sign in sign up
<<
Home , Alcoholic ketoacidosis, Magnesium, Malt beer, Potomania

The new england journal of medicine

Review Article

Julie R. Ingelfinger, M.D., Editor Disturbances in Patients with Chronic -Use Disorder

Biff F. Palmer, M.D., and Deborah J. Clegg, Ph.D.​​

From the Department of Internal Medi- lectrolyte disturbances are common occurrences in patients cine, University of Texas Southwestern with chronic alcohol-use disorder, and the quantity and duration of a given Medical Center, Dallas (B.F.P.); and the Department of Biomedical Sciences, Dia- patient’s alcohol consumption generally determine the clinical significance betes and Obesity Research Institute, E of these disturbances. Electrolyte abnormalities tend to be most severe in patients Cedars–Sinai Medical Center, Los Angeles in whom protein-calorie malnutrition, deficiency, and intercurrent illness (D.J.C.). Address reprint requests to Dr. Palmer at the Department of Internal Med- play contributory roles. However, electrolyte disorders can also be present in pa- icine, University of Texas Southwestern tients who eat three nutritious meals per day; this implicates alcohol as having a Medical Center, 5323 Harry Hines Blvd., direct role in the underlying pathophysiological derangements. The prevalence of Dallas, TX 75390, or at ­biff​.­palmer@​ ­utsouthwestern​.­edu. among adults in the is estimated to be 14%, and approximately one quarter of admissions to community hospitals are related to N Engl J Med 2017;377:1368-77. DOI: 10.1056/NEJMra1704724 alcohol. Therefore, it is of paramount importance for clinicians to be familiar with 1,2 Copyright © 2017 Massachusetts Medical Society. the genesis and treatment of alcohol-related electrolyte disorders. Patients in whom electrolyte disorders develop are most commonly admitted to the hospital for reasons such as abdominal pain or the onset of persistent and that may or may not be related to alcohol use. Although metabolic and are often present on admission, other plasma concen- trations may be normal or only minimally deranged, despite hidden deficits that are often large. After the initiation of designed to treat acidosis and restore volume, deficits are unmasked; these deficits may result in life- threatening complications. Telltale signs of chronic alcohol ingestion are precipi- tous decreases in plasma concentrations of , , , and in the first 24 to 36 hours after admission. The pathophysiology account- ing for this temporal sequence of electrolyte disturbances is discussed below, with emphasis on the interrelationship between electrolyte disorders and approaches to therapy.

Acid– Disturbances Persons with chronic alcohol-use disorder are prone to a variety of acid–base distur- bances; one study showed that mixed disturbances were present in 78% of patients with this disorder.3 Alcoholic , which is present in 25% of patients who are admitted to the hospital with an alcohol-related disorder,4,5 was diagnosed approximately twice per week over a 9-month in one inner-city university- affiliated hospital.3 Alcoholic ketoacidosis commonly occurs in patients who have discontinued alcohol ingestion before presentation, and such patients often present with abdominal pain and vomiting due to alcohol-induced or . Nutritional intake is typically poor before admission, and laboratory features indi- cate an anion-gap that is primarily due to accumulation of keto- acids and lactic acid, with a smaller contribution from .6 In patients with protracted vomiting, elevations in the are greater than the decrease in

1368 n engl j med 377;14 nejm.org October 5, 2017 The New England Journal of Medicine Downloaded from nejm.org by LUIS ERNESTO GONZALEZ SANCHEZ on November 7, 2017. For personal use only. No other uses without permission. Copyright © 2017 Massachusetts Medical Society. All rights reserved. Electrolyte Disturbances in Alcohol-Use Disorder

