SGLT2 inhibitors-induced electrolyte abnormalities: An analysis of the associated mechanisms.

AIMS: Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of antidiabetic drugs that affect serum electrolytes levels. The aim of this review is the detailed presentation of the associated mechanisms of the SGLT2 inhibitors-induced electrolyte abnormalities. MATERIALS AND METHODS: Eligible trials and relevant articles published in PubMed (last search in July 2017) are included in the review. RESULTS: SGLT2 inhibitors induce small increases in serum concentrations of magnesium, potassium and phosphate. The small increase in serum phosphate concentration may result in reduced bone density and increased risk of bone fractures, mainly seen with canagliflozin, but recent meta-analyses did not show increased risk of bone fractures with SGLT2 inhibitors. CONCLUSION: The increases in serum electrolytes levels may play a role in the cardiovascular protection that has been recently reported with empagliflozin and canagliflozin.

Phosphate imbalance in patients with heart failure.

Patients with heart failure often exhibit electrolyte abnormalities, such as hyponatremia or hypokalemia/hyperkalemia. Although not as common as the other electrolyte disturbances observed in patients with heart failure, phosphate imbalance is also of high importance in this population. The aim of this review is to present the mechanisms of low or high phosphate serum levels in patients with heart failure and its role in the pathogenesis and progression of heart dysfunction. Hypophosphatemia in patients with heart failure may be the result of co-existing electrolyte and acid-base abnormalities, pharmacological treatments, decreased intestinal absorption or secondary to sympathetic nervous system activation and co-morbidities, such as diabetes mellitus or heavy alcohol consumption. Hypophosphatemia can affect multiple organ systems including the cardiovascular system. Depletion of phosphate can lead to ventricular arrhythmias and elimination of ATP synthesis, resulting in reversible myocardial dysfunction. Hyperphosphatemia, observed mainly in patients with chronic kidney failure, is also associated with cardiac hypertrophy, which may worsen cardiac contractility and heart failure. Studies have also shown an association of high-normal serum phosphate levels with vascular and valvular calcification. Therefore, serum phosphate imbalances may exhibit a causal role in the pathogenesis and progression of heart failure.

MANAGEMENT OF ENDOCRINE DISEASE: Hypothyroidism-associated hyponatremia: mechanisms, implications and treatment.

BACKGROUND: Patients with moderate to severe hypothyroidism and mainly patients with myxedema may exhibit reduced sodium levels (<135 mmol/L). SUMMARY: The aim of this short review is the presentation of the mechanisms of hyponatremia and of the available data regarding its implications and treatment in patients with hypothyroidism. Hypothyroidism is one of the causes of hyponatremia, thus thyroid-stimulating hormone determination is mandatory during the evaluation of patients with reduced serum sodium levels. The main mechanism for the development of hyponatremia in patients with chronic hypothyroidism is the decreased capacity of free water excretion due to elevated antidiuretic hormone levels, which are mainly attributed to the hypothyroidism-induced decrease in cardiac output. However, recent data suggest that the hypothyroidism-induced hyponatremia is rather rare and probably occurs only in severe hypothyroidism and myxedema. Other possible causes and superimposed factors of hyponatremia (e.g. drugs, infections, adrenal insufficiency) should be considered in patients with mild/moderate hypothyroidism. Treatment of hypothyroidism and fluid restriction are usually adequate for the management of mild hyponatremia in patients with hypothyroidism. Patients with possible hyponatremic encephalopathy should be urgently treated according to current guidelines. CONCLUSIONS: Severe hypothyroidism may be the cause of hyponatremia. All hypothyroid patients with low serum sodium levels should be evaluated for other causes and superimposed factors of hyponatremia and treated accordingly.

Hyponatremia in patients with liver diseases: not just a cirrhosis-induced hemodynamic compromise.

