HYPERCALCEMIA : :::: CALCIUM HOMEOSTASIS

Hypercalcemia diagnosis and management

1. CALCIUM HOMEOSTASIS: HYPERCALCEMIA PRESENTER:SIDDHARTHA VATS MODERATOR:PROF. NILESH KUMAR

2. C alcium plays key role in:- C ontraction of skeletal, cardiac, & smooth muscles B lood clotting T ransmission of nerve impulses Normal calcium levels :9-11mg/dl 0.1 % of total body calcium is in extracellular fluid A bout 1 % in cells & organelles . R est is stored in bones. Guyton and hall :Textbook medical physiology 12 th edition CALCIUM REGULATION

3. Guyton and hall :Textbook medical physiology 12 th edition

4. Guyton and hall :Textbook medical physiology 12 th edition

5. Williams textbook of endocrinology 14 th edition Increases Ca++ and PO4 absorbtion

6. Williams textbook of endocrinology 14 th edition

7. Guyton and hall :Textbook medical physiology 12 th edition

8. HYPERCALCEMIA

9. Harrison Principles of internal medicine 21 st edition ETIOLOGY

10. E ntry of calcium into circulation exceeds excretion of calcium into urine / deposition in bone. This occurs when there is 1.A ccelerated bone resorption 2.E xcessive gastrointestinal absorption, or 3.De creased renal excretion of calcium . Among all causes of hypercalcemia, primary hyperparathyroidism & malignancy are most common, accounting for >90% of cases Hypercalcemia: A Review. JAMA 2022; 328:1624.

11. Primary hyperparathyroidism  —  P arathyroid hormone (PTH)-mediated activation of osteoclasts, causing increased bone resorption & elevated intestinal calcium absorption Most often d/t parathyroid adenoma. Patients typically have relatively minor elevations in serum calcium concentration :<12 mg/dL. Some patients have mostly high-normal values with intermittent hypercalcemia. Asymptomatic primary hyperparathyroidism: a medical perspective. Surg Clin North Am 2004; 84:787.

12. Tertiary hyperparathyroidism — In patients with advanced renal failure, parathyroid hyperplasia may gradually progress to autonomous overproduction of PTH The rise in plasma calcium is exacerbated by concomitant adynamic bone disease and markedly reduced bone turnover . Harrison Principles of internal medicine 21 st edition

13. Familial hypocalciuric hypercalcemia —   R are autosomal dominant disorder C haracterized by 1.M ild hypercalcemia . 2.H ypocalciuria . 3.N ormal - mod . elevated serum magnesium . 4.Normal-slightly increased serum PTH . The majority of these patients have few /no symptoms of hypercalcemia & require no therapy . The primary defect is loss-of-function mutation in calcium sensing sensor on parathyroid cells and kidneys Rare causes of hypercalcemia. J Clin Endocrinol Metab 2005; 90:6316.

14. Metaphyseal chondrodysplasia — R are form of dwarfism. P rimary defect is mutation in PTH- PTHrP receptor gene, resulting in continuous activation of receptor at normal / l ow levels of PTH secretion P atients have short-limbed dwarfism d/t abnormal regulation of chondrocyte maturation in growth plates of bone that are formed through endochondral process. Clinical review: Rare causes of hypercalcemia. J Clin Endocrinol Metab 2005; 90:6316

15. In patients with bone metastases, direct induction of local osteolysis by tumor cells . Cytokines such as TNF & IL-1 play a role by stimulating the differentiation of osteoclast precursors into mature osteoclasts . S olid tumors a /w hypercalcemia, particularly squamous cell and renal tumors, produce PTHrP . D irect bone marrow invasion occurs with hematologic malignancies such as leukemia, lymphoma, & multiple myeloma. H ypercalcemia is caused by PTH-independent, extrarenal production of calcitriol from calcidiol by activated mononuclear cells in lymphoma. Hypercalcemia: A Review. JAMA 2022; 328:1624. Malignancy

16. Sarcoidosis and Other Granulomatous Diseases Macrophages from granulomatous tissue convert 25(OH)D to 1,25(OH)2 D at increased rate M acrophages increase production of vitamin D receptor and of 1 α- hydroxylase in response to tumor necrosis factor & other inflammatory stimuli. PTH levels are usually low and 1,25(OH)2 D levels are elevated . SILICONE GRANULOMATOUS INFLAMMATION RESULTING IN HYPERCALCEMIA: A REVIEW OF THE LITERATURE. AACE Clin Case Rep 2019; 5:e119.

