HYPERCALCEMIA: APPROACH TO THE DIAGNOSIS Palak Choksi, MD Assistant Professor of Medicine Metabolism, Endocrinology and Diabetes

Disclosures NONE

Intended Learning Outcomes Review calcium metabolism Describe symptoms of hypercalcemia Review the etiology of hypercalcemia Discuss the treatments for hypercalcemia Conclusions

Intended Learning Outcomes Review calcium metabolism Describe symptoms of hypercalcemia Review the etiology of hypercalcemia Discuss the treatments for hypercalcemia Conclusions

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 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

ROLE OF PARATHYROID HORMONE

Calcium Total calcium Free (ionized) calcium (50%) Protein bound calcium (40%) Calcium complexed with organic and inorganic molecules (10%) Actual % may vary with health and disease 80% is albumin bound

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]

Intended Learning Outcomes Review calcium metabolism Describe symptoms of hypercalcemia Review the etiology of hypercalcemia Discuss the treatments for hypercalcemia Conclusions

Hypercalcemia - symptoms CNS GI SKELETON KIDNEY STONES BONES GROANS MOANS Mild hypercalcemia: Asymptomatic Non specific symptoms

Renal (stones) Polyuria Renal insufficiency (rarely seen in mild disease, although in severe cases may cause a reversible drop in GFR) Nephrolithiasis Nephrogenic DI

Skeleton (Bones) Bone pains Arthritis Osteoporosis Osteitis fibrosa cystica

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

Gastro-intestinal (Moans) Constipation Anorexia Nausea Pancreatitis Peptic Ulcers Gastrointestinal symptoms are probably related to the depressive action of hypercalcemia on the autonomic nervous system and resulting smooth-muscle hypotonicity

Cardiovascular Increases myocardial contractility and irritability Shortened QT interval Prolonged PR Wide QRS complexes Calcium deposition in coronary arteries and myocardial fibers Hypertension

Intended Learning Outcomes Review calcium metabolism Describe symptoms of hypercalcemia Review the etiology of hypercalcemia Discuss the treatments for hypercalcemia Conclusions

Severity of hypercalcemia 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

Causes of hypercalcemia PTH Vitamin D Malignancy Medicines Endocrine Genetic

Endocrine causes Thyrotoxicosis Adrenal failure Pheochromocytoma Drugs: Thiazides, Estrogen, Tamoxifen, Lithium, Vitamin A Milk-Alkali Syndrome Immobilization

Algorithmic Approach 8.5 to 10.3 > 10.3 mg % < 8.0 mg % ? Suspect  Calcium Serum Calcium 8.5 to 10.3 > 10.3 mg % < 8.0 mg % Normal calcium Hypocalcemia

Approaching the diagnosis Medications > 10.3 mg% I-PTH High/Normal PTH Low Vit D Toxicity Milk-Alkali Cancers/ Lymphoma PTHrP

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 PHPT – most common cause in the ambulatory setting

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: ? PHPT – most common cause in the ambulatory setting

Approaching the diagnosis Medications > 10.3 mg% I-PTH High/Normal PTH Low Vit D Toxicity Milk-Alkali Cancers/ Lymphoma PTHrP

Case Likely diagnosis: Primary hyperparathyroidism 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 PHPT – most common cause in the ambulatory setting

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 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.

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

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) Hypercalcemia of malignancy: 30% of individuals with cancer develop hypercalcemia– typically late in the disease course. Calcium levels are generally higher

Approaching the diagnosis > 10.3 mg% I-PTH Low PTHrP Vit D Toxicity Milk-Alkali Cancers/ Lymphoma High/Normal PTH

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 Hypercalcemia of malignancy: 30% of individuals with cancer develop hypercalcemia– typically late in the disease course. Calcium levels are generally higher

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 Usually, this term is applied to patients with excessive tumoral production of PTH-related peptide (PTHrP).

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

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 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.

Intended Learning Outcomes Review calcium metabolism Describe symptoms of hypercalcemia Review the etiology of hypercalcemia Discuss the treatments for hypercalcemia Conclusions

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

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

I.V. Saline Hydration & Diuresis The Four Rx Modalities I.V. Saline Hydration & Diuresis Gluco-Corticoids Anti-resorptives Calcitonin I.M/S.C.

Treatment 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 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

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

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

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) Cautious use when EGFR 35 or less ONJ: Limited relevance when used for management of acute hypercalcemia

NEWER THERAPIES DENOSUMAB monoclonal antibody RANKL inhibitor Humoral hypercalcemia of malignancy Bisphosphonate refractory hypercalcemia

Treatment 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

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: Better drugs Frequent monitoring of lytes

Dialysis Renal insufficiency Congestive heart failure Life threatening hypercalcemia Both hemo and peritoneal

Treatment 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

Glucocorticoids Vitamin D intoxication or endogenous production of calcitriol (sarcoidosis, TB) Prednisone 20-40 mg Lowers calcium in 2-5 days

Intended Learning Outcomes Review calcium metabolism Describe symptoms of hypercalcemia Review the etiology of hypercalcemia Discuss the treatments for hypercalcemia Conclusions

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

palak@med.umich.edu