Phosphorus and Calcium Imbalance

Table I.

Management of Hypocalcemia

Key points

• Management depends on the severity of symptoms

• Severity of symptoms depends on absolute concentration of ionized calcium and rate of decrease

• In patients with acute symptomatic hypocalcemia intravenous Ca gluconate is the preferred therapy

• Severity indicators include: carpopedal spasm, tetany, seizures; prolonged QT interval and acute decrease <7.5 mg/dl (1.9 mM)

• In patients with chronic hypocalcemia, oral calcium supplements and vitamin D supplements are indicated

Intravenous calcium

• Initial infusion of Ca gluconate 1-2 g [equivalent to 90-180 mg elemental Ca] in 50 ml of 5% dextrose in water infused over 10-20 minutes

• Avoid faster infusion rate because of risk of severe cardiac dysfunction or arrest

• This dose will be effective for 1-2 hours; initial injection should be followed by continuous infusion

  10% Ca gluconate (90 mg elemental Ca/10 ml) or 10% Ca chloride (270 mg elemental Ca/10 ml) can be used to prepare the solution:

  Ca gluconate safer for peripheral infusion as it is associated with lesser risk of tissue necrosis if extravasation occurs

  Intravenous solution 1 mg/ml (11 g Ca gluconate in saline or 5% dextrose final volume 1000 ml). Typical infusion rate 0.5 to 1.5 mg/kg/hour to maintain stable ionized calcium level

• Avoid simultaneous infusion of phosphate or bicarbonate and – if needed – give via a separate line to avoid precipitation of calcium phosphate or carbonate

• Simultaneous infusion of active vitamin D such as Calcitriol 0.25-0.5 mcg twice daily is usually necessary

Concurrent hypomagnesemia

• Hypomagnesemia can lead to resistant hypocalcemia by decreasing PTH secretion and causing resistance to PTH effects

• If serum Mg is initially low, administer 2 g (16 mEq) of Mg Sulphate as a 10% solution over 10-20 minutes followed by 1 g (8 mEq) in 100 ml fluid per hour

• Continue Mg repletion until serum Mg level >0.8 mEq/L (1 mg/dl)

• Monitor EKG continuously and renal dysfunction: patients with renal failure are at high risk of Mg toxicity

Oral calcium

• Adequate for milder degrees of acute hypocalcemia (serum ionized Ca above 3-3.2 mg/dl (0.8 mM) or for chronic hypocalcemia

• Initial treatment 1500-2000 mg elemental Ca as calcium carbonate or calcium citrate daily in divided doses

Vitamin D metabolites

• The dose varies greatly between individuals and clinical situations

• Patients with hypoparathyroidism should receive 1,25(HO)2D (calcitriol), initial dose 0.25-0.5 mcg twice daily

• Monitor serum Ca and urinary Ca excretion

  Hypercalciuria (Ca excretion >300 mg/day, >4 mg/Kg/day) may occur in the absence of hypercalcemia especially in patients with hypoparathyroidism

  If hypercalciuria develops calcitriol discontinuation will resolve the problem; if persistent, a short course of oral glucocorticoids will be effective

Hypoparathyroidism

• Most patients with hypoparathyroidism require lifelong Ca and vitamin D supplementation

• Initial dose Ca 1.0-1.5 g elemental calcium/day in divided doses

  Calcium carbonate is inexpensive and widely available

  Calcium citrate may be easier to absorb for elderly patients with hypochlorhydria

  Calcitriol 0.25-0.5 mcg twice daily is usually necessary, dose can be increased up to 2.0 mcg/day

• Prevent hypercalciuria: patients with hypothyroidism reabsorb Ca less efficiently and tend to develop hypercalciuria, with associated risks of nephrolithiasis and nephrocalcinosis

• Thiazidediuretics 25-100 mg/day may prevent hypercalciuria; sodium restriction potentiates the effect and K supplementation may be necessary

• Recombinant PTH, now only approved for the treatment of osteoporosis, may be available in the future to correct hypoparathyroidism

Hypoparathyroidism in pregnancy and during lactation

• An especially important situation especially in the third trimester of pregnancy or post delivery, a problem in lactating mothers

• During pregnancy serum levels of 1,25(OH)2D double but serum PTH concentrations remain normal, indicating that other mechanisms, poorly established and likely including PTHrP, stimulate kidney 1-alphahydroxylase

• There is disagreement whether hypoparathyroid mothers experience decreased calcitriol requirements during late pregnancy, but lactating mothers generally show decreased calcitriol requirements

• Measure serum Ca frequently during late pregnancy and lactation in hypoparathyroid women to avoid hypercalcemia; decrease calcitriol supplements accordingly

• Calcitriol requirements will return to antepartum levels upon cessation of pregnancy

