Electrolyte disturbances in patients with chronic alcohol-use disorder

Mindaugas Petrašiūnas

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.

Introduction

Electrolyte disturbances are a common issue in patients with Chronic Alcohol-Use Disorder (DSM-5 classification term encompassing harmful use and addiction). The duration and quantity of alcohol consumption most accurately predict the clinical course of electrolyte disturbances. The most severe electrolyte imbalances occur in patients with inadequate nutrition (insufficient protein, vitamin intake) and concurrent illnesses. Alcohol directly contributes to acid-base and electrolyte imbalances, which can also occur with adequate nutrition. Patients who develop electrolyte disturbances are often hospitalized due to abdominal pain, prolonged nausea, and vomiting. Typically, upon admission, this patient population is diagnosed with metabolic acidosis and hyponatremia. Despite often having a significant electrolyte deficit, their concentrations upon admission may fall within normal limits or only be minimally altered. This electrolyte deficit becomes apparent after acidosis treatment and extracellular fluid volume correction, potentially leading to life-threatening complications. A hallmark of chronic harmful alcohol consumption is a rapid decrease in phosphate, magnesium, potassium, and calcium concentrations within the first 24-36 hours of hospitalization (1). This review discusses the pathophysiology and treatment of electrolyte disturbances.

Acid-Base Imbalances

Individuals with Chronic Alcohol-Use Disorder are prone to various acid-base imbalances. Acid-base disturbances are identified in up to 78% of these patients (2). Alcoholic ketoacidosis occurs in about 25% of patients hospitalized for chronic alcohol-related disorders. This most commonly happens in patients who cease alcohol intake due to abdominal pain, nausea, or vomiting (alcohol-induced gastritis or pancreatitis). Therefore, ethanol may not be detected in hospitalized patients (2). Laboratory tests typically reveal increased anion gap metabolic acidosis, attributed to the accumulation of ketone bodies, lactate, and acetic acid. Additionally, a normal anion gap acidosis may be present due to indirect bicarbonate loss in the urine (3).

Pathophysiology of Alcoholic Ketoacidosis

Development of Ketoacidosis

Intensified mobilization and entry of long-chain fatty acids into the liver lead to the development of ketoacidosis. These fatty acids convert into ketone bodies in the liver. Ketogenesis arises in conditions of insulin deficiency and excess glucagon. Insulin deficiency occurs as glycogen stores decrease due to fasting, with suppressed gluconeogenesis and pancreatic beta-cell insulin secretion inhibition due to sympathetic nervous system activation (3–5).

A crucial factor in ketogenesis is the ratio of reduced to oxidized nicotinamide adenine dinucleotide (NADH/NAD), which increases due to alcohol oxidation to acetaldehyde and acetate. This increased ratio leads to the following changes (6, 7):

• Stimulation of Beta-Hydroxybutyric Acid Production: Qualitative reactions of ketone substances, using sodium nitroprusside (a reaction sensitive only to acetone and acetoacetate), may mislead by attributing increased anion gap acidosis to another cause. Therefore, in cases of suspected chronic alcohol abuse, directly measuring beta-hydroxybutyric acid concentration is beneficial.

• Promotion of Pyruvate Conversion to Lactate: This can result in lactic acidosis, usually mild. If patients with alcohol use disorder present severe lactic acidosis, suspect other causes, such as sepsis, tissue hypoperfusion, or thiamine deficiency.

• Inhibition of Hepatic Gluconeogenesis: This partially leads to hypoglycemia, which develops in about a quarter of patients with ketoacidosis.

Variability in Glucose Concentration

Glucose concentration in patients with alcoholic ketoacidosis can vary – being normal, decreased, or increased (up to 15.3 mmol/l). In a study of 74 patients with alcoholic ketoacidosis, 12% had a glucose concentration <3.3 mmol/l, and 11% had >13.9 mmol/l. These patients did not have diabetes or impaired glucose tolerance (1, 2). Hypoglycemia in alcoholic ketoacidosis often occurs when patients consume a small amount of food after their last alcohol intake. The coexistence of ketoacidosis and hypoglycemia can be life-threatening, as the progression from alcoholic stupor to hypoglycemic coma may go unnoticed (1).

