1. Description of the problem

Hyperphosphatemia – Overview

Three groups of conditions:

Decreased urinary excretion

Redistribution

Exogenous administration

Symptoms

  • Secondary hyperparathyroidism

  • Secondary hypocalcemia

    Calcium precipitation

    Decreased production of 1,25(OH)2D

    Decreased intestinal calcium absorption

  • Ectopic calcifications

    Skin, vascular, joints, cornea

Treatment

  • Dietary P restriction

  • Phosphate binders

  • Volume expansion and acetazolamide

  • Severe hyperphosphatemia associated to tumor lysis syndrome may require extracorporeal removal by dialysis.

Hypophosphatemia – Overview

Three groups of conditions:

Excessive loss: urinary, or renal replacement therapy

Decreased gastrointestinal absorption

Abnormal distribution

Symptoms

Mild: asymptomatic

Symptomatic: blood P levels <1 mg/dl

  • Hematologic

    Hemolysis

    Decreased erythrocyte 2,3 diphosphoglycerate and increased hemoglobin affinity for oxygen

    Decreased white blood cell phagocytosis

  • Musculoskeletal

    Muscle weakness including myocardial failure and respiratory failure

    Proximal myopathy

    Rhabdomyolysis

    Increased osteolysis and excessive formation of uncalcified osteoid leading to osteomalacia

  • Renal

    Decreased proximal tubular reabsorption

    Decreased Ca reabsorption up to frank hypercalciuria

Treatment

Serum P not always a good measure of body P stores, especially in clinical situations involving translocation of P among body compartments.

Mild to moderate (down to 2 mg/dl) increased oral supplementation with milk products and/or oral phosphorus supplementation (NeutraPhos).

Severe (<1 mg/dl), symptomatic

  • Intravenous P replenishment:

    Usually 2.5 mg/Kg body weight [0.08 mM/Kg body weight] of elemental P over a 6 hour period

Severe, symptomatic hypophosphatemia may require 5 mg/Kg body weight [0.16 mM/Kg] replenishment of elemental P over a 6 hour period

  • Discontinue parenteral P replenishment when serum P >2 mg/dl.

Calcium Disorders – Overview

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 deficiency: 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 pmol/L

  • 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.

Hypophosphatemia – Clinical Features

Excessive loss: Urinary excretion or renal replacement therapy

  • Volume expansion

  • Fanconi’s syndrome

  • Hyperparathyroidism

  • Acetazolamide and osmotic diuretics

  • Recovery phase of acute kidney injury

  • Glucocorticoids

  • Tumor-induced osteomalacia

  • Inherited defects

    Hereditary hypophosphatemic rickets with hypercalciuria

    X-linked hypophosphatemic rickets

    Autosomal dominant hypophosphatemic rickets

    Autosomal recessive hypophosphatemic rickets

  • Vitamin D deficiency or resistance (rickets)

  • Post-renal transplant

  • Continuous renal replacement therapy without concurrent adequate feeding

Decreased gastrointestinal absorption

  • Inadequate P intake

  • Chronic diarrhea, malabsorption

  • Phosphate-binding drugs and antacids

  • Chronic severe alcoholism and malnutrition

Abnormal distribution

  • Acute respiratory alkalosis

  • Post parathyroidectomy: ‘hungry bone syndrome’

  • Diabetic ketoacidosis: after administration of insulin to chronically malnourished diabetic patients, P shifts intracellularly and severe hypophosphoremia ensues

  • Refeeding in chronically malnourished individuals and alcoholics

  • Acute leukemia and leukemic complications of lymphoma.

Hyperphosphatemia – Clinical Features

Associated conditions

Decreased phosphate urinary excretion

  • Hypoparathyroidism, pseudohypoparathyroidism

  • Abnormal circulating parathyroid hormone

  • Acromegaly (growth hormone excess)

  • Biphosphonates

  • Chronic kidney disease

    GFR<60 ml/min (CKD 3) resulting in impaired P excretion and hyperphosphatemia

    GFR<30 ml/min (CKD4) worsens hyperphosphatemia and secondary hyperparathyroidism, increased production of FGF-23

    GFR<15 ml/min (CKD 5) associated with frank hyperphosphatemia which can only be corrected by initiation of dialysis

  • Familial tumor calcinosis

    Deficiency of phosphatonin FGF-23

  • Hyperostosis hyperphosphatemia syndrome

Redistribution of phosphate

  • Tumor lysis syndrome

  • Respiratory acidosis

  • Hypercatabolism

  • Severe trauma, traumatic rhabdomyolysis

Pseudohyperphosphatemia

  • Multiple myeloma

  • Waldenstrom’s macroglobulinemia.

