Diabetic ketoacidosis. Induction of hypocalcemia and hypomagnesemia by phosphate therapy.

A nine year old boy with previously undiagnosed diabetes mellitus presented with severe ketoacidosis. His hyperglycemia (plasma glucose = 786 mg/dl), acidosis (arterial pH = 6.86), dehydration and coma responded well to therapy with intravenous fluids, bicarbonate and insulin. Potassium supplementation was given as a phosphate salt.Despite marked clinical and biochemical improvement, 28 hours after therapy was initiated he was found to have profound hypocalcemia (2.6 meq/liter), hypomagnesemia (0.8 meq/liter) and hyperphosphatemia (9.2 mg/dl). All three electrolyte levels had been normal upon admission, and they were gradually corrected with appropriate supplementation of calcium and magnesium and discontinuation of the intravenous phosphate. We interpret these iatrogenic electrolyte abnormalities in the patient described to have been the result of the massive phosphate load administered, resulting not only in hypocalcemia, but also in hypomagnesemia that inhibited parathyroid hormone release.Current recommendations suggest replacement of the potassium losses in diabetic ketoacidosis with the phosphate salt to compensate for depleted stores of 2,3-diphosphoglycerate. We caution physicians that such a regimen can result in severe electrolyte disturbances which potentially may be life threatening. Judicious use of potassium phosphate as an adjunct to traditional potassium chloride therapy, and close monitoring of serum calcium, magnesium and phosphorus, appears to be a preferable therapeutic regimen than potassium phosphate alone.     

Hypokalemia, hypomagnesemia and ventricular arrhythmia during diuretic treatment of arterial hypertension

Diuretics have been used for 25 years in the treatment of arterial hypertension, where they have proved effective and well tolerated. However, recent therapeutic trials have failed to demonstrate a significant reduction of coronary disease mortality in moderately hypertensive patients under antihypertensive therapy. These disappointing results have led to a reappraisal of the cardiovascular risk inherent in antihypertensive treatments and notably diuretics. Thiazides and the so-called heigh-ceiling diuretics increase urinary potassium excretion, thereby reducing serum potassium levels by 0.3 to 0.6 mmol/l on average. Kalaemia falls below 3.0 mmol/l in 1 to 7 percent of the patients. The long-term consequences of hypokalaemia are imperfectly known. Several authors have used continuous or exertion electrocardiographic recordings to evaluate the risk of ventricular arrhythmia induced by hypokalaemia, but their results are conflicting and inconclusive. The risk of ventricular arrhythmia is perhaps not negligible when hypokalaemia occurs in certain patients with coronary disease or left ventricular hypertrophy who are under digitalis therapy. Diuretics also reduce serum levels of magnesium. The consequences of isolated hypomagnesaemia are obscure. The risk of hyperexcitability seems to be increased when hypokalaemia is associated with digitalis toxicity. The fall in serum concentrations of potassium and magnesium is dose-dependent, and it occurs mainly with the excessive doses formerly prescribed. The dose-response curve of antihypertensive agents is relatively flat, which suggests that diuretics should be used in lower dosage.     

Transient neonatal hypocalcemia, hypomagnesemia, and high serum parathyroid hormone with maternal hyperparathyroidism.

Findings in a case of neonatal tetany in a child whose mother had elevated blood parathyroid hormone levels because of a parathyroid adenoma are given. The child was found to have hypocalcemia, hypomagnesemia, and hyperphosphatemia. Parathyroid hormone in the infant was found to be elevated. It has been postulated that the pathophysiologic mechanism of the hypocalcemia in this syndrome is transient hypoparathyroidism. The present case suggests a different mechanism: hypomagnesemia and end-organ refractoriness to parathyroid hormone, a state analogous to pseudohypoparathyroidism.     

Primary hypomagnesemia with secondary hypocalcemia,diarrhea and insensitivity to parathyroid hormone

That diarrhea may be associated with hypomagnesemia and/or hypocalcemia is clearly shown by the relationship of magnesium, calcium and gut function in a 2-month-old male hospitalized with seizures, diarrhea, anasarca, hypoalbuminemia, hypocalcemia and hypomagnesemia. Calcium, phosphorus, sodium, potassium and nitrogen balances were positive, but magnesium balance was negative with fecal excretion approximating oral intake. Urinary protein loss was 40 mg/24 hr;⁵¹Cr albumin loss was 1.8%. Administration of parathyroid hormone during magnesium depletion did not produce any rise in serum calcium, but a normal response was observed after magnesium repletion. All clinical abnormalities cleared when magnesium was given, first parenterally and later orally. Thus, hypomagnesemia appears to have resulted from a selective defect in magnesium absorption. Hypocalcemia resulted from parathyroid hormone unresponsiveness during magnesium deficiency. No explanation for diarrhea, other than hypomagnesemia and/or hypocalcemia, was found. The presence of hypoalbuminemia in the face of a positive nitrogen balance suggests that albumin was not synthesized at its usual rate while the patient was depleted of magnesium.     