Treatment Principles

The main principles of treating ketoacidosis in patients with chronic alcohol consumption include ensuring hemodynamic stability and interrupting the ketogenic process. Initially, administer 100 mg of thiamine (vitamin B1) intravenously or intramuscularly (8). Thiamine should be given before glucose-containing fluids to prevent Wernicke's encephalopathy, although evidence for these recommendations comes from individual case reports (9, 10). An exception is patients with hypoglycemia, for whom glucose-containing fluids should be administered immediately. Dextrose administration stimulates insulin secretion, reduces the production of ketone bodies, and intensifies the metabolism of formed ketone bodies. This restores the level of bicarbonates, partially correcting metabolic acidosis. A 5% intravenous dextrose solution is typically administered at a rate of 7-7.5 g/h, usually correcting acidosis within 12-24 hours. A 0.9% NaCl solution restores the extracellular fluid deficit, typically developing due to vomiting (vomiting frequency in this patient population is about 73%) and loss of Na and K with beta-hydroxybutyrate and acetoacetate salts through the kidneys. Additionally, blood volume restoration reduces catecholamine and glucagon levels, which stimulate ketogenesis (11). Dextrose solutions should not be administered to only a small portion of patients with hyperglycemia and severe hypokalemia, as insulin would decrease potassium levels. Insulin administration is contraindicated as it could further reduce potassium, phosphorus, and magnesium levels (1, 8-10).

Administer bicarbonates only when necessary, as the metabolism of lactate and ketone bodies leads to endogenous bicarbonate synthesis. Mild normal anion gap acidosis may persist after anion gap correction due to indirect bicarbonate loss in the urine. Renal bicarbonate loss usually normalizes within 24-36 hours (1).

Sodium Imbalance

Acute alcohol consumption promotes water diuresis due to suppression of vasopressin (antidiuretic hormone - ADH) release from the pituitary, resulting in dehydration and hypernatremia (12, 13). During continued alcohol consumption, the suppression of ADH release decreases - increased vasopressin concentration is influenced by factors that outweigh alcohol's inhibitory effect (e.g., increased plasma osmolality, nausea, pain, decreased circulating volume). In these patients, the increasing vasopressin concentration leads to increased urine osmolality and decreased free water clearance. This leads to hyponatremia (about 17% of patients with chronic alcohol use disorder) (1). The treatment of hyponatremia in patients with chronic alcohol use disorder is the same as for hyponatremia due to other causes. When treating a patient with hyponatremia, it is important to determine whether hyponatremia indicates hypoosmolar state or if the kidneys' ability to dilute urine is intact. Chronic alcohol consumption is associated with increased plasma triglyceride concentrations, so it is important to differentiate from pseudohyponatremia. Clinically significant pseudohyponatremia should only be diagnosed when triglyceride concentration is >17 mmol/l (1, 14). Beer potomania is a vasopressin-independent hyponatremia that develops in individuals who drink large amounts of beer without adequate food intake. In laboratory tests, patients with beer potomania may have severe hyponatremia (plasma Na concentration -     Sodium chloride usually rapidly corrects decreased sodium concentration, but rapid correction of prolonged hyponatremia is dangerous as it can cause osmotic demyelination, which occurs in about 18% of patients. Risk factors for this complication are hypokalemia and hypophosphatemia. To avoid osmotic demyelination, it is important to limit the correction of plasma sodium concentration to 4-6 mmol per 24 hours (1).

Potassium Imbalance

Hypokalemia develops in almost 50% of hospitalized patients with chronic alcohol use disorder (15). Like magnesium and phosphates, potassium concentration upon admission to the hospital may be normal and later decrease over several days due to potassium movement into cells. A decrease in potassium concentration after hospitalization indicates depleted reserves, which develop due to inadequate potassium intake from food, gastrointestinal loss due to vomiting or diarrhea, potassium excretion in the urine (ketone anion salts). Concurrent hypomagnesemia promotes potassium excretion in the urine. Under normal circumstances, intracellular magnesium limits potassium secretion in the distal tubules, but with insufficient magnesium concentration, potassium excretion in the kidneys increases. Stimulation of beta-2 adrenergic receptors in skeletal muscles (hyperactivity of the autonomic nervous system) and increased pH (respiratory alkalosis) also contribute to the development of hypokalemia in hospitalized patients (1). The most dangerous complication of hypokalemia is cardiac rhythm disturbances, which can range from asymptomatic ECG changes to life-threatening arrhythmias. Most patients with chronic alcohol use disorder are found to have severe hypokalemia - many symptoms improve after potassium concentration is restored (16). The effect of chronic alcohol use on skeletal muscles can manifest as acute myopathy, characterized by severe weakness without muscle pain or swelling. It is important to remember that harmful alcohol consumption can also cause acute rhabdomyolysis, whose main symptoms are sudden muscle pain, swelling, weakness, along with a sudden increase in plasma creatine kinase concentration and myoglobinuria. For these patients, skeletal muscle necrosis and potassium leakage from myocytes are common causes of hyperkalemia (1).

