Hypercalcemia

Question 1

Pathophysiology of hypercalcemia and correction of serum Ca relative to albumin 1

Answer 1

• HyperCa arises wen the rate of Ca entry to blood (from gut or skeleton) is greater than ability of kidneys to eliminate it
• The first thing to do in a pt w/ high or low Ca is to check the albumin, since it will affect the true serum Ca level
• High albumin makes the measured Ca look higher than it really is, and low albumin makes the measured Ca look lower than it is (true Ca = measured Ca + (4-alb)x.8)

Question 2

Pathophysiology of hypercalcemia and correction of serum Ca relative to albumin 2

Answer 2

• For every 1g of albumin less than 4g, add .8 from the measured Ca and that gives you the true Ca (i.e. low albumin can mean pt is actually hyperCa even tho their measured Ca is normal)
• For every 1g of albumin more than 4g, subtract .8 from the measured Ca and that gives you the true Ca (i.e. high albumin can mean pt is actually hypoCa even tho their measured Ca is normal)

Question 3

HyperCa due to bone resorption

Answer 3

• The majority of hyperCa pts are b/c of increased bone resorption
• In hospitalized pts the most common cause for this is malignancy, either bone mets or paraneoplastic syndrome (PTHrp) of the CA
• In the outpatient setting the most common cause of increased bone resorption and hyperCa is hyperparathyroidism
• Other potential causes of hyperCa due to bone resorption: immobilization and loss of gravity promotes bone loss (bedridden or astronauts)
• Hyperthyroidism can cause increased bone resorption (mediated by both T3 and TSH)
• Acute adrenal insufficiency can cause increased bone resorption and proximal tubules Ca reabsorption

Question 4

HyperCa due to increased intestinal absorption

Answer 4

• Possible causes include vitamin D intoxication (often secondary to primary hyperpara)
• High vitamin D levels lead to increased absorption of Ca from gut
• Granulomatous diseases (i.e. sarcoidosis, TB) can cause high levels of 1,25OHD b/c the dysfxnal pulmonary macs synthesize and release large amounts of 1,25OHD
• Some lymphomas can also cause excess 1,25OHD production
• Can also be iatrogenic (overRxing w/ 1,25OHD) or factitious supplementation

Question 5

HyperCa due to increased renal reabsorption 1

Answer 5

• PTH and PTHrp (due to 1o hyperpara or malignancy) will increase Ca reabsorption
• Familial hypocalcuric hypercalcemia (FHH): mutation of the Ca-sensing receptor in the parathyroid gland and kidney
• This results in an inappropriate secretion of PTH and enhanced peripheral effect of PTH on the kidney (gland and kidneys can’t sense the high Ca levels), resulting in renal Ca reabsorption

Question 6

HyperCa due to increased renal reabsorption 2

Answer 6

• Drugs can increase reabsorption of Ca: thiazide diuretics increase reabsorption of Ca
• Lithium: alters the Ca-PTH set point in the kidney (reabsorbs more Ca) and gland (Li-induced hyperparathyroidism)
• Acute adrenal insufficiency can cause increased bone resorption and proximal tubules Ca reabsorption

Question 7

HyperCa of malignancy

Answer 7

• Humoral hyperCa of malignancy (paraneoplastic syndrome, no mets): PTHrP or 1,25OHD excess (lymphomas)
• Multiple skeletal mets (think lung, breast): local release of growth factors (IGF, TGF, PDGF, EGF), PTHrP
• Primary hematologic malignancy: multiple myeloma (IL1, PTHrP, RANKL release, decreased release and increased destruction of OPG)
• Vicious cycle of mets/1o bone malignancy: tumor growth releases PTHrP/cytokines that stimulate osteoclasts, then activated osteoclasts release GFs that stimulate further tumor growth
• 5% of CA cases have coexistent 1o hyperpara

Question 8

Primary hyperparathyroidism

Answer 8

• Main causes of 1o hyperpara: adenoma, hyperplasia (MEN I and IIa), CA, familial
• If the Ca level is >16 and there is hyperpara the Dx is parathyroid CA UPO
• All familial forms are hyperplasia
• MEN syndromes only found in young people (<30)
• Vast majority of 1o hyperpara are from adenomas (85%)
• These are due to abnormal set point of Ca receptor: right shifted so there is high PTH at high Ca levels)

Question 9

Things to ask when pt is hyperCa

Answer 9

• Is it real (albumin)?
• Is it PTH or non-PTH origin? (is PTH high or low)
• Drugs?
• Sx?

