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Flashcards in Hypercalcemia Deck (19)
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Why does Hypercalcemia occur?

hint: talk about 3 general mechanisms.

It results when the entry of calcium into the circulation exceeds the excretion of calcium into the urine or deposition in bone.
-Accelerated bone resorption
-Excessive gastrointestinal absorption
-Decreased renal excretion of calcium


What two causes of hypercalcemia account for >90% of cases?

-Primary hyperparathyroidism


What are causes of accelerated bone resorption in Hypercalcemia?

Primary hyperparathyroidism
-PTH-mediated activation of osteoclasts
-typically have relatively minor elevations in serum calcium concentrations

Secondary and tertiary hyperparathyroidism
-2ndary hyperPTH assoc with severe chronic kidney disease usually have parathyroid hyperplasia and frankly low or low-normal serum calcium concentrations. However, with prolonged disease, some patients may develop hyperCa.
-Tertiary hyperparathyroidism associated with elevated PTH levels and Calcium lvls. This is assoc with advanced and prolonged renal failure; parathyroid hyperplasia may gradually progress to autonomous overproduction of PTH that is not suppressible by elevated serum calcium concentrations.

- In general, serum calcium levels are higher in patients with malignancy than in those with primary hyperparathyroidism
-MoA depends
a) with bone mets: direct induction of local osteolysis by the tumor cells is common.
b) Cytokines such as tumor necrosis factor and interleukin-1 appear to play an important role by stimulating the differentiation of osteoclast precursors into mature osteoclasts
c) In nonmetastatic solid tumors - secretion of PTH-related protein (PTHrP)

-Thyroid associated bone resorption

Other less common
-Paget's disease of the bone
-Hypervitaminosis A
-meds e.g. anti-estrogens


What are causes of calcium absorption in Hypercalcemia?

Increased calcium intake
-A high calcium intake alone is rarely a cause of hypercalcemia due to PTH feedback loops
-However, in patients who have decreased urinary calcium excretion due to reduced glomerular filtration, increased calcium intake can cause hypercalcemia. This combination of high calcium intake and low urine calcium excretion occurs in two clinical situations: chronic kidney disease and the milk-alkali syndrome.

Hypervitaminosis D
-increasing calcium absorption and bone resorption


Rarer miscellaneous causes of hypercalcemia?

Other rare causes
-Adrenal insufficiency
-Rhabdomyolysis and acute renal failure
-Theophylline toxicity
-Familial hypocalciuric hypercalcemia
-Metaphyseal chondrodysplasia
-Congenital lactase deficiency


3 major MoA for hyperCa of malignancy?

3 MoA for hypercalcemia of malignancy:
-Tumor secretion of parathyroid hormone-related protein (PTHrP) --> both increased bone resorption and distal renal tubular calcium reabsorption
-Osteolytic metastases with local release of cytokines (including osteoclast activating factors) --> bone resorption
-Tumor production of 1,25-dihydroxyvitamin D (calcitriol)
--> combo of increased intestinal Ca absorption and bone resorption
-RARE: Ectopic tumoral secretion of PTH


Diagnostic Approach to hypercalcemia?

See uptodate algorithm.
-Elevated serum Ca --> repeat and check for corrected Ca using Ca calculator --> PTH serum levels.
-Based on serum PTH levels, will order PTHrP, 1,25-Vit D, 25-Vit D, SPEP, UPEP, serum-free light chain assay


Symptoms of hypercalcemia?

Stones (renal stones), Bones (painful bone condition), groans (abdo pain), and psychiatric overtones (delirium)


Hypercalcemia thresholds?

Mild hypercalcemia
-Total albumin-corrected calcium <12 mg/dL [3 mmol/L]
-Ionized calcium <8 mg/dL [2 mmol/L]

Moderate hypercalcemia
-Total albumin-corrected calcium 12 - 14 mg/dL [3 to 3.5 mmol/L]
-Ionized calcium 8 - 10 mg/dL [2 to 2.5 mmol/L]

Severe hypercalcemia
-Total albumin-corrected calcium >14 mg/dL [3.5 mmol/L] -Ionized calcium >10 mg/dL (2.5 mmol/L)


When do you treat for hypercalcemia?

Mild hypercalcemia — Patients with asymptomatic or mildly symptomatic hypercalcemia. However, they should be advised to avoid factors that can aggravate hypercalcemia
Moderate hypercalcemia — Asymptomatic or mildly symptomatic individuals with chronic moderate hypercalcemia may not require immediate therapy.
Severe hypercalcemia - Treatment regardless of symptoms


What preventative factors should you do to avoid worsening of mild asymptomatic hypercalcemia?

Avoid factors that can aggravate hypercalcemia including:
-meds (thiazide diuretics and lithium carbonate therapy), -volume depletion
-prolonged bed rest or inactivity
-high calcium diet (>1000 mg/day).
-Encourage adequate hydration (at least six to eight glasses of water per day) is recommended to minimize the risk of nephrolithiasis.


