Introduction
Electrolyte imbalances are a common problem in patients with alcohol use disorder (AUD), as defined by DSM-5, encompassing both harmful alcohol use and alcohol dependence. The duration and quantity of alcohol consumption are the strongest predictors of the clinical course of electrolyte disturbances. The most severe electrolyte abnormalities occur in patients with poor nutritional status, including inadequate protein and vitamin intake, as well as concurrent illnesses. Alcohol directly contributes to acid-base and electrolyte disturbances, which may occur even in individuals with an otherwise balanced diet.
Patients who develop electrolyte imbalances are commonly hospitalized because of abdominal pain, prolonged nausea, and vomiting. Metabolic acidosis and hyponatremia are frequently diagnosed on admission. Despite often substantial depletion of electrolyte stores, serum concentrations at presentation may remain within normal limits or show only minor abnormalities. These deficits become apparent after treatment of acidosis and correction of extracellular fluid volume. They may subsequently lead to life-threatening complications. A hallmark of chronic harmful alcohol consumption is a rapid decline in phosphate, magnesium, potassium, and calcium concentrations during the first 24-36 hours after hospitalization (1).
This review discusses the pathophysiology of electrolyte disturbances and current treatment approaches.
Acid-Base Disorders
Individuals diagnosed with alcohol use disorder are prone to a variety of acid-base disturbances. Such abnormalities are identified in up to 78% of patients. Alcoholic ketoacidosis occurs in approximately 25% of patients hospitalized because of chronic alcohol-related disorders. It most commonly develops in patients who stop consuming alcohol because of abdominal pain, nausea, or vomiting caused by alcohol-induced gastritis or pancreatitis. Consequently, ethanol may not be detectable at the time of hospitalization.
Laboratory testing typically reveals high-anion-gap metabolic acidosis caused by the accumulation of ketone bodies, lactate, and acetic acid. Normal-anion-gap metabolic acidosis resulting from indirect urinary bicarbonate loss may also be observed.
Pathophysiology of Alcoholic Ketoacidosis
The development of ketoacidosis results from increased mobilization of long-chain fatty acids and their transport to the liver. In the liver, these fatty acids are converted into ketone bodies. This process occurs under conditions of ketogenesis, characterized by insulin deficiency and glucagon excess. Insulin deficiency develops because glycogen stores become depleted during fasting, gluconeogenesis is suppressed, and insulin secretion from pancreatic beta cells is inhibited through activation of the sympathetic nervous system.
An important factor in the development of ketogenesis is the ratio of reduced to oxidized nicotinamide adenine dinucleotide (NADH/NAD), which increases during the metabolism of alcohol to acetaldehyde and acetate. This elevated ratio leads to the following changes:
- stimulation of beta-hydroxybutyrate production. Qualitative ketone body testing using sodium nitroprusside, which detects only acetone and acetoacetate, may be misleading and result in incorrect attribution of high-anion-gap acidosis to another cause. Therefore, when chronic alcohol misuse is suspected, direct measurement of beta-hydroxybutyrate concentration is useful;
- increased conversion of pyruvate to lactate, which may lead to lactic acidosis, typically of mild severity. If severe lactic acidosis develops in patients with alcohol use disorder, alternative causes such as sepsis, tissue hypoperfusion, or thiamine deficiency should be considered;
- inhibition of hepatic gluconeogenesis, contributing in part to hypoglycemia, which occurs in approximately one-quarter of patients with alcoholic ketoacidosis.
In patients with alcoholic ketoacidosis, glucose concentrations may be normal, decreased, or elevated, usually up to 15.3 mmol/L. In one study involving 74 patients with alcoholic ketoacidosis, 12% had glucose concentrations <3.3 mmol/L and 11% had concentrations >13.9 mmol/L. None of these patients had diabetes mellitus or impaired glucose tolerance. Patients who develop hypoglycemia during alcoholic ketoacidosis often consume little food after their last alcohol intake. The coexistence of ketoacidosis and hypoglycemia can be life-threatening because progression from alcoholic stupor to hypoglycemic coma may go unrecognized.
The main treatment goals in alcoholic ketoacidosis are restoration of hemodynamic stability and termination of ketogenesis. Initial treatment generally includes administration of 100 mg of thiamine (vitamin B1) intravenously or intramuscularly (8). Thiamine should be administered before glucose-containing fluids to reduce the risk of Wernicke encephalopathy, although the evidence supporting this recommendation is limited and largely based on individual case reports (9, 10). An exception is patients with hypoglycemia, who should receive glucose-containing fluids immediately.