Question 10

Signs and Sx of 1o hyperpara

Answer 10

• 80% of pts are ASx (vs majority of pts w/ hyperCa of malignancy are overtly ill)
• 39% of 1o hyperpara pts have hyperCa, 17% have kidney stones, 1.4% have skeletal disease
• Height loss may be present (due to multiple vertebral compression fractures)
• Other possible signs/Sx: calcification of cornea (band keratopathy; white ring around cornea), pseudogout (calcification of joint space)
• Osteitis fibrous (browns tumor): PTH diverts osteoblasts into fibroblasts along w/ coast stimulation-> lots of scar tissue and bone breakdown
• Subperiosteal erosion of fingers

Question 11

Signs/Sx of hyperCa

Answer 11

• GI: dry mouth, thirst, polydipsia (high Ca prevents ADH action), anorexia, N/V, constipation
• GU: polyuria/nocturia (Ca-induced nephrogenic DI), nephrolithiasis, uremia
• Calcification: corneal/conjunctival and vascular calcification, nephrocalcinosis (long term)
• MSK: fatigue, muscle weakness, arthralgia, bone pain, osteoporosis
• Neuro: drowsiness, lethargy, stupor/coma, confusion, speech defects, blurred vision, decreased or absent DTRs

Question 12

Tests for hyperCa 1

Answer 12

• All tests should be directed toward determining if hyperCa is mediated by PTH or not
• Serum Ca and compare to alb
• PTH level: a nl (or high)serum PTH in presence of hyperCa is inappropriately nl relative to the serum Ca and indicates hyperpara
• Pts w/ hyperCa not due to hyperpara will have LOW PTH levels

Question 13

Tests for hyperCa 2

Answer 13

• Serum PTHrP can distinguish humoral hyperCa of malignancy vs 1o hyperpara
• Serum 1,25OHD can tell you if there is granulomatous disease or lymphoma causes (will also be high in 1o hyperpara due to high PTH), will be low in other causes
• Other tests (not reliable): serum Cl and bicarb (hyperpara generally high Cl low bicarb, malignancy generally low Cl high bicarb)
• Serum PO4: should be low in hyperpara, nl or high in others

Question 14

Rx of mild hyperCa

Answer 14

• In ASx pts: avoid inactivity (walk), avoid salt restriction and dehydration
• Avoid diuretics
• Restrict dietary Ca only if hyperCa is mediated by 1,25OHD (may cause hyper absorption)
• Must walk and drink water!

Question 15

Rx of moderate or severe hyperCa

Answer 15

• Symptomatic + rehydration: drink water and saline if needed (will increase Na excretion and Ca will follow)
• Dont use lasix: will volume deplete and Ca will rise
• Drugs to decrease bone resorption

Question 16

Antiresorptive Rx

Answer 16

• Pamidronate and zoledronic acid are bone bisphosphanates which prevent the osteoclast from binding to bone and inhibit osteoclast formation of acidic compounds that are required for bone resorption
• They will lower serum Ca as well as prevent osteoporosis
• These can be nephrotoxic
• Calcitonin may help when used in conjunction w/ a bisphosphanate by normalizing serum Ca more quickly

Question 17

Surgical indication for Rx of primary hyperpara

Answer 17

• Bone mineral density T score of 1mg above nl (rr: 8.5-10.3) means they need surgery
• Cr clearance is reduced by 30% means onset of renal failure and they need surgery
• Urine Ca >400mg/day they need surgery

Question 18

FHH vs 1o hyperpara

Answer 18

• PTH levels high in both (FHH causes hyperplasia of parathyroids)
• Get spot urine Ca/Cr and serum Ca/Cr then calculate: (UcaxScr/UcrxSca)
• Nl ratio is .01
• FHH will have ratio < .01
• Hyperpara ratio > .01
• Cannot do parathyroidectomy on pts w/ FHH