hypophosphatemia
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Dr Abrar Ali Katpar 15/17/2013
Dr. Abrar Ali Katpar
Nephrology Department
King Khalid Hospital-Hail
Hypophosphatemia
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Phosphate is most abundant intracellular anion & is essential in All cells for: Membrane structure, Energy storage, & Transport
It produces ATP, which provides energy for nearly all cell functions. Is an essential component of DNA & RNA. Is also necessary in RBCs for production of 2,3-diphosphoglycerate (2,3-
DPG), which facilitates release of O2 from Hb. 85% phosphorus is in bone as hydroxyapatite, 15% is present in soft tissue. Only 0.1% present in extracellular fluid, and it is this fraction that is
measured with a S.Phos level. Reducing available phosphate may compromise any organ system, alone or
in combination. The critical role phosphate plays in every cell, tissue, and organ explains
the systemic nature of injury caused by phosphate deficiency. Normal range = 2.5-4.5 mg/dL or 0.81-1.45 mmol/L
Background
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Hypophosphatemia is defined as:Mild 2-2.5 mg/dL, or 0.65-0.81 mmol/L Moderate 1-2 mg/dL, or 0.32-0.65 mmol/LSevere < 1 mg/dL, or 0.32 mmol/L
Mild to moderately severe hypophosphatemia is usually asymptomatic.
Major clinical sequelae occurs in severe hypophosphatemia.
As in the case of other intracellular ions (eg, K, Mag), a decrease in the level of serum phosphate should be distinguished from a decrease in total body storage of phosphate (phosphate deficiency).
Definition
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Phosphorus homeostasis is complex and regulated by the actions of several hormones.
PTH causes phosphate to be released from bone and inhibits renal reabsorption of phosphorus, resulting in phosphaturia.
Vitamin D aids in intestinal reabsorption of phosphorus. Thyroid hormone and growth hormone act to increase renal
reabsorption of phosphate. Finally, a new class of phosphate-regulating factors, the so-
called phosphatonins, have been shown to be important in phosphate-wasting diseases, such as : oncogenic osteomalacia, X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemia, and tumoral calcinosis.
Pathophysiology
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Hypophosphatemia is caused by: 1. Intracellular shift of phosphate from serum, 2. Increased urinary excretion of phosphate, 3. Decreased intestinal absorption of phosphate, 4. Decreased dietary intake.
Hypophosphatemia may be transient, reflecting intracellular shift with minimal clinical consequences.
The disease also may reflect a deeper state of total body phosphate depletion with significant sequelae.
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Pathophysiology
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Respiratory alkalosis moves phosphate into cells by activating phosphofructokinase, which stimulates intracellular glycolysis.
Glycolysis leads to phosphate consumption as phosphorylated glucose precursors are produced.
Any cause of hyperventilation (eg, sepsis, anxiety, pain, heatstroke, alcohol withdrawal, DKA, hepatic encephalopathy, salicylate toxicity) can precipitate hypophosphatemia.
Since respiratory alkalosis is one of the most common causes of hypophosphatemia, discovery of hypophosphatemia should prompt a search for the serious causes of hyperventilation, when clinically appropriate.
Pathophysiology1. Intracellular shift
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Administering carbohydrate lowers serum phosphate by stimulating the release of insulin, which moves phosphate and glucose into cells.
This so-called refeeding syndrome occurs when starving or chronically malnourished patients are refed or given intravenous (IV) glucose, and typically produces a hypophosphatemic state by treatment day 3 or 4.
In addition, during refeeding, cells switch to an anabolic state, resulting in further phosphate depletion as this essential substrate is incorporated into cells and cell products.
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1. Intracellular shift
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DK is also an important cause of hypophosphatemia. Metabolic acidosis and insulin deficiency will mobilize
intracellular phosphate stores, causing them to shift to the extracellular space and leading to urinary losses.
Treatment of DKA with insulin causes phosphate to move back into cells resulting in a decrease of serum phosphate levels.
