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Hypercalcemia- Approach to the Diagnosis Palak Choksi.pptx
- 1. HYPERCALCEMIA: APPROACH TO THE DIAGNOSIS Palak Choksi, MD Assistant Professor of Medicine Metabolism, Endocrinology and Diabetes
- 3. Intended Learning Outcomes –Review calcium metabolism –Describe symptoms of hypercalcemia –Review the etiology of hypercalcemia –Discuss the treatments for hypercalcemia –Conclusions
- 4. Intended Learning Outcomes –Review calcium metabolism –Describe symptoms of hypercalcemia –Review the etiology of hypercalcemia –Discuss the treatments for hypercalcemia –Conclusions
- 5. Calcium metabolism • Absorption from GI tract is by passive diffusion and active transport • Most of the calcium is reabsorbed by the kidney – net loss is about 2% • Calcium is controlled by both PTH and calcitonin
- 7. Calcium • Total calcium - Free (ionized) calcium (50%) - Protein bound calcium (40%) - Calcium complexed with organic and inorganic molecules (10%)
- 8. Role of albumin High albumin states (volume depletion or multiple myeloma) may lead to pseudohypercalcemia. Low albumin states like malnutrition, total serum calcium may appear low while ionized calcium is again not very affected. Ca2+= serum Ca2+ + 0.8 x [normal alb-patient alb]
- 9. Intended Learning Outcomes –Review calcium metabolism –Describe symptoms of hypercalcemia –Review the etiology of hypercalcemia –Discuss the treatments for hypercalcemia –Conclusions
- 10. Hypercalcemia - symptoms • CNS • GI • SKELETON • KIDNEY STONES BONES GROANS MOANS
- 11. Renal (stones) • Polyuria • Renal insufficiency (rarely seen in mild disease, although in severe cases may cause a reversible drop in GFR) • Nephrolithiasis • Nephrogenic DI
- 12. Skeleton (Bones) • Bone pains • Arthritis • Osteoporosis • Osteitis fibrosa cystica
- 13. Neuro-psychiatric (Groans) • Depression • Anxiety • Cognitive dysfunction • Lethargy, confusion, stupor, and coma may occur in patients with severe hypercalcemia • More likely to occur in the elderly and in those with rapidly rising calcium concentrations
- 14. Gastro-intestinal (Moans) • Constipation • Anorexia • Nausea • Pancreatitis • Peptic Ulcers
- 15. Cardiovascular • Increases myocardial contractility and irritability • Shortened QT interval • Prolonged PR • Wide QRS complexes • Calcium deposition in coronary arteries and myocardial fibers • Hypertension
- 16. Intended Learning Outcomes –Review calcium metabolism –Describe symptoms of hypercalcemia –Review the etiology of hypercalcemia –Discuss the treatments for hypercalcemia –Conclusions
- 18. Causes of hypercalcemia Ca++ PTH Vitamin D Malignancy Medicines Endocrine Genetic
- 19. Endocrine causes • Thyrotoxicosis • Adrenal failure • Pheochromocytoma • Drugs: Thiazides, Estrogen, Tamoxifen, Lithium, Vitamin A • Milk-Alkali Syndrome • Immobilization
- 20. Algorithmic Approach ? Suspect Calcium Serum Calcium 8.5 to 10.3 > 10.3 mg % < 8.0 mg % Hypocalcemia Normal calcium
- 21. Medications > 10.3 mg% I-PTH High/Normal PTH Low Vit D Toxicity Milk-Alkali Cancers/ Lymphoma Low PTHrP Approaching the diagnosis
- 22. Case • 40/ W noted to have mild elevations in serum calcium on routine testing. Calcium at the last two visits is 10.4- 10.6 mg/dL. • She is relatively asymptomatic. • You obtain labs: • PTH: • 120
- 24. Case • 40/ W asymptomatic hypercalcemia • You obtain labs: • PTH: 120 • Phos: 2.0 • Vitamin D (25OHD): 40 • Creatinine: 1.0 • Albumin: 4.0 • Likely diagnosis: ?
