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

2. Disclosures
NONE

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
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

6. ROLE OF
PARATHYROID HORMONE

7. 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

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 Ca 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
Mild hypercalcemia: Asymptomatic
Non specific symptoms

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
Gastrointestinal symptoms are probably related to the depressive action of hypercalcemia on the autonomic nervous system and resulting smooth-muscle hypotonicity

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

17. Severity of hypercalcemia
Calcium between mg/dl maybe well tolerated if elevated chronically
Acute rises: polyuria, polydipsia, dehydration, anorexia, nausea, muscle weakness, and changes in sensorium

18. Causes of hypercalcemia
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 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

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

22. Case
40/ W noted to have mild elevations in serum calcium on routine testing. Calcium at the last two visits is mg/dL.
She is relatively asymptomatic.
You obtain labs:
PTH:
120
PHPT – most common cause in the ambulatory setting

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: ?
PHPT – most common cause in the ambulatory setting

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

26. 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 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

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
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.

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

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

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

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

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
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.

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

39. 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

40. Treatment IV fluids Depending on clinical status
ml/hour to maintain UO of ml/hour
Dehydration can make hypercalcemia worse by impairing the renal excretion of calcium

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

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

45. 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

46. Loop diuretics WITH SALINE Correct volume depletion first!
mg every 2-6 hours
Monitor lytes, large losses of K and Mg
Fallen out of favor:
Better drugs
Frequent monitoring of lytes

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

48. 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

49. Glucocorticoids
Vitamin D intoxication or endogenous production of calcitriol (sarcoidosis, TB)
Prednisone 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