Routine replacement of phosphate in the setting of DKA is not proven to decrease morbidity or mortality.
However, because patients in DKA are often hypokalemic and hypophosphatemic, some clinicians replete these losses with potassium phosphate salts.
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1. Intracellular shift
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Catecholamines and beta-receptor agonists also stimulate phosphate uptake into cells.
Certain rapidly growing malignancies (eg, acute leukemia, lymphomas) may consume phosphate preferentially, leading to hypophosphatemia.
In most cases of intracellular phosphate shift, serum phosphate normalizes once the precipitating cause is removed.
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1. Intracellular shift
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Since PTH stimulates the kidneys to excrete phosphate, hypophosphatemia is a common sequela of primary and secondary hyperparathyroidism.
Urinary loss of phosphate also occurs with acute volume expansion due to a dilution of serum calcium, which, in turn, triggers an increase in the release of PTH.
Osmotic diuresis, such as seen in hyperosmolar hyperglycemic syndrome (HHS), also produces increased urinary excretion of phosphorus.
Diuretics, including loop diuretics, thiazides, and carbonic anhydrase inhibitors (eg, acetazolamide) interfere with the ability of the proximal tubule to reabsorb phosphorus, thus producing hyperphosphaturia and potentially leading to hypophosphatemia. Patients with transplanted kidneys, congenital defects (X-linked hypophosphatemia [XLH] and autosomal dominant hypophosphatemic rickets [ADHR]), or Fanconi syndrome (proximal tubule dysfunction) also may excrete excess urinary phosphate.
There is also evidence that shows estrogen to be a downregulator of a renal sodium phosphate cotransporter, causing significant hypophosphatemia in patients.
Pathophysiology2. Increased urinary excretion
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Phosphate may be lost via the gut, as in chronic diarrhea, malabsorption syndromes, severe vomiting, or NG suctioning.
Phosphate may also be bound in the gut, thereby preventing absorption (eg, chronic use of sucralfate, or phosphate-binding antacids, including aluminum hydroxide, aluminum carbonate, and calcium carbonate).
Also, the intestine "senses" luminal concentrations of phosphate and regulates the excretion of phosphate in the kidney by elaborating novel factors that alter renal phosphate reabsorption.
Pathophysiology3. Decreased intestinal absorption
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Decreased dietary intake of phosphate is a rare cause of hypophosphatemia because of the ubiquity of phosphate in foods.
Dietary sources of phosphate include fruits, vegetables, meats, and dairy products.
Vitamin D enhances the absorption of both phosphate and calcium.
Certain conditions such as anorexia nervosa or chronic alcoholism may lead to hypophosphatemia in part due to this mechanism, as well as increased renal excretion.
Pathophysiology4. Decreased dietary intake
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Weakness of skeletal or smooth muscle. It can involve any muscle group, alone or in combination, ranging
from ophthalmoplegia to proximal myopathy to dysphagia or ileus. Rhabdomyolysis via ATP depletion and the consequent inability of
muscle cells to maintain membrane integrity. Acute alcohol withdrawal= vulnerable to rhabdomyolysis secondary to
hypophosphatemia, which is caused by the rapid uptake of phosphate into muscle cells.
Rarely rhabdomyolysis in DKA or being refed after starvation. Respiratory insufficiency = with severe hypophosphatemia,
particularly in malnourishment. Impaired cardiac contractility = occurs, leading to myocardial
depression. BP and stroke volume have been shown to improve when serum
phosphorus is corrected. The hypophosphatemic myocardium also has a reduced threshold for
ventricular arrhythmias.
PathophysiologyManifestations of phosphate deficiency
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Phosphate deficiency = impairs neurologic function, which may be manifested by confusion, seizures, and coma. Peripheral neuropathy and ascending motor paralysis, similar to
GB syndrome. Extrapontine myelinolysis also reported.