Hyponatremia (Na(+) <135 mmol/l) is the most common electrolyte disorder. Cirrhosis represents a rather frequent cause of hyponatremia mainly due to systemic and splanchnic vasodilation resulting in decreased effective arterial blood volume, which leads to excessive non-osmotic secretion of antidiuretic hormone. However, hyponatremia of multifactorial origin may be seen in patients with liver diseases. The review focuses on the factors and pathogenetic mechanisms of decreased sodium levels other than the hemodynamic compromise of cirrhosis in patients with liver diseases. The mechanisms and causal or contributing role of pseudohyponatremia, hyperglycemia, infections, drugs and toxins as well as of endocrine disorders, renal failure and cardiac disease in patients with liver disease are meticulously discussed. Hyponatremia of multifactorial origin is frequently observed in patients with liver diseases, and special efforts should be made to delineate the underlying causative and precipitating factors as well as the risk factors of the osmotic demyelination syndrome in order to properly manage this serious electrolyte disorder and avoid treatment pitfalls.

Ten common pitfalls in the evaluation of patients with hyponatremia.

Hyponatremia is the most common electrolyte disorder in hospitalized patients associated with increased morbidity and mortality. On the other hand, inappropriate treatment of hyponatremia (under- or mainly overtreatment) may also lead to devastating consequences. The appropriate diagnosis of the causative factor is of paramount importance for the proper management and avoidance of treatment pitfalls. Herein, we describe the most common pitfalls in the evaluation of the hyponatremic patient, such as failure to exclude pseudohyponatremia or hypertonic hyponatremia (related to glucose, mannitol or glycine), to properly assess urine sodium concentration and other laboratory findings, to diagnose other causes of hyponatremia (cerebral salt wasting, reset osmostat, nephrogenic syndrome of inappropriate antidiuresis, prolonged strenuous exercise, drugs) as well as inability to measure urine osmolality or delineate the diagnosis and cause of the syndrome of inappropriate antidiuretic hormone secretion. Clinicians should be aware of these common clinical practice pitfalls, which could endanger patients with hyponatremia.

Medication-induced hypophosphatemia: a review.

Hypophosphatemia (serum phosphorus concentration <2.5 mg/dl, 0.8 mmol/l), although rare in the general population, is commonly observed in hospitalized patients and may be associated with drug therapy. In fact, hypophosphatemia frequently develops in the course of treatment with drugs used in every-day clinical practice including diuretics and bisphosphonates. Proper diagnostic approach of patients with low serum phosphorus concentrations should involve a detailed medical history with special attention to the recent use of medications. The clinical manifestations of drug-induced hypophosphatemia are usually mild but might also be severe and potentially life-threatening. This review aims at a thorough understanding of the underlying pathophysiological mechanisms and risk factors of drug therapy-related hypophosphatemia thus allowing prevention and effective intervention strategies.

Blood pressure drug therapy and electrolyte disturbances.

Antihypertensive pharmacologic treatment may be associated with diverse disturbances of electrolyte homeostasis. These drug-induced disorders are relatively common, typically including hyponatraemia, hypokalaemia, hyperkalaemia, hypomagnesaemia, hypophosphataemia and hypercalcaemia. Diuretics, beta-blockers, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are particularly likely to cause these complications. Recognised risk factors include high-dosage regimens (especially diuretics), old age, diabetes and impairment of renal function. Strategies to prevent these adverse drug reactions involve careful consideration of risk factors and clinical and laboratory evaluation in the course of treatment.

Reversible tubular dysfunction that mimicked Fanconi's syndrome in a patient with anorexia nervosa.

Patients with anorexia nervosa exhibit acid-base and electrolyte disturbances. Hypophosphatemia is commonly found in these patients during nutritional recovery. However, marked, possibly, life-threatening hypophosphatemia associated with proximal tubular dysfunction has not been previously described. We report a case of anorexia nervosa complicated by a nonacidotic proximal tubulopathy, which was manifested by renal glycosuria, as well as inappropriate phosphaturia and uricosuria resulting in hypophosphatemia and hypouricemia.

Partially reversible renal tubular damage in patients with obstructive jaundice.