Hypocalcemia – Clinical Features

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: Clinical Features

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

2. Emergency Management

Management of Hypophosphatemia

Symptoms of hypophosphoremia will not develop unless phosphorus depletion is severe, as indicated by severe lowering of serum P

  • Symptomatic hypophosphatemia: generally serum P less than 2 mg/dl [0.64 mM]

  • Serious symptoms of hypophosphoremia (including rhabdomyolysis and decreased respiratory drive): generally serum P less than 1 mg/dl [0.32 mM]

Management should be aimed at the underlying cause

  • Correct malnutrition and nutritional deficiencies (e.g. alcoholic patients, malabsorption)

  • Correct vitamin D deficiency (vit D-deficient rickets)

  • Additional supplementation necessary for patients on drugs such as phenytoin which enhance Vitamin D catabolism

Phosphate supplementation

  • Indicated for patients who have symptomatic hypophosphatemia

  • Indicated for renal tubular defects leading to phosphate wasting

Point:

  • Phosphate supplementation is potentially dangerous: it can induce hypocalcemia, renal failure due to calcium phosphate precipitation or arrhythmia. Therefore, oral supplementation is preferable to intravenous.

    ORAL SUPPLEMENTATION: 2.5-3.5 g [80-110 mM] per day in divided doses

    INTRAVENOUS SUPPLEMENTATION:

    Moderate hypophosphatemia (1.25 to 2.5 mg/dl): administer 0.08-0.24 mM/Kg (maximum 30 mM) over 6 hours

    Severe hypophosphatemia (<2.5 mg/dl): 0.25 to 0.5 mM/Kg (maximum dose 80 mM) over 8-12 hours

    In very severe hypophosphoremia (<1.5 mg/dl) higher IV phosphorus doses have been used

    Monitor P and Ca levels every 8 hours and adjust replacement as needed.

Management of Hyperphosphatemia

Dietary restriction

  • Difficult to achieve as most foodstuffs contain sizable amounts of phosphorus

  • Phosphate binders

  • Calcium carbonate

  • Sevelamer (gastrointestinal phosphate binder)

  • Avoid aluminum containing antacids in renal failure, as they lead to aluminum intoxication, osteomalacia and brain dysfunction

  • Dialysis effective in removing phosphorus: continuous renal replacement therapies (CRRT) most effective and well tolerated.

Management of Hypercalcemia

Key points

  • The degree of hypercalcemia and the rate of increase determine the need for treatment and the choice of measures to correct it

  • Acute onset of hypercalcemia is worse tolerated than chronic hypercalcemia: symptomatic hypercalcemia requires aggressive treatment

  • Patients with serum Ca>14 mg/dl require treatment regardless of symptoms

Mild hypercalcemia

  • Asymptomatic or serum Ca <12 mg/dl [3 mM]

    No immediate treatment required

    Avoid Ca supplements and medications such as lithium or thiazides which can exacerbate hypercalcemia, avoid immobility and ensure adequate hydration

Moderate hypercalcemia

  • Asymptomatic or mildly symptomatic with chronic moderate hypercalcemia (serum Ca 12-14 mg/dl [3-3.5 mM])

    Same precautions as mild hypercalcemia

    Severely symptomatic patients must be treated as those with severe hypercalcemia

    Typically treatment consists of biphosphonates and saline hydration

Severe hypercalcemia

  • Serum Ca >14 mg/dl [3.5 mM]

    Volume expansion with isotonic saline 200-300 ml/hour, adjust rate to maintain diuresis 100-200 ml/hour

    If congestive heart failure or renal failure is not present, avoid diuretics: they are ineffective and other medications such as biphosphonates will address the mechanism of hypercalcemia

    Salmon calcitonin 4 units/kg and repeat serum Ca 8-12 hours later: if Ca decreases, patient is CT sensitive and the CT can be repeated every 12 hours 4-8 units/kg

    Concurrent administration of biphosphonates: zoledronic acid (4 mg IV over 15 minutes) or pamidronate (60-90 mg infused over 2 hours)

    Zoledronic acid more powerful than pamidronate

    CT plus saline should decrease serum Ca within 12-24 hours; the biphosphonate will be effective within 2-4 days

    Treat underlying disease such as malignancy

    Consider hemodialysis in the severely symptomatic patient with serum Ca 18-20mg/dl [4.5-5 mM] and neurologic symptoms but hemodynamically stable

Additional measures

  • Primary hyperparathyroidism: manage with calcimimetics or adenoma resection

  • Lymphoma, sarcoidosis or other granulomatous diseases have hypercalcemia due to overproduction of calcitriol causing elevated intestinal absorption of Ca: main measures include low Ca diet, corticosteroids will inhibit 1,25(OH)2D synthesis, and treatment of the underlying disease

  • Excess calcitriol dose: effects only lasts 1-2 days due to short half-life,and resolves spontaneously. Consider hydration or iv saline

    Calcidiol or vit D intoxication will need more prolonged treatment and pamidronate may be necessary

