Item 10, answer A A serum phosphorous level of <1.0 mg/dL would be compatible with severe hypophosphatemia.

Irritability, apprehensiveness, muscle weakness, numbness, and paresthesia are common symptoms of severe hypophosphatemia. Seizures, coma, and death may occur if the phosphorous level is very low (<0.2 mg/dL). These manifestations result because phosphate is an essential component of ATP. ***** HYPOPHOSPHATEMIA Teaching Points Defined as serum phosphorus concentration below 2.5 mg/dL. Most common cause is chronic alcoholism. Usually asymptomatic but in severe cases may be associated with irritability and muscle weakness. Treatment is by correcting underlying problem and repleting phosphorous. Demographics Most common cause is probably chronic alcoholism. Over 50% of the hospitalized alcoholics become hypophosphatemic when they are unable to eat for a period of days or develop an alcohol withdrawal state. Excessive renal excretion of phosphorus is also a common cause of hypophosphatemia. Increased renal clearance of phosphorus occurs in pirmary hyperparathyroidism, vitamin D deficiency, vitamin D resistant and vitamin D dependent rickets, hyperglycemic states, and oncogenic osteomalacia. Intracellular shifts of phosphorus by insulin infusion can also cause an abrupt fall in serum phosphorus. In 42% of patients with hypophosphatemia is not recognized or is inappropriately treated. Clinical Features Mild cases of hypophosphatemia are often asymptomatic. In severe cases (<1.0 mg/dL), patients may become irritable, apprehensive, and hyperventilate, causing muscle weakness, numbness, and paresthesia. Seizures, coma, and death may occur as a sequel. Since phosphate is an essential component of ATP and creatine phosphate, fatigue, muscle weakness, myalgia, and myopathy are probably the most common manifestations. Respiratory insufficiency can result with severe muscle weakness. Rhabdomyolysis can develop in chronic alcoholics in the setting of hypophosphatemia. Rhabdomyolysis can also be precipitated during treatment for diabetic ketoacidosis or by hyperalimentation or refeeding in a malnourished patient. Severe hypophosphatemia may also result in a cardiomyopathy. Patients may suffer a reduced cardiac output, hypotension, and ventricular

arrhythmias. Cardiac abnormalities are often corrected with restoration of phosphorus deficits. Other manifestations include erythrocyte and leukocyte dysfunction, impaired phagocytosis and opsonization (increased infection), and mineralization defect of the skeleton (rickets and osteomalacia).

Pathogenesis Chronic alcoholic abuse often leads to hypophosphatemia mainly due to poor dietary intake, increased urinary excretion, and vomiting. Alcohol may be associated with calcium and vitamin D deficiency and secondary hyperparathyroidism, which worsen the condition by increased urinary wasting of phosphorus. Increased hyperventilation in alcoholic ketoacidosis induces marked phosphaturia. Increased renal excretion can be explained in various settings. In vitamin D deficiency, serum phosphorus is low because of decreased intestinal absorption as well as secondary hyperparathyroidism, which increases phosphorus losses in the urine. In X-linked hypophosphatemic rickets, there is a genetic defect in the PHEX gene, which encodes a neutral endopeptidase presumed to degrade the phosphaturia hormone known as phosphatonin. As a result, an increased urine leakage of phosphorus is observed. This condition may also lead to a decreased intestinal phosphorus absorption caused by a defect in hypophosphatemia-mediated stimulation of 25(OH)D1a-hydroxylase. Acidosis and/or hyperglycemic ketoacidosis can also cause large amounts of inorganic phosphorus into the circulation leading to urinary excretion due to an enhancement of intracellular and organic phosphorus degradation. Respiratory alkalosis with prolonged hyperventilation can cause hypophosphatemia through a different mechanism. An increase in intracellular pH activating glycolysis, which accelerates the formation of phosphorylated carbohydrate compounds within the cell. Intracellular shifts of phosphorus can occur with insulin infusion during the treatment of patients with diabetic ketoacidosis or in patients who have an increased consumption after prolonged starvation (refeeding syndrome). Insulin increases the cellular uptake of phosphorus. Insulin production increases as a normal response to food intake. Intracellular shifts of phosphorus can occur abruptly in patients who have anorexia nervosa, chronic alcoholism, classic marasmus or kwashiorkor, massive weight loss in obese patients, and prolonged intravenous hydration. Likewise, an increased intracellular uptake as seen in blast crisis of advanced leukemia can cause hypophosphatemia from rapid uptake in rapid dividing cells. Treatment Correcting the underlying cause of the hypophosphatemia is usually enough to correct mild abnormalities (phosphorus >0.3 mg/dL). Oral supplementation may be helpful with milk (1g of phosphorus per liter), carbonated beverages (phosphoric acid), or drugs (Neutraphos or Kphos at 3 g/d/24hr).

