Published on March 6, 2014
Dr Abrar Ali Katpar 5/17/2013 1
Dr. Abrar Ali Katpar Nephrology Department King Khalid Hospital-Hail
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 Dr Abrar Ali Katpar 5/17/2013 3
Hypophosphatemia is defined as: Mild Moderate Severe 2-2.5 mg/dL, 1-2 mg/dL, < 1 mg/dL, or 0.65-0.81 mmol/L or 0.32-0.65 mmol/L 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). Dr Abrar Ali Katpar 5/17/2013 4
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 phosphatewasting diseases, such as : oncogenic osteomalacia, X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemia, and tumoral calcinosis. Dr Abrar Ali Katpar 5/17/2013 5
Hypophosphatemia is caused by: Intracellular shift of phosphate from serum, 2. Increased urinary excretion of phosphate, 3. Decreased intestinal absorption of phosphate, 4. Decreased dietary intake. 1. 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. Dr Abrar Ali Katpar 5/17/2013 6
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. Dr Abrar Ali Katpar 5/17/2013 7
1. Intracellular shift 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. Dr Abrar Ali Katpar 5/17/2013 8
Dr Abrar Ali Katpar 5/17/2013 9
1. Intracellular shift 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. Dr Abrar Ali Katpar 5/17/2013 10
1. Intracellular shift 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. Dr Abrar Ali Katpar 5/17/2013 11
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. Dr Abrar Ali Katpar 5/17/2013 12
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. Dr Abrar Ali Katpar 5/17/2013 13
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. Dr Abrar Ali Katpar 5/17/2013 14
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. Dr Abrar Ali Katpar 5/17/2013 15
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 oxygenhemoglobin dissociation curve. Leukocyte function is affected, which results in impaired chemotaxis and phagocytosis. Dr Abrar Ali Katpar 5/17/2013 16
Dr Abrar Ali Katpar 5/17/2013 17
Frequency United 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. Sex No predilection is known. Age In All ages. Dr Abrar Ali Katpar 5/17/2013 18
Weakness is the most common symptom and may involve any muscular system to any extent. Diplopia Dysarthria Dysphagia Weakness of trunk or extremities, particularly large muscle groups Symptoms of respiratory insufficiency or myocardial depression may indicate hypophosphatemia. Neurologic symptoms may vary, ranging from simple paresthesias to profound alterations in mental status. Dr Abrar Ali Katpar 5/17/2013 19
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. Dr Abrar Ali Katpar 5/17/2013 20
Patients withdrawing from alcohol. Patients undergoing treatment for DKA. Other risk factors Chronic alcoholism Chronic ingestion of phosphate-binding antacids Total parenteral nutrition (TPN) with inadequate phosphate supplementation Refeeding 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. Dr Abrar Ali Katpar 5/17/2013 21
Dr Abrar Ali Katpar 5/17/2013 22
Alcoholic Ketoacidosis Anxiety CBRNE - Botulism Diabetic Ketoacidosis Guillain-Barré Syndrome Hyperparathyroidism Hyperventilation Syndrome Dr Abrar Ali Katpar 5/17/2013 23
Serum phosphate level Normal range 2.5-4.5 mg/dL. Hypophosphatemia Mild = Moderate = Severe = 2-2.5 mg/dL 1-2 mg/dL < 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. Dr Abrar Ali Katpar 5/17/2013 24
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. Dr Abrar Ali Katpar 5/17/2013 25
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. Dr Abrar Ali Katpar 5/17/2013 26
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). Dr Abrar Ali Katpar 5/17/2013 27
Class Summary These 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. Dr Abrar Ali Katpar 5/17/2013 28
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. Dr Abrar Ali Katpar 5/17/2013 29
Tablet of = 250mg/298mg 852 mg dibasic potassium phosphate/155 mg monobasic Adverse Effects potassium phosphate/130 mg sodium phosphate per tablet yields 250 mg phosphorus/298 mg (13 mEq) Frequency Not Defined 1. Headache 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. Dr Abrar Ali Katpar 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. Dizziness Confusion Weakness or heaviness of legs Numbness or tingling Tachycardia Shortness of breath Gastrointestinal upset Mild laxative effect Lower extremity swelling Weight gain Low urine output Thirst 5/17/2013 30
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. Dr Abrar Ali Katpar 5/17/2013 31
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. Dr Abrar Ali Katpar 5/17/2013 32
Consultations Based 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. Dr Abrar Ali Katpar 5/17/2013 33
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Dr Abrar Ali Katpar 5/17/2013 35
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Dr Abrar Ali Katpar 5/17/2013 37
Hypophosphatemia is an electrolyte disturbance in which there is an abnormally low level of phosphate in the blood. The condition has many causes, but is ...
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