17. MEDICATIONS Lithium  —  M ost likely d/t increased secretion of PTH due to increase in set point at which calcium suppresses PTH release. The hypercalcemia usually, but not always, subsides when the lithium is stopped. Lithium can also unmask previously unrecognized mild hyperparathyroidism. Williams textbook of endocrinology 14 th edition

18. Thiazide diuretics : Thiazide diuretics lower urinary calcium excretion, an effect that is useful in treatment of patients with hypercalciuria & recurrent calcium nephrolithiasis H ypocalciuric effect appears to reflect enhancement of proximal tubular resorption of sodium and calcium in response to sodium depletion. If hormonal function & calcium and bone metabolism are normal, homeostatic controls counteract the calcium-elevating effect of the thiazides. C an lead to hypercalcemia in patients with underlying hyperpar athyroidism , since homeostatic mechanisms are ineffective. Williams textbook of endocrinology 14 th edition

19. Milk alkali syndrome – H igh intake of milk / calcium carbonate, leading to hypercalcemia, metabolic alkalosis, & renal insufficiency . Calcium is absorbed in small intestine via both active & passive transport. The former is more important physiologically & stimulated by vitamin D metabolites. But w hen calcium intake is >2g/d, substantial amounts of calcium is absorbed passively. Williams textbook of endocrinology 14 th edition

20. ENDOCRINE DISORDERS Thyrotoxicosis — Mild hypercalcemia occurs in ~ 15 - 20 % of thyrotoxic patients, d/t thyroid hormone-mediated increase in bone resorption. It typically resolves following correction of hyperthyroidism. If the hypercalcemia persists after restoration of euthyroidism , serum PTH should be measured to assess for concomitant hyperparathyroidism. Williams textbook of endocrinology 14 th edition

21. Pheochromocytoma  —   R are complication of pheochromocytoma . It can be due to concurrent hyperparathyroidism or pheochromocytoma itself . The hypercalcemia appears to be d / t tumoral production of PTHrP Serum PTHrP concentrations can be reduced by alpha adrenergic blockers, suggesting role for alpha-stimulation Clinical review: Rare causes of hypercalcemia. J Clin Endocrinol Metab 2005; 90:6316

22. Immobilization R are cause of hypercalcemia in adults in absence of associated disease C ause hypercalcemia in children & adolescents, particularly after spinal cord injury & paraplegia / quadriplegia. The mechanism is disproportion between bone formation & bone resorption; the former decreased and latter increased. Immobilization of an adult with disease associated with high bone turnover, such as Paget’s disease, may cause hypercalcemia. Immobilization induced hypercalcemia. Clin Cases Miner Bone Metab 2016; 13:46.

23. CLINICAL FEATURES

24. Asymptomatic Obtundation & coma The symptoms of hypercalcemia depend upon :- 1.D egree of hypercalcemia 2.R ate of onset of elevation in s erum calcium . The symptoms & signs a/w hypercalcemia are typically independent of etiology. Study of 464 patients from Indian PHPT registry from 2005-2015, 95% patients with PHPT were symptomatic. The most common symptoms at presentation included bone pain (56%), renal calculi (31%), & fatigability (59%). Williams textbook of endocrinology 14 th edition A Comparison between Silent and Symptomatic Renal Stones in Primary Hyperparathyroidism. Indian J Endocrinol Metab 2019;23:46.