Phosphate concentration disorders

Due to chronic alcohol use, acute hypophosphatemia occurs in 50% of patients within the first 2-3 days after hospitalization. Phosphate concentration often drops to <0.32 mmol/l (17). Phosphate deficiency usually develops due to inadequate consumption of phosphorus-containing products (meat, poultry, fish, nuts, beans, dairy products). Additional factors contributing to hypophosphatemia include chronic diarrhea, vomiting, reduced intestinal phosphate absorption (1, 18). Despite low phosphorus reserves and hypophosphatemia, phosphorus excretion in the urine is usually increased due to generalized dysfunction of kidney tubules. In addition, renal phosphate excretion in metabolic acidosis is increased due to intensified phosphate mobilization from bones (1). Reduced phosphate reabsorption may be due to vitamin D deficiency, which, when resulting in hypocalcemia, leads to increased circulating parathyroid hormone (PTH) concentration. Decreased magnesium concentration can also contribute to phosphate excretion. Experimental data show that selective magnesium deficiency can lead to decreased skeletal muscle phosphate and increased urinary excretion (19). The emergence of phosphate deficiency after hospitalization is due to 2 main reasons (18): •    these patients usually receive dextrose-containing fluids, which promote insulin secretion and phosphate entry into cells. If dextrose solutions are discontinued, hypophosphatemia can develop due to insulin secretion induced by refeeding syndrome; •    acute respiratory alkalosis is caused by discontinuation of alcohol use or other causes of hyperventilation. Extracellular pH increase leads to a similar pH change in cells due to the diffusion of carbon dioxide through cell membranes. Intracellular alkalosis stimulates phosphofructokinase, which activates glycolysis and phosphate movement into cells. Hypophosphatemia causes various symptoms, such as skeletal muscle weakness and rhabdomyolysis, likely developing due to ethanol-induced myopathy. In patients with alcohol abuse and hypophosphatemia, a sudden decrease in plasma phosphates explains the increased frequency of acute rhabdomyolysis after stopping alcohol consumption. The absence of rhabdomyolysis in healthy patients who hyperventilate or in patients treated for diabetic ketoacidosis indicates the importance of alcoholic myopathy in the development of rhabdomyolysis.

Magnesium and calcium balance disorders

Hypomagnesemia develops in about 30% of patients with chronic alcohol use disorder (20). Plasma magnesium concentration usually decreases from normal or slightly reduced to severe hypomagnesemia within a few days of emergency hospitalization. Such changes in magnesium concentration reflect depletion of total body magnesium reserves. Magnesium reserves decrease due to inadequate consumption of magnesium-rich foods, such as green vegetables, nuts, meat. Chronic diarrhea and steatorrhea reduce gastrointestinal absorption, and the latter also leads to the formation of fatty acids and magnesium complexes. Magnesium is lost in the urine due to reversible ethanol-induced tubular dysfunction, which resolves within 4 weeks of abstinence (1, 21). Hypomagnesemia after hospitalization develops as magnesium enters cells when acidosis is corrected and glucose-containing fluids are administered. Increased catecholamine concentration and respiratory alkalosis contribute to magnesium movement into cells as well (1). A clinical sign of hypomagnesemia is neuromuscular irritability, manifested as weakness, tremors, and a positive Trousseau sign. Decreased magnesium concentration suppresses PTH secretion and induces peripheral resistance. This explains the persistence of hypocalcemia until hypomagnesemia is corrected. Hypocalcemia is easily corrected when normal plasma magnesium concentration is restored. Elevated residual plasma ethanol concentration can also limit the response to PTH (1). For these patients, vitamin D deficiency is an additional factor leading to hypocalcemia. Risk factors for vitamin D deficiency include inadequate intake through diet, lack of direct sunlight exposure, alcohol's effect on vitamin D metabolism, and reduced absorption in patients with alcoholic steatorrhea. Rhabdomyolysis can cause hypocalcemia due to calcium phosphate deposition in damaged muscle tissue (1).