Subclinical hyponatremia, hyperkalemia and hypomagnesemia in patients with poorly controlled diabetes mellitus

Diabetes mellitus is associated with disturbances in electrolyte metabolism. We studied 68 patients with insulin-requiring diabetes mellitus followed up in the Home Monitoring Clinic in order to assess the relationship between electrolyte disturbances and severity of diabetes. There is a significant correlation of serum sodium (r = -0.323, P less than 0.01), potassium (r = 0.416, P less than 0.001), magnesium (r = -0.292, P less than 0.02) with fasting glucose. Thus, in patients with high fasting blood glucose, sodium and magnesium tend to be lower while potassium is higher. Among the three parameters, only serum magnesium significantly correlates with the level of hemoglobin A1 (r = -0.356, P less than 0.001) and thus may be related to the long-term control of diabetes. On the other hand, the hyponatremia and hyperkalemia are more likely to be related to short-term metabolic control as reflected by fasting blood glucose. To conclude, minor changes in electrolytes have been found in a group of 68 Chinese patients receiving insulin. There is a remote possibility that these electrolyte changes may influence the chemical events responsible for long-term diabetic complications.     

Severe hypophosphatemia. Pathophysiologic implications, clinical presentations, and treatment

We conducted this review to heighten the awareness and describe pathologic manifestations of hypophosphatemia. We present 3 cases of varied manifestations of hypophosphatemia where recognition was delayed. In certain settings, severe hypophosphatemia has significant morbidity and potential mortality. Appreciation of the pathophysiologic basis for organ dysfunction in severe hypophosphatemia should result in early recognition and treatment. We reviewed the English-language literature for reported cases and research studies dealing with pathophysiologic mechanisms subserving clinical manifestations. We observed that depletion of adenosine triphosphate (ATP) would explain most of the derangement noted in cellular functions. Phosphate plays a key role in the delivery of oxygen to the tissue. Lack of phosphate, therefore, leads to tissue hypoxia and hence disruption of cellular function. Severe hypophosphatemia becomes clinically significant when there is underlying phosphate depletion. Otherwise, short-term acute hypophosphatemia is not usually associated with any specific disorder. Chronic hypophosphatemia, on the other hand, results in hematologic, neuromuscular, and cardiovascular dysfunction, and unless corrected, the consequences can be grave. Most of the time hypophosphatemia results from renal loss of phosphate, diagnosed by a fractional secretion of phosphate > 5%. It is hard to provide precise estimates of how many patients are seen with hypophosphatemia annually at academic medical centers. This is complicated by use of chemistry panels that do not measure inorganic phosphate unless specifically ordered. This often leads to delay in correct diagnosis, and, therefore, additional delay in providing appropriate management. A high index of suspicion alone avoids the unnecessary withholding of treatment that can be life saving.     

Chondrocalcinosis and hypomagnesemia: clinical and radiological progression

Hypomagnesemia is a rare secundary metabolic disorder associated with calcium pyrophosphate dihydrate cristal deposition disease in joint structures and may cause asymptomatic chondrocalcinosis (linear calcification of cartilage), pseudogout, and chronic arthropathy. We report 2 young men with relapsing acute knee monoarthritis with chondrocalcinosis and hypomagnesemia. After follow-up clinical and radiological events al least for 5 years and treatment with magnesium lactate, these patients have not shown new pseudogout attacks. We discuss knee radiological evolution in both patients, outstanding major knee radiological deterioration in the patient with early symptoms and a familial chondrocalcinosis association, in spite of clinical asymptomatic status.     