25. Uptodate : Hypercalcemia; Clinical features

26. DIAGNOSIS

27. Williams textbook of endocrinology 14 th edition

28. Williams textbook of endocrinology 14 th edition

29. TREATMENT

30. The degree of hypercalcemia, along with rate of rise of serum calcium, determines symptoms & urgency of therapy. Patients with asymptomatic / mildly symptomatic hypercalcemia don’t require immediate treatment. A n acute rise may cause marked changes in sensorium, which requires more aggressive measures. Patients with serum calcium >14 mg/dL require more aggressive treatment, regardless of symptoms. A practical approach to hypercalcemia. Am Fam Physician 2003; 67:1959.

31. MILD-MODERATE HYPERCALCEMIA . A dvised to avoid factors that aggravate hypercalcemia : Thiazide diuretics Lithium Volume depletion Prolonged bed rest . A high-calcium diet (>1000 mg/day) Vitamin D supplements in excess of 800 international units/day . Adequate hydration (at least 6-8 glasses of water/da y) is recommended to minimize risk of nephrolithiasis . A cute rise cause marked changes in sensorium, treat ed same for severe hypercalcemia . Evaluation and therapy of hypercalcemia. Mo Med 2011; 108:99.

32. SEVERE HYPERCALCEMIA Initial therapy of severe hypercalcemia includes : Si multaneous administration of isotonic saline, subcutaneous calcitonin, & bisphosphonate. A dministration of calcitonin + saline hydration result in substantial reduction in serum calcium within 12- 48 hours. The bisphosphonate will be effective by 2 nd -4 th day & provide more sustained effect, thereby maintaining control of the hypercalcemia. Evaluation and therapy of hypercalcemia. Mo Med 2011; 108:99.

33. Volume expansion with isotonic saline  —  Isotonic saline for 24 - 48 hours corrects volume depletion d /t hypercalcemia induced urinary salt wasting . The rate of saline infusion depends upon several factors, including severity of hypercalcemia, age of patient, & presence of comorbid conditions. In absence of edema, administ e r isotonic saline at initial rate of 200- 300 mL/hour to maintain urine output at 100-1 50 mL/hour. In individuals renal insufficiency / heart failure, careful monitoring & judicious use of loop diuretics is required to prevent fluid overload. Primer on the Metabolic Bone Dis eases and Disorders of Mineral Metabolism, 9th ed , Bilezikian JP (Ed), Wiley- Blackw ell, Hoboken, NJ 2018. p.639

34. Calcitonin —  A dministered intramuscularly or subcutaneously . The initial dose is 4 units/kg. The serum calcium is repeated in 4-6 hours. If hypocalcemic response is noted, then patient is calcitonin sensitive & calcitonin can be repeated every 12 hours for a total duration of 24 - 48 hours. If the response is not satisfactory, dose may be increased to 8 units/kg every 6 to 12 hours. E fficacy of calcitonin is limited to 1 st 48 hours, even with repeated doses, indicating the development of tachyphylaxis . A Systematic Review Supporting the Endocrine Society Clinical Practice Guideline on the Treatment of Hypercalcemia of Malignancy in Adults. J Clin Endocrinol Metab 2023; 108:585.

35. Bisphosphonates —  Bisphosphonates are relatively inexpensive, nontoxic compounds with long track record of safety & efficacy for treatment of hypercalcemia. They are usually preferred agents for management of hypercalcemia d/t excessive bone resorption Their maximum effect occurs in 2-4 days, so they are usually given with saline and/or calcitonin, which reduce calcium more rapidly . Overall survival improvement in patients with lung cancer and bone metastases treated with denosumab versus zoledronic acid: subgroup analysis from a randomized phase 3 study. J Thorac Oncol 2012; 7:1823

36. Denosumab - For patients in whom bisphosphonates are contraindicated / patients with hypercalcemia refractory to zoledronic acid, denosumab can be administered concurrently with calcitonin & saline hydration The risk of subsequent hypocalcemia is lower with bisphosphonates than denosumab . Denosumab versus intravenous bisphosphonate use for hypercalcemia in multiple myeloma. Leuk Lymphoma 2022; 63:3249.