  • Familial hypocalciuric hypercalcemia should not be treated

Other considerations

  • Loop diuretics: have fallen out of favor as they can induce volume contraction, hypokalemia, hypomagnesemia and metabolic alkalosis

  • Calcitonin is only effective within the first 24-48 hours

  • Biphosphonates have potential renal toxicity and should be used with caution in patients with severely impaired renal function (serum creatinine >4.5mg/dl)

Table I. Management of hypercalcemia

Table I.
INTERVENTION MODE OF ACTION ONSET OF ACTION DURATION OF ACTION
Isotonic saline hydration Intravascular volume expansion
Increase ECa
Hours During infusion
Loop diuretics Decreased RCa TALH Hours During therapy
Calcitonin Inhibit bone reabsorption Increases ECa 4-6 hours 48 hours
Biphosphonates Inhibit bone reabsorption decreasing osteoclast 24-72 hours 2-4 weeks
Glucocorticoids Decrease intestinal absorption Ca
Decrease 1,25(OH)2D production in granuloma
2-5 days Days to weeks
Gallium nitrate Inhibits osteoclasts 3-5 days 2 weeks
Calcimimetics CaSR agonist reduces PTH secretion 2-3 days During therapy
Dialysis Low Ca dialysate Hours During therapy

ECa=Calciumexcretion; RCa=Calciumreabsorption; TAHL=Thick ascending loop of Henle; CaSR=Calcium-sensing receptor; PTH=Parathyroid hormone

From: Shane E, Dinaz I (see references)

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

Table II.
Condition Phosphate PTH Vit D
Hypoparathyroidism High Low 1,25vitD nl. or low
Pseudohypoparathyroidism High High 1,25vitD nl or low
Tumor lysis syndrome High High Normal
Vit D deficiency Low High 25OHvitD Low
Vit D dep. rickets Type 1 Low High 1,25vitD Low
Vit D dep. rickets Type 2 Low High 1,25vitD High
Hypomagnesemia nl to High Low 1,25vitD nl or low

• PTH=Parathyroid hormone; 25OHD=Calcidiol; 1,25(OH)D=Calcitriol; Vit D=Vitamin D

• Modified from: McKay, CP. Disorders of calcium metabolism. In: Fluid and Electrolytes in Pediatrics. Feld LG, Kaskel FJ (Eds). Humana Press, a part of Springer Science+Business Media, New York, NY, 2009. p 105.

Pathophysiology

Phosphate metabolism

The terms phosphate and phosphorus concentrations are used interchangeably. Throughout the text we will use the most common denomination, phosphate (P) concentration, when referring to the elemental phosphorus contents of body fluids such as urine, serum, plasma or tissue.

Paraproteinemia may cause spurious hypophosphatemia

Phosphate concentration (P) can be measured in mg/dl or mM/L. Equivalences:

1 mM phosphate = 31 mg elemental phosphorus

1 mM phosphate = 3.1 mg/dl of phosphorus

1 mg phosphorus = 0.032 mM phosphate

1 mg/dl phosphorus = 0.32 mM/L phosphate

In blood, P is dissolved in plasma as inorganic phosphate (Pi), and organic phosphate components including phospholipids and phosphate esters. Filtered phosphorus is in the form of inorganic phosphate radicals HPO4= and H2PO4. The ratio between mono and divalent phosphate radicals depends on the pH of the solution. At pH 7.4, the ratio is 1.8.

10% of phosphate in blood is protein-bound and non-filterable; in vivo, the ratio between filterable and non-filterable Pi is approximately 1.

Table III. Plasma phosphorus concentration at different ages

Table III.
Age P concentration (mg/dl)
Infants 0-3 months 4.8 to 7.4
Children 1-2 years 4.5-5.8
Children 3-12 3.5-5.5
Adolescents and young adults 3.5-5.0
Older adult males Progressive decrease from 3.5 to 3.0
Premenopausal Females Same as males
Menopausal Females Increase to 3.4
Older females >70 years Further increase to 3.7

Total body P increases progressively throughout the age of the individual, from 0.6% of body weight in the newborn to 1% (600-700 g) in the adult. In the growing child, P balance remains positive and becomes zero in adulthood.