Decreased serum uric acid levels resulting from renal urate wasting have been occasionally encountered in jaundiced patients. However, in these cases, there are no data concerning the underlying renal tubular defects. In the present study, we investigated the renal tubular function in 35 patients with obstructive jaundice of various severity and causes (11 with lithiasis, 17 with carcinoma, and 7 with intrahepatic cholestasis). A detailed study of the renal tubular function was performed. Beyond the conventional methods, (1)H-NMR spectroscopy of urine was used to evaluate noninvasively renal damage by the characteristic perturbation in the excretion pattern of low-molecular weight endogenous metabolites. On admission, patients with obstructive jaundice had significantly lower serum uric acid and phosphate levels and higher bile acid concentrations compared with 40 age- and sex-matched controls. Serum uric acid levels presented a negative correlation with the total and direct bilirubin as well as the fractional excretion of uric acid. Furthermore, a great number of the patients studied developed one or more proximal tubular dysfunction manifestations beyond uricosuria, such as renal glucosuria, phosphaturia, and increased excretion of alpha(1)-microglobulin. (1)H-NMR spectroscopy of the urine showed decreased levels of citrate and hippurate and increased levels of 3-hydroxybutyrate and acetate. In 12 patients partial or complete remission of jaundice was followed by an improvement of the proximal renal tubular damage. In conclusion, obstructive jaundice can cause a partially reversible generalized proximal tubular dysfunction.

Hyperosmolar syndrome in a patient with uncontrolled diabetes mellitus.

Nonketotic hyperglycemic hyperosmolar syndrome (HHS) is found mostly in type 2 diabetic patients with marked hyperglycemia. HHS is a metabolic emergency and is associated with a high mortality rate. It is characterized by extreme dehydration and neurologic symptoms, which are related directly to the degree of hyperosmolality. We describe a 65-year-old patient who was admitted because of impaired consciousness caused by HHS. The relevant clinical and laboratory findings are discussed, and a brief overview of the pathophysiology and therapeutic management is provided.

Acute pancreatitis-induced hypomagnesemia.

We describe the case of an alcoholic patient admitted to our hospital with alcohol-induced acute pancreatitis who developed severe hypomagnesemia (serum magnesium 0.36 mmol/l) during hospitalization. The underlying pathogenetic mechanisms of hypomagnesemia are discussed.

Hyperosmolar nonketotic syndrome with hypernatremia: how can we monitor treatment?

We report the case of a 62 year-old symptomatic patient with severe hyperglycemic hyperosmolality associated with hypernatremia. During treatment, the progressive decrease in serum tonicity, which resulted in the amelioration of the neurological symptoms, followed the decrease in serum glucose and mainly the corrected serum sodium levels rather than the decrease in the uncorrected serum sodium levels. The case illustrates the usefulness of glucose - corrected serum sodium levels to monitor treatment in such conditions in order to avoid neurological consequences caused by the decrease in serum osmolality.

Mechanisms of hyponatraemia in alcohol patients.

Hyponatraemia is commonly reported in chronic alcoholic patients. However, the underlying pathogenetic mechanisms are not well delineated. In the current study, we analysed the possible pathophysiological mechanisms of hyponatraemia in a group of alcoholic patients (n = 127) admitted to our hospital for causes related to alcohol misuse. Hyponatraemia (serum sodium <134 mmol/l) was found in 22 patients (17.3%). The most common cause of hyponatraemia in our cohort was hypovolaemia (12 patients); pseudohyponatraemia was diagnosed in six patients with alcohol-induced severe hypertriglyceridaemia. It is of interest that two patients fulfilled the criteria of the so-called 'beer potomania' syndrome, while in two others, hyponatraemia was due to reset osmostat or to cerebral salt wasting syndrome, not previously described in alcoholic patients. It is concluded that hyponatraemia is a frequently observed electrolyte disorder in hospitalized alcoholic patients and is related to various pathophysiological mechanisms.

Tamoxifen-induced severe hypertriglyceridemia and pancreatitis.

Tamoxifen exhibits favorable effects on the lipid and lipoprotein profile since it decreases the total and LDL cholesterol levels as well as the Lp(a) levels. Additionally, a small increase in serum triglycerides is commonly found after tamoxifen administration. However, severe hypertriglyceridemia which can sometimes be associated with life-threatening complications is occasionally noticed. Herein, we describe a patient who developed tamoxifen-induced severe hypertriglyceridemia and pancreatitis. An analysis of the underlying pathogenetic mechanisms as well as a review of the relevant literature is also provided.