct effects of bone mets 2. Humoral hyperCa of malignancy (HHM)  Secretion of PTHrp by malignant tumours 3. 1,25(OH)2 Vit D – secreting lymphomas 4. Ectopic secretion of PTH (very rare)
  • 12.  LOH accounts for 20% of cases of hypercalcemia of malignancy.  Extensive bone lysis due to tumor metastases  Characterized by ↑Ca, N/↑ se PO4,↓PTH, ↑ALP, ↑24(h) urinary calcium excretion, increase marker of bone resorption.
  • 13.  Result from the production of PTHrP  Most often have squamous ca ( lung, esophagous, head, neck, cervic,ovary)  Has N-terminal amino acid sequence similar to PTH  Permit binding of identical receptors and stimulation of second messanger, (cAMP).  Thus, able to induce actions of PTH • Increase bone resorption↑Ca, ↓PTH • Inhibit proximal tubule phosphate transport  ↓PO4
  • 14. Multiple myeloma ◦ Release of osteoclast activating factors by the tumour cells ◦ IL-1B, lymphotoxin, TNF, IL-6, macrophage CSF, hepatocyte GF ◦ Actions: stimulates osteoclastic activity In Hodgkin lymphoma, ◦ induced by production of 1,25(OH)2D ◦ Malignant lymphocyte & macrophage converting the 25(OH)D to 1,25(OH)D  bone resorption and intestinal Ca2+ absorption
  • 15.  1 HPTH is the leading cause of hyperCa.  Often, pts are women in their 50s who have parathyroid adenoma  Incidence ; 1 in 500 to 1 in 1000  Occur sporadically or assoc with MEN Type 1or 2
  • 16.  In primary HPTH due to adenomas, ◦ PTH secretion is independent of the negative feedback mechanism ◦ :. Secretion continues despite elevated Ca2+ level.  Pathophysiology ◦ Excess PTH leads to  Direct increase in renal Ca absorption  Increase in serum Calcitriol  Increasing GIT Ca absorption  Increase bone turnover, resorption > formation
  • 17.  Diagnosis = Hypercalcaemia + raised [iPTH]  Additional lab findings - ↓ serum phosphate - urinary excretion of Ca2+ ( PTH  amount of filtered Ca2+ > normal resorptive capacity of the kidney xs Ca2+ secreted in urine) -↑ Se ALP (when bone disease present) -↑ se Cl and ↓ se Bicarb - ↑1,25 (OH)2D -bone markers(↑bone specific ALP,osteocalcin)  Other Ix ◦ Sestamibi scan of the Parathyroid
  • 18.  Rare, life threathening cx of primary hyperparathyroidism  Sx: acutely ill wt profound dehydration,GIT sx, urinary symptom,altered mental status& cardiac arythmia.  Lab ix;significantly ↑se Ca,↑PTH,↑ ALP.
  • 19.  In ESRF, prolonged hypocalcaemia will cause autonomous PTH secretion by parathyroid.  This in turn will cause hypercalcaemia (Tertiary hyperparathyroidism)  Hypercalcaemia may manifest for the first time in patient post renal transplant when there is normalization of calcitriol production  Increases the PTH effect on bone Directly enhances intestinal Ca absorption
  • 20. ◦ Pt with sarcoidosis have increased sensitivity to vitamin D. ◦ High Ca may develop in normocalcaemic pt after minimal intake of vit D and sunlight exposure ◦ Caused by increase production of 1,25(OH)2D from non-renal sites. ◦ Macrophage from sarcoid granuloma may cause 1-hydroxylation of 25-(OH)D to produce calcitriol  Ca 2+ ◦ High/inappropriately elevated se 1,25(OH)D despite PTH level is suppressed and se PO4 is relatively elevated.
  • 21.  Thiazide diuretics: ◦ Enhance ca reabsorption in the distal tubule ↓urinary ca excretion. • Rarely cause Ca in N persons, but lead to Ca in pt with underlying bone resorption (eg in hyperparathyroidism) • Mild hypercalcaemia,↓/N PTH  Lithium therapy: ◦ Increased PTH secretion  Increasing set point of PTH, hence higher [Ca] to switch off PTH ◦ Lab ix: high Ca, PTH, low urinary 24(h) calcium
  • 22.  The most commonly available vit D supplement  25-(OH)Vit D ◦ Excess of VIT D 25000-50000 IU/week ◦ Resulting primarily from a combination of increase bone resorption of calcium and increase bone reabsortion ◦ Lab ix: ↑Ca, ↑Po4,↓/N PTH, ↑25(OH)D, N/slightly 25(OH)D
  • 23.  In immobilization,  Decreased stimulus to bone formation and continued resorption rapid efflux of ca fr bone suppresed PTH 1,25(OH) D  results in hypercalciuria  Hypercalcemia seen if there is pre-existing increased bone turnover  Paget’s disease  Hyperparathyroid  Malignancy associated hypercalcemia
  • 24.  Prev – milk alkali syndrome ◦ Milk-alkali syndrome: ingestion of milk/antacids(alkaline) for treatment of dyspepsia .  Alkali increases renal reabsorption of filtered calcium.  Precise mechanism unknown  Calcium-alkali syndrome ◦ Due to Rx of osteoporosis ◦ Triad of hypercalcemia,systemic alkalosis and renal insufficiency. ◦ Lab Ix: ↑ca,↓/ N PTH,↑/N PO4, ↓urinary 24 (h) Ca