37. Pretreatment considerations 1. Vitamin D – Some patients have hypercalcemia and concomitant vitamin D deficiency. Such patients are more likely to develop hypocalcemia after treatment with zoledronic acid / denosumab . If the 25hydroxyvitamin D level is < 20 ng/dL, vitamin D should be cautiously replaced ( eg , 400-800IU/day ) 2. Creatinine – If renal function is impaired, the bisphosphonate should be infused at a slower rate . Patient and Physician Decisional Factors Regarding Hypercalcemia of Malignancy Treatment: A Novel Mixed-Methods Study. J Clin Endocrinol Metab 2023; 108:563.

38. Choice of drug and dosing — Zoledronic acid : 4 mg IV over 15 minutes repeated every 7 days. P amidronate : 60 to 90 mg over 2-24 hours repeated every 7 days. Ibandronate : 2-6mg IV over 2 hours. Denosumab :120 mg once weekly for up to 3 doses ; if the cause of hypercalcemia persists, may continue at 120 mg every 4 weeks starting 2 weeks after initial 3 weekly doses Side effects and precautions  — Flu-like symptoms (fever, arthralgias , myalgia, fatigue, bone pain), O cular inflammation (uveitis), Hypocalcemia H ypophosphatemia A practical approach to hypercalcemia. Am Fam Physician 2003; 67:1959. Patient and Physician Decisional Factors Regarding Hypercalcemia of Malignancy Treatment: A Novel Mixed-Methods Study. J Clin Endocrinol Metab 2023; 108:563.

39. Dialysis – Hemodialysis with little or no calcium in dialysis fluid & peritoneal dialysis are both effective therapies for hypercalcemia. Dialysis may be indicated in patients with severe malignancy-associated hypercalcemia and renal insufficiency / heart failure, in whom hydration cannot be safely administered A Systematic Review Supporting the Endocrine Society Clinical Practice Guideline on the Treatment of Hypercalcemia of Malignancy in Adults. J Clin Endocrinol Metab 2023; 108:585.

40. Harrison Principles of internal medicine 21 st edition

41. PREVENTING RECURRENCE Many patients with malignancy may also have metastatic bone disease and receive zoledronic acid or pamidronate every 3-4 weeks to prevent skeletal complications. In patients with renal insufficiency & history of hypercalcemia, calcium intake should be limited to 1000 mg /day . Excessive vitamin D supplements should be avoided. The diagnosis and management of hypercalcaemia . BMJ 2015; 350:h2723.

42. DISEASE-SPECIFIC APPROACH Hyperparathyroidism – The treatment is typically parathyroidectomy or monitoring for complications of primary hyperparathyroidism. The primary treatment of parathyroid carcinoma is surgery. When the tumor is no longer curable by surgical intervention, treatment becomes focused on the control of hypercalcemia with medical therapy . Evaluation and Management of Primary Hyperparathyroidism: Summary Statement and Guidelines from the Fifth International Workshop. J Bone Miner Res 2022; 37:2293.

43. Harrison Principles of internal medicine 21 st edition

44. Granulomatous diseases –The major modalities of therapy are a low-calcium diet, glucocorticoids, and treatment of underlying disease. Glucocorticoids (prednisone : 20- 40 mg/d) will reduce serum calcium concentrations within 2-5 days . Hypervitaminosis D – Calcitriol – U sually lasts ~ 1-2 days . S topping calcitriol, increasing salt & fluid intake, or hydrating with IV saline may be only therapy that is needed. Vitamin D – Hypercalcemia caused by calcidiol lasts longer, so more aggressive therapy such as glucocorticoids ( eg , prednisone- 20-40 mg/d) & zoledronic acid or pamidronate may be necessary. SILICONE GRANULOMATOUS INFLAMMATION RESULTING IN HYPERCALCEMIA: A REVIEW OF THE LITERATURE. AACE Clin Case Rep 2019; 5:e119. Vitamin D intoxication causes hypercalcaemia by increased bone resorption which responds to pamidronate . Clin Endocrinol ( Oxf ) 1995; 43:531.

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