Severe cases (phosphorus <0.2 mg/dL) may require more than 3 g/d of phosphorus supplementation over several days. Intravenous phosphorus can be given (1g in 1L over 8-12 hr) if the patient is unable to eat. Soft tissue calcification and nephrocalcinosis may be a complication and, therefore, caution should be instituted when using an IV infusion. Intramuscular or subcutaneous routes are not recommended due to the risk of soft tissue necrosis and muscle discomfort.

Hyperphosphatemia Defined as an absolute serum phosphorus level above 4.5 mg/dL (1.46 mmol/L). Teaching points Defined as serum phosphorus concentration >4.5 mg/dL. Renal failure most common cause. Usually asymptomatic. Metastatic calcification is most feared complication. Treatment is by dietary restriction and the use of phosphate binders. Demographics Despite the fact that several clinical syndromes are associated with hyperphosphatemia, acute or chronic renal failure is by far the most common etiology. The causes of hyperphosphatemia can arbitrarily be classified into four major categories. o Pseudohyperphosphatemia. o Increased exogenous phosphorus load. o Increased endogenous load or transcellular phosphorus shifts. o Reduced urinary Phos excretion. Clinical Features Patients with hyperphosphatemia are often asymptomatic but since phosphate metabolism is closely coupled with calcium, patients may manifest signs of hypocalcemia. Metastatic calcification: keratitis and calciphylaxis may result from calcium deposition in the cornea and blood vessels (leading to gangrene of involved extremities). Other organ systems may also be involved including skin (causing pruritus), lungs (mimicking pulmonary thromboembolism), myocardial and valvular calcification (valvular dysfunction), and nephrocalcinosis. Renal failure. Secondary hyperparathyroidism resulting from hyperphosphatemia causes calcium-phosphorus precipitation in tubules invoking tubulointerstitial nephritis and acceleration of renal failure. Furthermore, skeletal resistance to the calcemic effect of PTH in a uremic patient with hyperphosphatemia may predispose patients on dialysis to aluminum toxicity. Pathogenesis and Etiology Impairment of renal function below a certain threshold (GFR < 20 mL/min ) often severely reduces renal excretion of phosphate. o A similar effect can be observed if there is an enhanced tubular reabsorption of phosphorus from the kidneys. o PTH, 1,25-(OH)2D3, calcitonin, insulin, insulin-like growth factor I, growth hormone, glucorticoid, vasopressin, atrial natriuretic peptide, and pH all play important roles in regulation of phosphorus absorption and excretion.

A deficiency of PTH, as in primary or acquired hypoparathyroidism can manifest hyperphosphatemia and hypomagnesemia and/or hypocalcemia. Pseudohyperphosphatemia may be the result of an increased amount of protein which bind phosphorus at high-capacity (multiple myeloma) or the result of in vitro hemolysis and thrombocytosis raising the serum phosphorus levels in autoanalyzers. There is, however, a low level of 1,25-(OH)2D3 in patients who display this type of hyperphosphatemia. Hyperphosphatemia may also be the result of an increased exogenous phosphorus supplementation with phosphorus-containing salts. o This is often seen in infants who were fed humanized cows milk (phosphorus rich cows milk) and ingestion of rodenticides. Vitamin D intoxication can enhance the phosphorus absorption through the GI tract and cause the same effect. Frequent enemas in the elderly patients also lead to hyperphosphatemia. Hyperphosphatemia may be a complication of intravenous therapy when acid citrate dextrose is used as an anticoagulant solution for blood storage. Endogenous phosphorus can significantly increase serum phosphorus. o Cell death or injury releases phosphorus from intracellular source as seen in tumor lysis syndrome, rhabdomyolysis, bowel infarction and malignant hyperthermia. o These conditions combine toxic drug therapies, acute decline in renal function, volume depletion, and resultant acid-base imbalance as culprits to a rising phosphorus level. o Acidosis is strongly associated with hyperphosphatemia due to transcellular shift.

Treatment and Prognosis In patients who are undergoing treatments that may anticipate an increase in phosphorus load, it may be worthwhile to maintain renal function to prevent hyperphosphatemia. o In a patient with existing renal insufficiency or failure, treatment consists of removal of phosphorus via an extracorporeal route. o Hemodalysis as a mode of phosphorus removal has very poor effectiveness while peritoneal dialysis may be slightly more effective. o Phosphorus restriction and antacid administration may avoid further absorption through the GI tract. o Phosphate binders (calcium containing binders such as calcium carbonate or calcium acetate or a non-calcium-containing binder such as sevelemar) are usually mainstay in to control serum phosphorus. Patients with hyperphosphatemia have a substantial increase in mortality. o In patients on chronic dialysis, the relative risk of death for those with a serum phosphorus greater than 6.5 mg/dL was 1.27 times that of patients with serum phosphorus level between 2.4 and 6.5 mg/dL.

Predictors of serum phosphorus greater than 6.5 mg/dL were younger age at onset of end-stage renal disease, female sex, white race, diabetes mellitus, active smoking, and higher serum creatinine.