Treatment options for hypercalcemia?

Immediate therapy — The acute therapy of patients with severe hypercalcemia consists of a three-pronged approach
1) Volume expansion with isotonic saline at an initial rate of 200 to 300 mL/hour that is then adjusted to maintain the urine output at 100 to 150 mL/hour.
2) Administration of calcitonin (4 international units/kg) and repeat measurement of serum calcium in several hours. Patients may develop tachyphylaxis to calcitonin after 24 to 48 hours, so therapy is usually limited to this time period and then discontinued.
3)Bisphosphonates: administration of zoledronic acid or pamidronate
-ZA is preferable because it is superior to pamidronate in reversing hypercalcemia related to malignancy.
4)Avoidance of calcium-containing foods and supplements and vitamin D.


When are bisphosphates contraindicated in the treatment for hypercalcemia?

severe renal impairment

In patients with impaired renal function (creatinine >4.5 mg/dL), we suggest caution when using IV bisphosphonates to treat hypercalcemia. Adequate hydration with saline and treatment with a reduced dose and/or slower infusion rate (4 mg ZA over 30 to 60 minutes, 30 to 45 mg pamidronate over four hours, 2 mg ibandronate over one hour) may minimize risk.


When should you see effects in treatment for hypercalcemia? How do the treatment durations differ?

-The administration of calcitonin plus saline should result in substantial reduction in serum calcium concentrations within 12 to 48 hours.
-The bisphosphonate will be effective by the second to fourth day, thereby maintaining control of the hypercalcemia.

The efficacy of calcitonin is limited to the first 48 hours, even with repeated doses, indicating the development of tachyphylaxis, perhaps due to receptor downregulation Because of its limited duration of effect, calcitonin is most beneficial in symptomatic patients, when combined with hydration and bisphosphonates (or denosumab, in bisphosphonate-intolerant patients). Calcitonin and hydration provide a rapid reduction in serum calcium concentration, while a bisphosphonate provides a more sustained effect.


When is hemodialysis a treatment option for hypercalcemia?

Additional, more aggressive measures are necessary in the rare patient with very severe, symptomatic hypercalcemia. Hemodialysis should be considered, in addition to the above treatments, in patients who have serum calcium concentrations in the range of 18 to 20 mg/dL (4.5 to 5 mmol/L) and neurologic symptoms but a stable circulation or in those with severe hypercalcemia complicated by renal failure.


How do you prevent recurrences of hypercalcemia of malignancy?

In patients with hypercalcemia of malignancy, progressive hypercalcemia will inevitably accompany tumor progression, and therefore, the underlying disease causing the hypercalcemia should be treated, if at all possible.
-Many patients with malignancy may also have metastatic bone disease and will receive IV ZA or pamidronate every three to four weeks as part of their treatment to prevent skeletal complications. As a result, recurrent hypercalcemia will be prevented.


What fluids do you give for hypercalcemia and why?

Isotonic saline corrects possible volume depletion due to hypercalcemia-induced urinary salt wasting and, in some cases, vomiting. Hypovolemia exacerbates hypercalcemia by impairing the renal clearance of calcium

The rate of saline infusion depends upon several factors, including the severity of hypercalcemia, the age of the patient, and presence of comorbid conditions, particularly underlying cardiac or renal disease. A reasonable regimen, in the absence of edema, is the administration of isotonic saline at an initial rate of 200 to 300 mL/hour that is then adjusted to maintain the urine output at 100 to 150 mL/hour.

Saline therapy requires careful monitoring since it can lead to fluid overload in patients who cannot excrete the administered salt because of impaired renal function, which can be induced by hypercalcemia or heart failure

Saline therapy beyond that necessary to restore euvolemia has fallen out of favor for two reasons
-The availability of drugs such as the bisphosphonates and calcitonin
-The requirement for careful monitoring because of the potential fluid and electrolyte complications resulting from a massive saline infusion and furosemide-induced diuresis


Side-effects of IV bisphosphonates?

Although IV bisphosphonates are generally well tolerated, side effects may include flu-like symptoms (fever, arthralgias, myalgia, fatigue, bone pain), ocular inflammation (uveitis), hypocalcemia, hypophosphatemia, impaired renal function, nephrotic syndrome, osteonecrosis of the jaw, and atypical femur fractures (in patients who require long-term therapy)


What treatment can be given if IV bisphosphonates are contraindicated?

Denosumab is an option for patients with hypercalcemia that is refractory to zoledronic acid (ZA) or in whom bisphosphonates are contraindicated due to severe renal impairment.

However, careful monitoring of serum calcium levels is necessary in these patients because there is a higher risk of hypocalcemia with denosumab than with bisphosphonates.