Administration of dextrose stimulates insulin secretion, thereby reducing ketone body production and accelerating ketone metabolism. Metabolism of beta-hydroxybutyrate and acetoacetate restores bicarbonate levels and partially corrects metabolic acidosis. A 5% dextrose solution is usually administered intravenously at a rate of 7-7.5 g/h and typically corrects acidosis within 12-24 hours.
A 0.9% sodium chloride solution corrects extracellular fluid deficits, which commonly develop because of vomiting, reported in approximately 73% of these patients, and due to renal losses of sodium and potassium bound to beta-hydroxybutyrate and acetoacetate. Restoration of intravascular volume also decreases circulating catecholamines that stimulate ketogenesis and reduces glucagon concentrations (11).
Dextrose solutions should not be administered to the small subset of patients with severe hyperglycemia and marked hypokalemia because insulin secretion may further decrease potassium levels. Administration of insulin is contraindicated because it may worsen deficiencies of potassium, phosphate, and magnesium (1, 8-10).
Bicarbonate administration is generally not indicated because metabolism of lactate and ketone bodies results in endogenous bicarbonate production. Mild normal-anion-gap metabolic acidosis may persist after correction of the anion gap because of indirect urinary bicarbonate loss. Renal bicarbonate losses usually normalize within 24-36 hours (1).
Sodium Disorders
Acute alcohol consumption promotes water diuresis through suppression of vasopressin secretion (antidiuretic hormone, ADH) from the pituitary gland, resulting in dehydration and hypernatremia (12, 13). During continued alcohol consumption, however, inhibition of ADH secretion diminishes. Increased vasopressin concentrations become driven by factors that outweigh alcohol's suppressive effects, including elevated plasma osmolality, nausea, pain, and reduced circulating volume.
As vasopressin concentrations increase, urine osmolality rises and free water clearance decreases. Consequently, hyponatremia develops and is observed in approximately 17% of patients with alcohol use disorder (1).
Treatment of hyponatremia in patients with alcohol use disorder follows the same principles as treatment of hyponatremia from other causes. It is important to determine whether hyponatremia reflects a true hypo-osmolar state and whether the kidneys retain the ability to dilute urine. Chronic alcohol consumption is associated with elevated plasma triglyceride concentrations; therefore, pseudohyponatremia should be excluded. Clinically significant pseudohyponatremia should be considered only when triglyceride concentrations exceed 17 mmol/L (1, 14).
Beer potomania is a form of vasopressin-independent hyponatremia that develops in individuals who consume large quantities of beer while maintaining inadequate dietary intake. In laboratory testing, patients with beer potomania may present with severe hyponatremia (plasma sodium concentration—
Sodium chloride administration usually rapidly corrects sodium deficiency; however, overly rapid correction of chronic hyponatremia is dangerous because it can cause osmotic demyelination syndrome, which occurs in approximately 18% of patients. Risk factors for this complication include hypokalemia and hypophosphatemia. To avoid osmotic demyelination, correction of plasma sodium concentration should be limited to 4-6 mmol/L per 24 hours (1).
Potassium Disorders
Hypokalemia develops in nearly 50% of hospitalized patients with alcohol use disorder (AUD) (15). Similar to magnesium and phosphate, potassium concentrations may be normal at hospital admission and subsequently decline over several days because of intracellular potassium shifts. A decrease in potassium concentration after hospitalization reflects depleted potassium stores resulting from inadequate dietary intake, gastrointestinal losses due to vomiting or diarrhea, and urinary potassium losses associated with ketone anion excretion. Concurrent hypomagnesemia further promotes renal potassium wasting. Under normal physiological conditions, intracellular magnesium limits potassium secretion in the distal tubules; therefore, magnesium deficiency increases urinary potassium excretion. Stimulation of beta-2 adrenergic receptors in skeletal muscle due to autonomic nervous system hyperactivity, as well as increased pH associated with respiratory alkalosis, also contribute to the development of hypokalemia in hospitalized patients (1).
The Most Dangerous Complication of Hypokalemia
The most serious complication of hypokalemia is cardiac arrhythmia, which may range from asymptomatic electrocardiographic abnormalities to life-threatening rhythm disturbances. Most patients with alcohol use disorder who develop hypokalemia present with significant potassium deficiency, and many symptoms improve following correction of serum potassium concentrations (16).
The effects of chronic alcohol consumption on skeletal muscle may manifest as acute alcoholic myopathy, characterized by marked muscle weakness without significant pain or swelling. It is important to remember that harmful alcohol consumption can also cause acute rhabdomyolysis, the main manifestations of which include sudden muscle pain, swelling, weakness, a rapid increase in plasma creatine kinase concentration, and myoglobinuria. In these patients, skeletal muscle necrosis and potassium release from damaged myocytes are common causes of hyperkalemia (1).