Treatment of patients with mixed electrolyte imbalances

Phosphate, magnesium, potassium, calcium deficiency in these patients should be corrected as much as possible with oral electrolyte supplements. Oral sodium and potassium phosphate preparations containing 30–80 mmol of phosphates can be administered daily. Intravenous phosphates may be necessary for patients with life-threatening hypophosphatemia symptoms (muscle weakness, signs of rhabdomyolysis, respiratory failure, hemolytic anemia), and laboratory test results show a significant decrease in plasma phosphate concentration (<0.32 mmol/l). For such patients, the administration of 42–67 mmol of phosphates over 6–9 hours, but not exceeding 90 mmol/day, is appropriate to avoid hyperphosphatemia and its complications (hypocalcemia, acute kidney injury, arrhythmias) (1, 18). The treatment of electrolyte imbalances is summarized in Table 1. Table 1. Electrolyte imbalances in patients with chronic alcohol use disorder (1)

Disorder	Mechanism	Comment	Treatment
Acid-Base Balance
Alcoholic ketoacidosis	Increased anion gap metabolic acidosis due to decreased insulin/glucagon ratio	Increased NADH/NAD ratio promotes beta-hydroxybutyric acid production	5% dextrose with 0.9% NaCl infusion
Lactic acidosis	Increased NADH/NAD ratio due to ethanol metabolism	Average lactate concentration is 3 mmol/l; consider the possibility of sepsis or thiamine deficiency at higher concentrations	5% dextrose with 0.9% NaCl infusion
Hyperchloremic normal anion gap metabolic acidosis	Indirect bicarbonate loss due to urinary excretion of ketone acid salts	Renal bicarbonate regeneration reduces the deficit	Conservative treatment
Metabolic alkalosis	Vomiting	Anion gap increase greater than decrease in bicarbonate concentration, when alcoholic ketoacidosis is also present	Volume restoration with chloride-containing fluids, treatment of hypokalemia
Respiratory alkalosis	Alcohol cessation, chronic liver disease, pain, sepsis	Primary disturbance is often present in mixed acid-base disorders	Benzodiazepines after alcohol cessation, treatment of concurrent disorders
Electrolyte Imbalances
Hypophosphatemia	Alcohol-induced phosphate loss in urine, magnesium deficiency, acidemia, increased PTH concentration, inadequate nutrition, decreased gastrointestinal absorption, cellular shift due to insulin secretion, respiratory alkalosis, beta-2 adrenergic stimulation	Muscle weakness, rhabdomyolysis, tissue ischemia, hemolysis, heart dysfunction, urinary phosphate excretion >100 mg per 24 hours	Preference for oral preparations; if complications arise, administer 42–67 mmol of phosphates over 6–9 hours, not exceeding 90 mmol/day, to avoid lowering calcium and magnesium concentrations
Hypomagnesemia	Alcohol-induced magnesium loss in urine, phosphate deficiency, decreased gastrointestinal absorption, cellular shift due to insulin secretion, respiratory alkalosis, beta-2 adrenergic stimulation	Persistent renal magnesium loss can last for weeks; recurrent hypomagnesemia after correction indicates >25 mg/day magnesium excretion, indicating urinary magnesium loss	Oral preparations are the first choice, IV magnesium is reserved for patients with identified arrhythmias or neuromuscular irritability
Hypocalcemia	Decreased PTH concentration due to magnesium deficiency, alcohol-induced calcium loss in urine, vitamin D deficiency	Correction in case of low albumin concentration	Correction of magnesium deficit, vitamin D levels
Hypokalemia	Potassium loss in urine, magnesium deficiency, diarrhea, cellular shift, correction of acidosis, respiratory alkalosis, beta-2 adrenergic stimulation	Low or normal potassium levels in patients with rhabdomyolysis indicate a significant overall potassium deficit; >30 mmol/day potassium concentration in urine indicates urinary potassium loss	Oral preparations, for complications IV potassium chloride 10–20 mmol/hour; administer potassium before bicarbonates in patients with acidosis
Hyponatremia	Increased ADH secretion due to decreased blood volume	Increased risk of osmotic demyelination Restore electrolyte volume, increase protein intake; limit correction to 6-8 mmol in the first 24 hours.

