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![ 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](https://image.slidesharecdn.com/hypercalcemiaatee-130819074055-phpapp02/85/Hypercalcemia-atee-8-320.jpg)
![ 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](https://image.slidesharecdn.com/hypercalcemiaatee-130819074055-phpapp02/85/Hypercalcemia-atee-21-320.jpg)
![ 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](https://image.slidesharecdn.com/hypercalcemiaatee-130819074055-phpapp02/85/Hypercalcemia-atee-25-320.jpg)
Uploaded byKaryatee Hafiz
Hypercalcemia atee
Hypercalcemia is a common condition seen in up to 4% of hospitalized patients. The most common causes are primary hyperparathyroidism and malignancy-associated hypercalcemia. Hypercalcemia occurs when calcium influx into the extracellular fluid exceeds renal excretory capacity. It is defined as a total serum calcium level greater than 10.2 mg/dL. Treatment involves stabilizing the patient with intravenous fluids, promoting calcium excretion with diuretics, and administering bisphosphonates to reduce bone resorption in malignancy-associated cases. Surgical removal of parathyroid adenomas is required for symptomatic primary hyperparathyroidism.
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Hypercalcemia atee
- 1. Dr Nur Karyateebt Kassim Mpath 4th yr
- 2.
- 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 isdefined 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).
- 6. • Concentration inECF 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
- 8. Bone ◦ Inhibitsosteoblasts ◦ 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
- 9. Gut (Principal target) Increasesabsorption of Ca and PO4 Bone Enhances bone resorption
- 10. 32- aminoacid 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
- 12. 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
- 13. Most common Hypercalcaemiaof malignancy ◦ Solid tumours ◦ Haematological malignancies Primary Hyperparathyroidism (PHPT) Less common Adrenal insufficiency Vitamin D intoxication Drug treatment Chronic Renal Failure Endocrine ◦ Thyrotoxicosis Sarcoidosis Immobilisation
- 14. 30% ofpts 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)
- 15. LOH accountsfor 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.
- 16. Result fromthe 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
- 17. Multiple myeloma ◦ Releaseof 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
- 18. 1 HPTHis 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
- 19. In primaryHPTH 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
- 21. 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
- 22. Rare, lifethreathening 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.
- 23. 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
- 24. ◦ Pt withsarcoidosis 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.
- 25. 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
- 26. The mostcommonly 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
- 27. 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
- 28. 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
- 29. Hypercalcaemia seenin pt treated with ◦ Calcium carbonate or calcium acetate to bind dietary phosphate ◦ Calcitriol ( to reverse hypocalcaemia and secondary hyperparathyroidism) Endocrine ◦ Thyrotoxicosis-mild hypercalcemia ◦ Thyroid hormoneIncreased bone resorption ratereleases ca into circulation suppress PTH low 1,25(OH)D
- 30. How to approach? -Medical History - Physical Examination What Investigations? -Lab -Others
- 31. Acute orUnknown 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
- 32. Re-review History 1. Acuteor 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
- 33. 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
- 34. 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
- 35. 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
- 36. 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
- 37. Measurement urinarycalcium 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
- 38. Next step… Analyzevitamin 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
- 39. 42 PTH PTHrP 1,25DCa 1ry HyperPTH - 2nd HyperPTH - - 3ry HyperPTH - - CA High - Granuloma High
- 40. ◦ Se Immunoglobulin/Serum/urine electrophoresis Multiple myeloma ◦ Thyroid function test Thyrotoxicosis ◦ Renal function test to assses renal function ◦ Liver function testraised ALP level suggest bone involvement ◦ raised serum bicarb suggest Milk-alkali syndrome ◦ Chest xray reveal sign of sarcoidoisis & lung ca ◦ Mamogrambreast ca 43
- 41. DDX Ca PO4PTH 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 ↓
- 44. 1st stepin 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
- 45. 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
- 46. Acute parathyroidcrisis 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
- 47. Review /remove any known agents that cause / aggravate hypercalcaemia ◦ Medications Thiazide Lithium Over the counter supplements
- 48. Hypercalcaemia hasa 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.