Vitamin D deficiency

• Usual replacement dose is ergocalciferol 50,000 units weekly for 6-8 weeks

Chronic kidney disease

• Severe hypocalcemia is uncommon

• Calcium supplements are used to both replace Ca and to bind P in the intestine

• The majority of patients receive calcitriol to compensate for decreased 1-alpha hydroxylase activity in the insufficient kidney

• Calcimimetics such as cinacalcet are agonists of the parathyroid calcium receptor used to manage secondary hyperparathyroidism. These medications may induce hypocalcemia; close Ca monitoring is mandatory

3. Diagnosis

Hypophosphatemia – Diagnosis

• Assess medical and surgical history

• Measure fractional excretion of phosphate in the urine

  FEPi <5%: extrarenal causes

• Most likely:

  Intracellular translocation of P in a malnourished patient receiving insulin or glucose or with acute respiratory alkalosis

  Malabsorption due to chronic diarrhea or chronic anti-acid intake (such as magnesium hydroxide or calcium carbonate) binding P in the diet

  FEPi >5: renal Pi wasting

• Most likely:

  Primary hyperparathyroidism or secondary hyperparathyroidism due to vitamin D deficiency or vit D resistance (in children)

  Tubular defects (Fanconi syndrome) are rare

  Paraneoplastic: oncogenic osteomalacia due to phosphatonins produced by the tumor.

Diagnostic Tests – Disorders of Phosphate

Fractional excretion of P

Can be calculated as:

FEPi = (Upi x Pcr x 100) / (Ppi x Ucr)

In patients with hypophosphatemia of non-renal etiology, daily P excretion should be less than 100 mg/day and the FEPi should be below 5% (normal 5-20%)

A daily excretion of P greater than 100 mg/day or a FEPi>5% is consistent with renal P wasting

Fractional tubular reabsorption of P

• Is the percentage of filtered P which is reabsorbed by the renal tubules

• Gives a rough guide as to whether P reabsorption is normal

• Can be calculated with a random blood and urine sample:

TRPi (%) = (1-Upi x Pcr/Ucr x Ppi) x 100

where TRPi=tubular P reabsorption; Upi=urinary phosphate; Pcr=plasma creatinine; Ppi=plasma phosphate

• Given that TRPi is strongly affected by glomerular filtration rate (GFR), a more accurate measure of renal P handling is the ratio TmPi/GFR, fraction of actually filtered P that is maximally reabsorbed:

TmPi/GFR = Ppi – (Upi x Pcr/Ucr)

the ratio can also be calculated from nomograms.

Hyperphosphatemia: diagnosis

Pseudohyperphosphatemia

• Interference with analytical methods in patients with hyperglobulinemia (multiple myeloma, Waldenstrom’s macroglobulinemia), hyperlipidemia, hemolysis and hyperbilirubinemia or high-dose liposomal amphotericin-B treatment

Mechanisms of hyperphosphatemia include

Massive acute phosphate load overwhelms renal capacity to excrete phosphate:

Endogenous sources

Tumor lysis syndrome

Large tumor burden such as Burkitt’s lymphoma and non-Hodgkin’s lymphoma and leukemias, plus cytotoxic therapy lead to large cell breakdown and release of intracellular P

Frequently associated with hypocalcemia due to precipitation with phosphate

Syndrome also associated with acute kidney injury due to intrarenal precipitation of urates, further decreasing renal capacity to excrete P and potassium

Rhabdomyolysis

Simultaneous release of myoglobin causes AKI and further reduces renal capacity to eliminate P

Resolution of the rhabdomyolysis often leads to hypercalcemia, when phosphoremia decreases and Ca is mobilized from tissues

Lactic and ketoacidosis

Acidosis decreases intracellular P utilization

Osmotic gradient shifts P extracellularly

Exogenous sources

Phosphate containing laxatives like Fleet’s Phospho-soda has been associated with large absorption of phosphate and hyperphosphoremia, calcium phosphate precipitation in the kidney and renal failure

Volume contraction due to laxative effect and acidosis further shift P extracellularly

Renal failure limits the ability of the kidneys to eliminate phosphate:

Limited glomerular filtration rate will limit the ability of the kidneys to eliminate P in the acute and the chronic setting

Decreased tubular load is initially compensated by increased PTH causing decreased tubular reabsorption, but as GFR decreases <25% the compensation is no longer sufficient and hyperphosphoremia develops

Increased tubular reabsorption of phosphate

Hypoparathyroidism due to decreased secretion of PTH or renal resistance to the hormone (pseudohypoparathyroidism)

High-dose calcitriol may be effective treatment

Acromegaly

Growth hormone or insulin like growth factor stimulation of P reabsorption

Biphosphonates can increase serum P levels

Vitamin D toxicity via increase in intestinal absorption of Ca and P and renal failure

Familial tumoral calcinosis

Rare autosomal recessive condition leading to hyperphosphoremia due to increased renal reabsorption of P probably via decreased synthesis of FGF-23 (phosphatonins)