- 25. Medications > 10.3 mg% I-PTH High/Normal PTH Low Vit D Toxicity Milk-Alkali Cancers/ Lymphoma Low PTHrP Approaching the diagnosis
- 26. Case • 40/ W noted to have mild elevations in serum calcium on routine testing. Calcium at the last two visits is 10.4-10.6 mg/dL. • She is relatively asymptomatic. • You obtain labs: • PTH: 120 • Phos: 2.0 • Vitamin D (25OHD): 40 • Creatinine: 1.0 • Albumin: 4.0 • Likely diagnosis: Primary hyperparathyroidism
- 27. Primary Hyperparathyroidism • Most common cause in the outpatient setting • Renal calculi seen in 15-20% • Classic bone disease (brown tumors, osteitis fibrosa cystica, subperiosteal resorption) is rarely seen • Increased risk for vertebral fractures
- 28. Familial Hypocalciuric Hypercalcemia (FHH) • Rare, autosomal dominant condition • caused by an inactivating disorder of calcium- sensing receptors (CaSR) • PTH normal to mildly elevated, mild hypercalcemia • Fractional excretion of calcium is lower than 1%, despite hypercalcemia. • Genetic testing is not often required • ClCa/ClCr= (Uca X SCr) X (Sca X UCr) • A ratio of 0.01 or less is typically with FHH
- 29. Case • 70/M with history of renal cell carcinoma. Calcium levels are noted to be recently elevated at 13.0 mg/dL. • You obtain labs: - PTH: 23 - Phos: 2.1 - Vitamin D: 40 - Creatinine: 1.0 - Albumin 3.6 - PTH-rP: 1.0 (High)
- 30. > 10.3 mg% I-PTH Low PTHrP Low Vit D Toxicity Milk-Alkali Cancers/ Lymphoma High/Normal PTH Approaching the diagnosis
- 31. Case • 70/M with history of renal cell carcinoma. Calcium levels are noted to be recently elevated at 13.0 mg/dL. • You obtain labs: - PTH: 23 - Phos: 2.1 - Vitamin D: 40 - Creatinine: 1.0 - Albumin 3.6 - PTH-rp: 1.0 (High) - Likely diagnosis: Hypercalcemia of malignancy
- 32. Humoral Hypercalcemia of Malignancy • Usually have obvious malignant disease • Most common cause for inpatient hypercalcemia • PTH is low, PTH-rP is elevated • Associated with localized bone destruction
- 33. Case • 51/M presents with fatigue and trouble concentrating with a 5-lb weight loss. Calcium levels are noted to be recently elevated at 13.0 mg/dL. • You obtain labs: - PTH: 17 - Phos: 3.0 - CXR: Hilar lymphadenopathy 24 hour urine calcium is elevated - Vitamin D: 27, Creatinine is normal - DHVD: 110 - Likely diagnosis: Hypercalcemia due to granulomatous disease
- 34. Hypercalcemia associated with granulomatous diseases • Sarcoidosis is most commonly associated although can occur in any granulomatous disease • Increased activation of 1α hydroxylase that converts 25OHD to 1,25(OH)2D
- 35. Intended Learning Outcomes –Review calcium metabolism –Describe symptoms of hypercalcemia –Review the etiology of hypercalcemia –Discuss the treatments for hypercalcemia –Conclusions
- 36. Treatment • Asymptomatic or mildly symptomatic patients do not require immediate treatment • Chronic hypercalcemia with no symptoms 12-14 mg/dl can be monitored as well • > 14 mg/dl needs treatment even if asymptomatic
- 37. Treatment • Correction of dehydration/volume depletion • Correction of any electrolyte abnormalities • Discontinuation of medications that may cause calcium elevation • Reduction of dietary calcium in states of intestinal hyperabsorption (vitamin D intoxication and milk alkali) • Weight bearing or mobilization
- 38. The Four Rx Modalities I.V. Saline Hydration & Diuresis Gluco- Corticoids Anti- resorptives Calcitonin I.M/S.C.