Renal phosphate transport

  • Kidney is the main regulator of P metabolism by varying the degree of P tubular reabsorption

  • Normally, 80-97% of filtered P is reabsorbed by the renal tubules: 70% in the proximal tubule, the majority in the early proximal tubule, 10% distal tubule and additional 3-7% in collecting duct segments

  • Proximal tubular P transport rate limiting step is the entry across the apical membrane in a saturable, active transport driven by the extra-intracellular Na gradient maintained by the basolateral Na/K ATPase

  • The apical transport of P is regulated and is the target of physiologic P homeostatic mechanisms

  • Proximal transporters include type I Na/P cotransporter (Npt1), not a major regulator of reabsorption, and the type II Na/P cotransporter family (Npt2) largely responsible for renal phosphate reabsorption control. This family includes type IIa and IIc (renal) and IIb (intestinal)

Table IV. Factors affecting renal reabsorption of phosphorus

Table IV.
Factor Proximal Tubular Reabsorption
Volume expansion Decreased
P loading Decreased
P restriction Increased
Hypercalcemia  
Acute Increased
Chronic Decreased
Metabolic acidosis  
Acute No change
Chronic Decreased
Metabolic alkalosis  
Acute Decreased
Chronic Increased
Respiratory acidosis Decreased
Respiratory alkalosis Increased
Hormones  
PTH Decreased
Vit D (chronic) Decreased
Growth hormone Increased
Calcitonin Decreased
Thyroid hormone Increased
Insulin Increased
FGF-23 Decreased
Dopamine Decreased
Diuretics Decreased
Glucose Decreased in glycosuria
Glucocorticoids Decreased

Dietary phosphorus

  • The magnitude of P intake plays an important role in controlling renal P excretion and intestinal absorption by PTH-mediated and PTH-independent mechanisms

  • During P deprivation, type IIa renal and type IIb intestinal apical transporters increase and ensure more complete P absorption in the intestine and the kidney, leading to virtual disappearance of P from the urine

  • Early increase in intestinal and renal reabsorption of P is independent of PTH or vitamin D; later sustained increases are hormone and vitamin D-mediated

Parathyroid hormone

  • Major regulator of P tubular reabsorption via changes in type II Na/P transporters (internalization and inactivation of the transporter)

Vitamin D

  • Main source of vitamin D (cholecalciferol) is endogenous, synthesized in the skin subject to ultraviolet irradiation by sunlight

  • Cholecalciferol is subsequently hydrolyzed to 25-OH vit D3 in the liver (a poorly active intermediary) and to 1α,25(OH)2 vit D3 (calcitriol) in the kidney

  • PTH, acting as a trophic hormone, stimulates 1α-hydroxylase and therefore, changes in plasma ionized calcium indirectly regulate 1,25(OH)2D synthesis and therefore, intestinal Ca absorption

  • High serum P suppresses and low serum P stimulates 1α hydroxylase activity

Phosphatonins

  • A new class of regulators linking bone homeostasis and P metabolism

  • Newer molecules include FGF-23 (fibroblast growth factor 23) expressed in regions of osteogenesis and remodeling, FGF-7, MEPE (matrix extracellular phospho-glycoprotein) and sFRP4 (secreted frizzled related protein-4)

  • These phosphatonins decrease serum P via decreasing tubular Na/Pi cotransporters and reducing the production of 1,25(OH)2D and thus decreasing intestinal absorption of P

  • FGF-23 the best studied phosphatonin

    Inhibits renal P reabsorption and reduces 1,25(OH)2D production thus leading to body P depletion by inducing renal loss and decreased intestinal absorption

    Inhibits PTH synthesis and secretion, thus counteracting its renal tubular effects and potentiating the inhibition in 1,25(OH)2D synthesis

    Overall, FGF-23 keeps serum P levels low and acts as a bone P sensor controlling intestinal and renal handling of phosphate

Calcium metabolismSee metabolism of calcium

Epidemiology

NA

Special considerations for nursing and allied health professionals.

NA

What's the evidence?

Cerdá, J, Tolwani, A, Warnock, D. “Critical care nephrology: management of acid–base disorders with CRRT”. Kidney Inl.. vol. 82. 1 July 2012. pp. 9-18.

Agus, ZS, Massry, SG, Narins, RG. “Hypomagnesemia and hypermagnesemia”. Maxwell & Kleeman's Clinical Disorders of Fluid and Electrolyte Metabolism 5th Edition. 1994. pp. 1099-1119.

Reikes, S, Gonzalez, EA, Martin, KJ, DuBose, TD, Hamm, LL. “Abnormal calcium and magnesium metabolism”. Acid Base and Electrolyte Disorders. 2002. pp. 453-487.

Pollack, MR, Yu, ASL, Brenner, BM. “Clinical disturbances of calcium, magnesium and phosphate metabolism”. Brenner and Rector's The Kidney 7th Ed. vol. 1. 2004. pp. 535-571.

McKay, CP, Feld, LG, Kaskel, FJ. “Disorders of magnesium metabolism”. Fluid and Electrolytes in Pediatrics. 2009. pp. 149

McKay, CP, Feld, LG, Kaskel, FJ. “Disorders of calcium metabolism”. Fluid and Electrolytes in Pediatrics. 2009. pp. 105

Shane, E, Dinaz, I. “Hypercalcemia: pathogenesis, clinical manifestations, differential diagnosis and management”. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism 6th Edition. 2006. pp. 179

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