Summary

Patients with chronic alcohol use disorder may develop various acid-base and electrolyte imbalances. It is important to remember that these are characteristic not only of patients with unbalanced nutrition and concurrent illnesses but also of well-nourished individuals, as alcohol consumption directly contributes to the pathophysiology of these imbalances. Initiating initial treatment in these patients often reveals a deficiency in multiple electrolytes. Understanding the pathophysiological characteristics of these imbalances allows the physician to choose appropriate therapy and avoid potentially dangerous complications of these alterations. Publication "Internistas"

References:

1.    Palmer BF, Clegg DJ. Electrolyte Disturbances in Patients with Chronic Alcohol-Use Disorder. N Engl J Med. 2017;377(14):1368-1377 2.    Wrenn KD, Slovis CM, Minion GE, et al. The syndrome of alcoholic ketoacidosis. Am J Med 1991; 91:119-28. 3.    Halperin ML, Hammeke M, Josse RG, et al. Metabolic acidosis in the alcoholic: a pathophysiologic approach. Metabolism 1983; 32:308-15. 4.    Foster DW, McGarry JD. The metabolic derangements and treatment of diabetic ketoacidosis. N Engl J Med 1983; 309:159-69. 5.    Palmer BF, Clegg DJ, Taylor SI, et al. Diabetic ketoacidosis, sodium glucose transporter-2 inhibitors and the kidney. J Diabetes Complications 2016;30: 1162-6. 6.    Umpierrez GE, DiGirolamo M, Tuvlin JA, et al. Differences in metabolic and hormonal milieu in diabetic- and alcohol-induced ketoacidosis. J Crit Care 2000; 15:52. 7.    Krebs HA, Freedland RA, Hems R, et al. Inhibition of hepatic gluconeogenesis by ethanol. Biochem J 1969; 112:117. 8.    Mehta A, Emmett M. Fasting ketosis and alcoholic ketoacidosis In: UpToDate, Post, TW (Ed), UpToDate, Waltham, MA, 2018. 9.    Schabelman E, Kuo D. Glucose before thiamine for Wernicke encephalopathy: a literature review. J Emerg Med 2012; 42:488. 10.    Hack JB, Hoffman RS. Thiamine before glucose to prevent Wernicke encephalopathy: examining the conventional wisdom. JAMA 1998; 279:583. 11.    Young A. Inhibition of glucagon secretion. Adv Pharmacol 2005; 52:151. 12.    Eisenhofer G, Johnson RH. Effect of ethanol ingestion on plasma vasopressin and water balance in humans. Am J Physiol 1982;242: 522-527. 13.    Helderman JH, Vestal RE, Rowe JW, et al. The response of arginine vasopressin to intravenous ethanol and hypertonic saline in man: the impact of aging. J Gerontol 1978; 33:39-47. 14.    Sterns RH. Diagnostic evaluation of adults with hyponatremia. In: UpToDate, Post, TW (Ed), UpToDate, Waltham, MA, 2018. 15.    Elisaf M, Liberopoulos E, Bairaktari E, et al. Hypokalaemia in alcoholic patients. Drug Alcohol Rev 2002;21: 73-6. 16.    Rubenstein AE, Wainapel SF. Acute hypokalemic myopathy in alcoholism: a clinical entity. Arch Neurol 1977; 34:553-5. 17.    Elisaf MS, Siamopoulos KC. Mechanisms of hypophosphataemia in alcoholic patients. Int J Clin Pract 1997; 51:501-3. 18.    Yu ASL, Stubbs JR. Hypophosphatemia in the alcoholic patient. In: UpToDate, Post, TW (Ed), UpToDate, Waltham, MA, 2018. 19.    Cronin RE, Ferguson ER, Shannon WA Jr, et al. Skeletal muscle injury after magnesium depletion in the dog. Am J Physiol 1982;243:F113-F120. 20.    Elisaf M, Merkouropoulos M, Tsianos EV, et al. Pathogenetic mechanisms of hypomagnesemia in alcoholic patients. J Trace Elem Med Biol 1995; 9:210. 21.    Yu ASL. Causes of Hipomagnesemia. In: UpToDate, Post, TW (Ed), UpToDate, Waltham, MA, 2018.