Hematologic function may be impaired. The hemolytic anemia associated with severe hypophosphatemia
has been attributed to the inability of erythrocytes to maintain integrity of cell membranes in the face of ATP depletion, leading to their destruction in the spleen.
Compromises O2 delivery to the tissues due to decreases in erythrocyte 2,3-DPG and the resulting leftward shift in the oxygen-hemoglobin dissociation curve.
Leukocyte function is affected, which results in impaired chemotaxis and phagocytosis.
PathophysiologyManifestations of phosphate deficiency
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FrequencyUnited States
2-3% of hospitalized patients 30% of patients admitted to ICUs. 17% HIV-positive patients 38.5%, falciparum malaria,Fortunately, severe hypophosphatemia is rare, occurring
in no more than 0.5% of hospitalized patients.
SexNo predilection is known.
AgeIn All ages.
Epidemiology
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Weakness is the most common symptom and may involve any muscular system to any extent. DiplopiaDysarthriaDysphagiaWeakness of trunk or extremities, particularly large
muscle groupsSymptoms of respiratory insufficiency or myocardial
depression may indicate hypophosphatemia.Neurologic symptoms may vary, ranging from
simple paresthesias to profound alterations in mental status.
History
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Muscle weakness = most common physical finding; careful assessment of motor strength on neurologic
examination is critical. Weakness may be subtle or profound and may involve any
muscle group. Diminished respiratory rate & tidal volume;
Tachypnea may be present, an important clue to one of the most common etiologies (respiratory alkalosis).
Hypotension & cardiac compromise.Pale skin & conjunctivae secondary to the hemolytic
anemia.Signs of rhabdomyolysis.Mental status abnormalities.
Physical
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Patients withdrawing from alcohol. Patients undergoing treatment for DKA.Other risk factors
Chronic alcoholismChronic ingestion of phosphate-binding antacidsTotal parenteral nutrition (TPN) with inadequate phosphate
supplementationRefeeding after prolonged starvation (eg, anorexia nervosa)
Hypophosphatemia may also occur in the setting of thyrotoxic periodic paralysis (TPP). If considering this diagnosis, the presence of
hypophosphatemia suggests TPP rather than spontaneous periodic paralysis, in which phosphorus levels are likely to be normal.
Causes
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Alcoholic KetoacidosisAnxietyCBRNE - BotulismDiabetic KetoacidosisGuillain-Barré SyndromeHyperparathyroidismHyperventilation Syndrome
Differential Diagnoses
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Serum phosphate level Normal range 2.5-4.5 mg/dL. Hypophosphatemia
Mild = 2-2.5 mg/dL Moderate = 1-2 mg/dL Severe = < 1 mg/dL
Since the serum phosphate level may not accurately reflect the level of intracellular phosphate, always correlate serum phosphate levels with clinical findings, especially before embarking upon aggressive replacement therapy.
Abnormalities in serum magnesium, calcium, and potassium levels may occur. Hypomagnesemia often is associated with the shift of phosphate into
cells. Hypercalcemia is common in primary hyperparathyroidism. Derangements in serum K may occur with certain hypophosphatemia
causes, such as DKA and alcoholism.
Laboratory Studies
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Treatment is twofold. Correct any precipitating causes.Replace total body phosphates.
Depending on the clinical situation, replacement options include: Dietary phosphate, Oral phosphate preparations, & IV phosphate.
Care
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Hypophosphatemia and hypokalemia can coexist in certain disorders like DK & alcoholism, so replacement with K salt is most appropriate.
Mild to moderately severe, asymptomatic hypophosphatemia Spontaneously normalizes over several days when factors inducing are
corrected. May require oral phosphate replacement. In minimal symptoms or moderate hypophosphatemia, providing oral
phosphate replacement may be desirable. The average adult consumes 1 gram of phosphorus daily.
A quart of cow's milk provides this amount of phosphorus (1 mg phosphorus/mL).