Electrolyte Imbalances
Acute hypophosphatemia develops in approximately 50% of patients with alcohol use disorder within the first 2-3 days of hospitalization. Phosphate concentrations frequently decrease to <0.32 mmol/L (17). Phosphate deficiency usually results from inadequate intake of phosphorus-rich foods such as meat, poultry, fish, nuts, legumes, and dairy products. Additional contributing factors include chronic diarrhea, vomiting, and reduced intestinal phosphate absorption (1, 18).
Despite depleted phosphate stores and hypophosphatemia, urinary phosphate excretion is often increased because of generalized renal tubular dysfunction. Furthermore, phosphate excretion during metabolic acidosis increases because of enhanced phosphate mobilization from bone (1).
Reduced phosphate reabsorption may also result from vitamin D deficiency, which leads to hypocalcemia and a compensatory increase in circulating parathyroid hormone (PTH) concentrations. Magnesium deficiency may further contribute to phosphate wasting. Experimental studies have shown that isolated magnesium deficiency can reduce phosphate concentrations in skeletal muscle and increase urinary phosphate excretion (19).
The development of phosphate deficiency after hospitalization is primarily related to two mechanisms (18):
- patients frequently receive glucose-containing intravenous fluids, which stimulate insulin secretion and promote intracellular phosphate uptake. Even after discontinuation of glucose administration, hypophosphatemia may develop because of insulin secretion associated with refeeding syndrome;
- acute respiratory alkalosis may develop following alcohol cessation or as a result of other causes of hyperventilation. An increase in extracellular pH leads to a corresponding increase in intracellular pH because carbon dioxide readily diffuses across cell membranes. Intracellular alkalosis stimulates phosphofructokinase activity, thereby increasing glycolysis and promoting intracellular phosphate shifts.
Hypophosphatemia can cause a variety of symptoms, including skeletal muscle weakness and rhabdomyolysis, which likely develop in association with alcohol-induced myopathy. In patients with alcohol use disorder, the abrupt decline in plasma phosphate concentrations helps explain the increased incidence of acute rhabdomyolysis after alcohol cessation. The absence of rhabdomyolysis in otherwise healthy individuals who hyperventilate, or in patients treated for diabetic ketoacidosis, highlights the importance of alcoholic myopathy in the pathogenesis of rhabdomyolysis.
Imbalances in Magnesium and Calcium
Hypomagnesemia develops in approximately 30% of patients with alcohol use disorder (20). In acutely hospitalized patients, plasma magnesium concentrations often decline from normal or mildly decreased levels to severe hypomagnesemia within a few days. These changes reflect depletion of total body magnesium stores.
Magnesium deficiency develops because of inadequate intake of magnesium-rich foods, including green vegetables, nuts, and meat. Chronic diarrhea and steatorrhea reduce gastrointestinal magnesium absorption, while steatorrhea additionally promotes the formation of fatty acid-magnesium complexes. Urinary magnesium losses occur because of reversible ethanol-induced renal tubular dysfunction, which typically resolves within 4 weeks of abstinence (1, 21).
Hypomagnesemia after hospitalization develops as magnesium shifts into cells during correction of acidosis and administration of glucose-containing fluids. Elevated catecholamine concentrations and respiratory alkalosis further contribute to intracellular magnesium shifts (1).
A clinical manifestation of hypomagnesemia is increased neuromuscular excitability, presenting as weakness, tremor, and a positive Trousseau sign. Reduced magnesium concentrations suppress PTH secretion and induce peripheral resistance to PTH. This mechanism explains the persistence of hypocalcemia until hypomagnesemia is corrected. Hypocalcemia is usually readily corrected once normal plasma magnesium concentrations are restored. Persistently elevated plasma ethanol concentrations may also impair responsiveness to PTH (1).
Vitamin D deficiency is an additional factor contributing to hypocalcemia in these patients. Risk factors for vitamin D deficiency include inadequate dietary intake, insufficient sunlight exposure, alcohol-induced alterations in vitamin D metabolism, and impaired absorption in patients with alcoholic steatosis. Rhabdomyolysis may also contribute to hypocalcemia through deposition of calcium phosphate in damaged muscle tissue (1).
Dr. Mindaugas Petrašiūnas
Vilnius University Hospital Santaros Clinics
Prepared according to Palmer BF, Clegg DJ.
Electrolyte Disturbances in Patients with Chronic Alcohol Use Disorder. N Engl J Med. 2017;377(14):1368-1377.
Read more in "Internistas" No. 6, 2018.