X-linked hypophosphatemia: a clinical, biochemical, and histopathologic assessment of morbidity in adults

Research and management of XLH have concentrated on the disease in childhood, and the natural history and morbidity of XLH in adult life are thus poorly understood. We have studied 22 adults (6 men) with XLH to clarify these aspects of this most common inherited form of rickets and osteomalacia. Most study participants had presented with rickets in early childhood and had undergone tibial osteotomies on at least 1 occasion. Seventeen individuals had genu varum, 1 had genu valgum, and 4 had straight legs, attributable to successful osteotomies in 2. Five subjects reported increasing lower limb deformity in the late teens or subsequently. Eight subjects complained of bone pain, 6 of whom had radiologic evidence of pseudofractures; pseudofractures were found in 4 additional asymptomatic individuals. None of 16 subjects who underwent transiliac bone biopsy had normal double tetracycline labeling; accordingly, all were considered to have osteomalacia. Bone pain was associated with a relative osteoid volume in excess of 25%. Relative osteoid volume was inversely related to serum 1,25(OH)2D concentration (r = -0.74, p less than 0.02), but unrelated to serum concentrations of calcium and phosphate or their product. Eighteen participants complained of joint pain, predominantly in the knees and ankles. The severity of joint pain correlated with the degree of lower limb deformity (p = 0.011) which, in turn, was related to fasting serum phosphate concentration (r = -0.56, p less than 0.025) and TmP/GFR (r = -0.70, p less than 0.005). Enthesopathy affected 33% of those younger than 30 years, and all those above this age. Nineteen individuals had experienced significant dental problems, most commonly abscess formation. Eight had required complete dental clearance. Twelve women from the group had a total of 22 live births. Fifteen of these were by cesarean section, although radiologic evidence of pelvic narrowing was not found in any subject. Serum ALP was elevated in all but 3 of the 18 untreated subjects. Levels correlated with those of other indices of bone turnover (BGP r = 0.82, p less than 0.005; urine total HP r = 0.60, p less than 0.025; urine free HPr = 0.78, p less than 0.005), but were not related to the degree of osteomalacia found on bone biopsy. Serum levels of iPTH, 25(OH)D, 1,25(OH)2D, and thyroid hormones were generally normal in the untreated patients. We conclude that adults with untreated XLH have osteomalacia that is frequently symptomatic. Even greater morbidity is caused by degenerative joint disease arising from lower limb deformities.(ABSTRACT TRUNCATED AT 400 WORDS)     

Treatment of severe hypophosphatemia.

Aspects of phosphate biochemistry pertinent to therapy, the distribution of phosphorus in body compartments, therapeutic phosphorus preparations, prevention of hypophosphatemia, therapeutic guidelines, and side-effects of phosphorus therapy are reviewed. Severe hypophosphatemia (less than 0.32 mmol/litre or less than 1 mg/dl) can occur with normal or depleted body stores. Because a large amount of phosphorus may shift rapidly between the extracellular and intracellular or bone compartments, the size of a possible total body deficit cannot be estimated from the serum phosphorus level. Similar shifts may occur unpredictably during repair of hypophosphatemia. Therefore, correction of hypophosphatemia in any patient must be empiric and the response of serum levels to therapy should be followed closely. We discuss a method likely to correct hypophosphatemia while minimizing side-effects.     

Arginine-induced hypophosphatemia and hyperkaliemia in man.

The effects of a 0.5 g/kg body weight arginine infusion on plasma inorganic phosphates and potassium were examined in nineteen normal subjects. Plasma phosphorus displayed a highly significant (p less than 0.001) fall with a maximum depression below baseline of 1.11 +/- 0.15 mg/100 ml or 33 +/- 3% (mean +/- SEM); there was a significant correlation (p less than 0.01) between this fall and the insulin peaks induced by arginine. Plasma potassium levels displayed a distinct and significant increase in eleven of the twelve subjects studied; the maximum increase above baseline was 1.02 +/- 0.14 mEq/1 or 27 +/- 4.5% (p less than 0.001). No change occurred in blood pH values determined in four subjects. In six normal subjects, the test was repeated with the addition of somatostatin (250 micrograms bolus, followed by 500 micrograms/hr), which abolished the insulin and growth hormone response to arginine. It also abolished the fall in plasma phosphorus but appeared (if anything) to augment the increase in potassium. These findings show that arginine is responsible for a fall in plasma phosphorus related to the insulin response, and for an increase in plasma potassium of clinical significance, the mechanism(s) of which, however, are still obscure.     

Management of hyponatremia and clinical use of vasopressin antagonists

Hyponatremia, the most common electrolyte disorder in hospitalized patients, has been associated with high rate of mortality among both this population and nonhospitalized patients. This review describes briefly the classification and pathogenesis of hyponatremia, and, in greater detail, the management of hyponatremia with a particular emphasis on the clinical pharmacology of arginine vasopressin (AVP) antagonists. This review includes more in-depth discussion on the pharmacology of conivaptan, an AVP antagonist recently approved by the United States Food and Drug Administration.