  • 25.  Hypercalcaemia seen in pt treated with ◦ Calcium carbonate or calcium acetate to bind dietary phosphate ◦ Calcitriol ( to reverse hypocalcaemia and secondary hyperparathyroidism)  Endocrine ◦ Thyrotoxicosis-mild hypercalcemia ◦ Thyroid hormoneIncreased bone resorption ratereleases ca into circulation suppress PTH low 1,25(OH)D
  • 26. How to approach? - Medical History - Physical Examination What Investigations?  -Lab  -Others
  • 27.  Acute or Unknown duration ◦ PTH high; Acute paratyroid crisis ◦ PTH low ; CA, PTHrp  Chronic duration month ◦ PTH low ; granulomatous dz, Milk alkali, Li,thiazide, Immobilization, Vit D,Thyrotoxicosis ◦ PTH high ; 1,3 ry hyper PTH, MEN 34
  • 28. Re-review History 1. Acute or Chronic ??????  Classic presentation very rare – Stones – Bones – Abdominal groans – Psychic moans  Subtle manifestations more common – Fatigue – Weakness – Arthralgias – Depression – Impairment of intellectual performance  Associated conditions – Pseudogout – Nephrolithiasis – Evidence of MEN
  • 29.  Review medications – Thiazides – Lithium – Antacids – Food additives  Pursue symptoms of underlying malignancy – Breast – Lung – Hematological  Past History of head and neck irradiation during childhood  Family history  Risk factor of Ca
  • 30.  Step 1 – Confirm hypercalcemia – Ionized calcium – Serum albumin levels – Correction for the measured calcium (low albumin)  Step 2 – Once obvious causes ruled out, obtain serum intact PTH
  • 31.  Step 3: Measurement of the serum PTH concentration.  Ca, iPTH ;  1ry HyperPTH, Familial (MENI and MENII),Ectopic PTH secretion by tumors (rare) – Ca, N / iPTH; – Malignancy associated • Osteolytic • Humoral • Vitamin D mediated • Intoxication • Granulomatous disorders • Thyrotoxicosis • Prolonged immobilization • Acute /chronic renal failure • Milk alkali syndrome • Drug:Thiazide,Lithium
  • 32.  Step 4: Measurement of the serum phosphate concentration. ◦ Ca, PO4 ;  1ry HyperPTH, PTHrP SCC ◦ Ca, N / PO4 ;  3ry HyperPTH, Granulomatous dz, lymphoma, Vit D overdose , Immobilization, Metastatic bone dis. Milk Alkali Syndrome 39
  • 33.  Measurement urinary calcium excretion ◦ Urinary calcium excretion is usually raised or high- normal: ◦ hyperparathyroidism,hypercalcemia of malignancy,granulomtous disease,Vit D excess  3 disorders in which an increase in renal calcium reabsorption leads to relative hypocalciuria (<2.2 mmol/day): ◦ The milk-alkali syndrome ◦ Thiazide diuretics ◦ Familial hypocalciuric hypercalcemia (children) 40
  • 34. Next step…  Analyze vitamin d metabolite levels ◦ Elevated 25(OH)D  Vit D intoxication ◦ High 1,25 (OH)D  Primary HPTH sarcoidoisis & granulomatous dz  Analyze serum PTH-related protein level (PTHrp) ◦ May help in diagnosis of occult cancer – associated hypercalcemia.  41
  • 35. 42 PTH PTHrP 1,25D Ca 1ry HyperPTH - 2nd HyperPTH - - 3ry HyperPTH - - CA High - Granuloma High
  • 36. ◦ Se Immunoglobulin/ Serum/urine electrophoresis Multiple myeloma ◦ Thyroid function test Thyrotoxicosis ◦ Renal function test to assses renal function ◦ Liver function testraised ALP level suggest bone involvement ◦ raised serum bicarb suggest Milk-alkali syndrome ◦ Chest xray reveal sign of sarcoidoisis & lung ca ◦ Mamogrambreast ca 43
  • 37. DDX Ca PO4 PTH PTHrP 1,25(OH)D U Ca Malignancy 1)Solid tumor 2)Humoral ↑ ↑ N/↑ ↓ ↓ ↓ N ↑↑ ↓ ↓/N ↑ ↓/N Pry PTH ↑ ↓ ↑ N ↑ ↑ Granulomatous disease ↑ ↑ ↓ N ↑↑ ↑ Vit D excess ↑ ↑ ↓ N ↑↑ ↑ Thiazide ↑/N ↑ ↓/N N N ↓ Milk alkali syndrome ↑/N ↑ ↓/N N N ↓
  • 38.  1st step in Mx – Stabilising the pt!  Correct hypovolemia wt isotonic saline infusion and to promote renal excretion of calcium ◦ Replenish body fluids  2-4 L of IV normal saline per day
  • 39.  2nd Step ◦ Diuresis with furosemide  3rd Step ◦ Administration of bisphosphonates ◦ Zoledronate or Pamidronate  Block osteoclast activity and bone resorption  Reduce malignant bone pain  Delay onset of progressive bone disease in various Ca
  • 40.  Acute parathyroid crisis  urgent parathyroidectomy  For symptomatic PHPT ◦ Those <50 years ◦ Who cannot participate in appropriate follow up ◦ Ca level > 0.25 mmol/l above upper limit ◦ Complications of PHPT  Osteoporosis  Nephrocalcinosis  Severe psychoneurologic disorder
  • 41.  Review / remove any known agents that cause / aggravate hypercalcaemia ◦ Medications  Thiazide  Lithium  Over the counter supplements
  • 42.  Hypercalcaemia has a wide differential diagnosis and several investigations may be required to determine the underlying cause.  Clues pointing to the Dx of underlying disease can be obtained from careful history taking and physical examination.  Lab tests should be requested based on clinical suspicion.  Long term control of hypercalcaemia is best achieved by identifying and treating the underlying disease.