Calcium Disorders – Diagnostic evaluation

Key points

Understanding Ca disorders requires simultaneous measurement of Ca, P and Mg

• Formulas ‘correcting’ Ca by albumin levels are inaccurate: in the critically ill patient with Ca disorders it is best to directly measure ionized calcium

Measure PTH

• “Intact” PTH levels are the most accurate to evaluate parathyroid function

• Normal levels 10-65 pg/ml

• Correlate PTH levels with simultaneous blood Ca levels

• PTH levels below 25 pg/ml in 70-80% patients with non-PT hypercalcemia and >65 pg/ml in 90% patients with primary hyperparathyroidism

Measure 25-OH and 1,25(OH) vit D levels

• 25-OHD is the major circulating form of vitamin D and its levels reflect vitamin D body stores. Normal levels 10-80 ng/ml, vary with the season and latitude

  Vitamin D deficienty: 25-OHD levels <8 ng/ml; vit D intoxication: 25-OH > 200 ng/ml

• 1,25(OH)2D reflect highly regulated renal synthesis of the active metabolite. Normal levels 20-60 pg/ml and is not affected by season or latitude

  Levels decreased in renal dysfunction and in type 1 Vit D deficient rickets (lacking 1α-hydroxylase)

  Levels abnormally increased in

  Granulomatous diseases including sarcoidosis and lymphoma

  Vit D dependent rickets type 2 (vit D receptor dysfunction causing secondary hyperparathyroidism)

Skeletal evaluation with bone density studies and radiology may help in management

PTHrP when indicated: normal levels <1 pmol/L

• Associated with cancer and the syndrome of humoral hypercalcemia of malignancy: severe hypercalcemia, hypophosphoremia, suppressed PTH and elevated PTHrP >5 pm

Evaluation of renal function is essential to understand Ca metabolism disorders

• Renal Ca excretion

  Normal Ca excretion: 4 mg/kg body weight/day

  Ca/creatinine ratio in urine: varies by age, in adults <0.25 mg/mg

  Hypercalciuria: vitamin D induced hypercalcemia, primary hyperparathyroidism, immobilization and malignancy

  Hypocalciuria: vitamin D deficiency, malabsorption, hypoparathyroidism and familial hypocalciuric hypercalcemia

Hypocalcemia – Diagnosis

Clinical manifestations of hypocalcemia

Cardiovascular

• Prolonged QT interval on EKG

• Heart failure

Neuromuscular

• Paresthesias, perioral tingling

• Muscle cramps, tetany

• Laryngospasm

• Trousseau’s sign

• Chvostek’s sign

• Seizures

• Papilledema

• Irritability, changes in mental status

• Basal ganglion calcification.

Hypercalcemia: Diagnosis

Clinical manifestations of hypercalcemia

Key points

• Hypercalcemia is a relatively common clinical problem

• The two most common causes (>90%) are malignancy and primary hyperparathyroidism

• The most common manifestation of hypercalcemia is polyuria

Clinical manifestations vary depending on the severity of hypercalcemia and time course of onset:

Calcium <12 mg/dl (3 mM/L)

Generally asymptomatic or nonspecific symptoms: constipation, fatigue, depression

Calcium 12-14 mg/dl (3-3.5 mM)

Well tolerated chronically but acutely causes severe symptoms

Polyuria, polydipsia, dehydration

Anorexia, nausea and vomiting

Muscle weakness

Changes in sensorium

Calcium >14 mg/dl (3.5 mM)

Same symptoms, progressively more severe including stupor and coma

Calcium manifestations by organ system

Neuropsychiatric manifestations

• increasing in severity proportional to the degree of hypercalcemia

Gastrointestinal manifestations

• In addition to nausea and vomiting, patients may develop acute pancreatitis and peptic ulcer disease presumably due to hypercalcemia-induced gastrin secretion

• In patients with MEN1, Zollinger-Ellison syndrome is associated with hypergastrinemia and gastric ulcer and hyperparathyroidism

Renal dysfunction

• Nephrogenic diabetes insipidus (up to 20%)

  Down regulation of aquaporins by prolonged hypercalcemia

  Dehydration exacerbates hypercalcemia and renal dysfunction

• Nephrolithiasis due to chronic hypercalcemia and hypercalciuria

• Renal tubular acidosis type 1 (distal) infrequently

• Renal insufficiency

  moderate hypercalcemia 12-15 mg/dl can lead to reversible decrease in glomerular filtration rate due to vasoconstriction and natriuresis-induced volume contraction

  long-standing hypercalcemia and hypercalciuria may lead to nephrocalcinosis, interstitial fibrosis predominantly medullary

  the most common cause of renal insufficiency in patients with sarcoidosis

Cardiovascular manifestations

• Shortening of the myocardial action potential leads to decreased QT interval

• ST elevation mimicking myocardial infarction has been described

Musculoskeletal manifestations

• Muscle weakness

• Bone pains due to either metastasis or primary hyperparathyroidism

Table II. Laboratory findings in hypocalcemic syndromes