Dairy products have an additional advantage of supplying absorbable calcium, which can help avoid the hypocalcemia that may result with more aggressive replacement regimens.
Phosphorus preparations with Na & K are available, but they have disadvantages, including causing osmotic diarrhea, volume overload, or hyperkalemia.
Usual starting doses are 2-3 grams of elemental phosphorus in divided doses.
Care
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Severe/symptomatic hypophosphatemia Patients with symptoms of hypophosphatemia or with
serum phosphate levels < 1 mg/dL require IV phosphate replacement.
The intracellular nature of phosphate makes interpreting a low serum phosphate level difficult & predicting the amount required to replenish cellular stores nearly impossible.
Accordingly, recommendations for IV phosphate in the literature are varied & based on therapeutic experiences with limited numbers of patients.
Avoid hyperphosphatemia when replacing phosphorus intravenously, as this can lead to hypocalcemia (leading to tetany) and calcium-phosphate deposition in tissues (eye, heart, kidney, lung).
Emergency Care
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Class SummaryThese agents are used to increase serum phosphorus to
normal physiologic levels.Potassium phosphate/sodium acid phosphate
IV preparations are available as Sodium phosphate (Na2 HPO4 and NAH2 PO4)Potassium phosphate (K2 HPO4 and KH2 PO4)
Response to IV phosphorus supplementation varies widely and may be associated with hyperphosphatemia and hypocalcemia.
Rate of infusion and choice of initial dosage should be based on severity of hypophosphatemia and presence of symptoms.
When treating hypophosphatemia with potassium phosphate, potassium level may limit amount of phosphate that can be given safely.
Medication Electrolyte supplements
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One Canadian group recently reported: 30 mmol of potassium phosphate via central
line over 3 h for severe hypophosphatemia 15 mmol of potassium phosphate via central
line over 3 h for moderate hypophosphatemia.Another study reported safely administering
IV phosphate at a rate of:14.5 mmol of phosphate ions over 1 h.
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Medication Electrolyte supplements
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Tablet of = 250mg/298mg
852 mg dibasic potassium phosphate/155 mg monobasic potassium phosphate/130 mg sodium phosphate per tablet yields 250 mg phosphorus/298 mg (13 mEq) sodium /45 mg (1.1mEq) potassium
1. Hypophosphatemia= 1-2 tablets PO QID
2. Increase Urinary Phosphate= 1-2 tablets PO QID
Other Information Take with a full glass of water Avoid antacids containing aluminum, magnesium
or calcium May precipitate passing of existing kidney stones
Other Indications & Uses Lowers urinary calcium level in idiopathic
hypercalcuria Rickets may benefit from phosphate therapy, but
high serum phosphate may increase incidence of extra-skeletal calcification.
Potassium phosphate/sodium phosphateDosing Forms & Strengths
Adverse Effects
Frequency Not Defined1. Headache2. Dizziness3. Confusion4. Weakness or heaviness of
legs5. Numbness or tingling6. Tachycardia7. Shortness of breath8. Gastrointestinal upset9. Mild laxative effect10. Lower extremity swelling11. Weight gain12. Low urine output13. Thirst
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Severe or symptomatic = admission for IV replacement.
Equilibration of IV with intracellular phosphate usually leads to recurrence of hypophosphatemia, monitoring & replacement is necessary over 2-3 days.
A rational approach to IV replacement is to administer a predefined amount of phosphate, then reevaluate the resulting serum phosphate level every 6 hours to guide further treatment.
Further Inpatient Care
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Complications of IV phosphate replacement, including: hypocalcemia (tetany) and hyperphosphatemia.
Avoid hyperphosphatemia because it can cause crystal deposition in various tissues (eg, blood vessels, eye, lung, heart, kidney).
Always administer IV phosphate cautiously in patients with renal failure.
Complications
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ConsultationsBased on any underlying or suspected
etiologies.Patient Education
Patients and their families should be taught that 1 quart of cow's milk provides the amount of phosphate consumed by the average person/day.
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