- 39. • Agents that decrease the release of calcium from bone or increase the uptake of calcium into bone • Agents that increased urinary excretion of calcium • Agents that reduce intestinal absorption of calcium Treatment
- 40. • IV fluids Depending on clinical status 200-300 ml/hour to maintain UO of 100-150 ml/hour Dehydration can make hypercalcemia worse by impairing the renal excretion of calcium Treatment
- 41. Salmon Calcitonin • IM or SQ injections at dose of 4 IU/kg • At 6-12 hour intervals • Modest reductions and low toxicity profile • Vitamin D intoxication and immobilization • Acts quickly • Escape phenomenon may develop in 48 hours
- 42. Bisphosphonates • Inhibit release of calcium by interfering with osteoclast mediated bone resorption • More potent than saline and calcitonin • Can be used for hypercalcemia of any cause • Max effect seen in 2-4 days • Also used to prevent hypercalcemia and skeletal events in malignancy
- 43. Bisphosphonates • Pamidronate 60 or 90 mg IV over 2-4 hours • Zoledronic acid (ZA) 4 mg over 15 minutes • ZA preferred due to quicker infusion time • Side effects (low grade fever, myalgias, osteonecrosis of the jaw, atypical fractures)
- 44. NEWER THERAPIES • DENOSUMAB monoclonal antibody • RANKL inhibitor • Humoral hypercalcemia of malignancy • Bisphosphonate refractory hypercalcemia
- 45. • Agents that decrease the release of calcium from bone or increase the uptake of calcium into bone • Agents that increased urinary excretion of calcium • Agents that reduce intestinal absorption of calcium Treatment
- 46. Loop diuretics • WITH SALINE • Correct volume depletion first! • 80-120 mg every 2-6 hours • Monitor lytes, large losses of K and Mg • Fallen out of favor: 1) Better drugs 2) Frequent monitoring of lytes
- 47. Dialysis • Renal insufficiency • Congestive heart failure • Life threatening hypercalcemia
- 48. • Agents that decrease the release of calcium from bone or increase the uptake of calcium into bone • Agents that increased urinary excretion of calcium • Agents that reduce intestinal absorption of calcium Treatment
- 49. Glucocorticoids • Vitamin D intoxication or endogenous production of calcitriol (sarcoidosis, TB) • Prednisone 20-40 mg • Lowers calcium in 2-5 days
- 50. Intended Learning Outcomes –Review calcium metabolism –Describe symptoms of hypercalcemia –Review the etiology of hypercalcemia –Discuss the treatments for hypercalcemia –Conclusions
- 51. Conclusion • Most common cause of hypercalcemia in the outpatient setting is primary hyperparathyroidism • Most common cause of hypercalcemia in the inpatient setting is malignancy • Establishing the cause is important for treatment decisions
Editor's Notes
- Calcium is important for a number of intracellular reactions including muscle contraction, nerve cell activity, release of hormone through the process of exocytosis and activation of several enzymes, blood coagulation and structural integrity of teeth and bone. 99% of the body calcium is in the bones in the form of hydroxyapatite cyrstals. The next largest pool is the intracellular calcium. Smallest pool is in the ECF. Regulation of calcium involves the control of calcium movement between ECF, bone, GI tract and kidneys. Kidney serves as a route for excretion
- Actual % may vary with health and disease 80% is albumin bound
- Mild hypercalcemia: Asymptomatic Non specific symptoms
- Gastrointestinal symptoms are probably related to the depressive action of hypercalcemia on the autonomic nervous system and resulting smooth-muscle hypotonicity
- Calcium between 12-14 mg/dl maybe well tolerated if elevated chronically Acute rises: polyuria, polydipsia, dehydration, anorexia, nausea, muscle weakness, and changes in sensorium
- PHPT – most common cause in the ambulatory setting
- PHPT – most common cause in the ambulatory setting
- PHPT – most common cause in the ambulatory setting
- The underlying pathophysiology of HPT is caused by excessive secretion of parathyroid hormone (PTH), which leads to increased bone resorption by osteoclasts, increased intestinal calcium absorption, and increased renal tubular calcium reabsorption. The consequent hypercalcemia is also often accompanied by low-normal or decreased serum phosphate levels because PTH inhibits proximal tubular phosphate reabsorption.
- Hypercalcemia of malignancy: 30% of individuals with cancer develop hypercalcemia– typically late in the disease course. Calcium levels are generally higher
- Hypercalcemia of malignancy: 30% of individuals with cancer develop hypercalcemia– typically late in the disease course. Calcium levels are generally higher
- Usually, this term is applied to patients with excessive tumoral production of PTH-related peptide (PTHrP).
- The predominant mechanism for the development of hypercalcemia and hypercalciuria is increased intestinal absorption of calcium induced by elevated calcitriol levels, Activity of this enzyme is under negative feedback control in normal tissues. However, in granulomatous disorders, normal feedback inhibition is abolished, probably by the effects of interferon gamma.
- Cautious use when EGFR 35 or less ONJ: Limited relevance when used for management of acute hypercalcemia
- Both hemo and peritoneal