Figure 1. Mechanisms of Alcoholic Ketoacidosis. Alcohol withdrawal Alcoholic ketoacidosis results when mobilization of fatty ↓Glycogen stores Starvation acids occurs in conjunction with a ketogenic state in Volume depletion the liver; this is caused by a decreased ratio of insulin to glucagon. Reduced insulin levels result from glyco- Cortisol gen depletion from starvation, decreased gluconeo- Growth hormone genesis, and suppression of insulin release from the pancreatic beta cells due to activation of sympathetic nerves. Activation of the sympathetic nervous system Sympathetic-nerve and increased levels of cortisol, growth hormone, and activation ethanol account for the increased magnitude of fatty Lipolysis acid mobilization, as compared with simple starvation.7 Ethanol to an increased ratio of NADH ↓Insulin to oxidized nicotinamide adenine dinucleotide (NAD) ↑Glucagon that contributes to decreased and Fatty acids facilitates production of ketone bodies, specifically ↓Gluconeogenesis β-hydroxybutyric acid. Glycogen depletion, reductions in insulin release, and increased autonomic tone pro- Ketogenic state vide a stimulatory effect for glucagon release. Increased Ethanol NAD glucagon levels, along with the increased ratio of NADH NADH to NAD, enhance the ketogenic capacity of the liver. NADH NAD Acetaldehyde When ketoacids enter the extracellular fluid, the dis- NAD sociated reacts with bicarbonate to generate dioxide and water. As a consequence, the bicar- NADH Acetate bonate concentration decreases and the level of β-hydroxybutyric acid + NaHCO3 the ketoacid concentration increases; this accounts for the increase in the anion gap. The excretion of the keto- NaβOHB H CO acid salt into the urine with or potassium (rather 2 3 than hydrogen or ammonium) produces contraction of the extracellular fluid volume and stimulates renal re- CO2 and H2O tention of dietary sodium chloride. Volume contraction loss through lungs and retention of sodium chloride, combined with exog- enous loss of ketoacid , result in the generation of a mixed anion-gap acidosis and hyperchloremic normal- gap metabolic acidosis. H2CO3 denotes carbonic acid, Indirect loss of NaHCO3 NaβOHB sodium beta-hydroxybutyrate, and NaHCO3 .

the plasma bicarbonate concentration because of and glucagon excess (Fig. 1).11,12 Ketogenesis is the concomitant presence of metabolic . also facilitated by the metabolism of alcohol to A normal anion-gap acidosis may also be present acetaldehyde and acetate, resulting in an in- because of indirect loss of bicarbonate in the creased ratio of reduced NADH to oxidized nico- urine (Fig. 1).8 tinamide adenine dinucleotide (NAD), which Despite the presence of metabolic acidosis, leads to preferential formation of β-hydroxybutyric only approximately 50% of patients have acide- acid. The consequent increase in the level of mia, and almost one third of patients have alka- β-hydroxybutyrate is important to recognize, lemia.3,9 , which is frequent- since the use of strips or tablets that use a nitro- ly the primary disorder in a mixed disturbance, prusside reaction, which is only sensitive to is a manifestation of alcohol withdrawal, pain, acetoacetate, to detect the presence of ketones severe liver disease, or underlying sepsis, all of may cause the clinician to mistakenly attribute which can have contributory roles in the distur- an anion-gap acidosis to some other cause. Direct bance.10 measurement of β-hydroxybutyrate levels should The development of ketoacidosis results from be performed when is suspected. increased mobilization and delivery of long- The increased ratio of NADH to NAD also favors chain fatty acids to the liver, where are conversion of pyruvate to lactate, which accounts activated to convert these acids to ketone bodies; for increased production of hepatic lactate. Periph- this occurs under conditions of insulin deficiency eral tissues can oxidize lactic acid, so the degree

n engl j med 377;14 nejm.org October 5, 2017 1369 The New England Journal of Medicine Downloaded from nejm.org by LUIS ERNESTO GONZALEZ SANCHEZ on November 7, 2017. For personal use only. No other uses without permission. Copyright © 2017 Massachusetts Medical Society. All rights reserved. The new england journal of medicine

Box 1. A 52-year-old homeless man presents to the emergency department plasma potassium, phosphorus, and magnesium ­reporting weakness. levels (Box 1). Bicarbonate therapy is not usually required, He typically drinks 1 pint of whisky daily. He noted the onset of epigastric pain since the metabolism of lactate and ketoacid 3 days previously but continued to drink until 1 day before presentation, when nausea and persistent vomiting developed. He reports having had no in- anions leads to the production of endogenous take over the previous 24 hours. The physical examination is noteworthy for a bicarbonate. In fact, exogenous bicarbonate ther- blood pressure of 138/90 mm Hg while the patient is supine and 110/74 mm Hg apy can be complicated by reductions in the while he is standing. The pulse rate is 105 beats per minute. The remainder of the examination reveals tenderness on palpation in the epigastrium but no re- ionized fraction of calcium and plasma potassium bound tenderness. The laboratory values on admission are as follows: sodium, concentration. A mild normal-gap acidosis may 142 mmol per liter; potassium, 3.8 mmol per liter; chloride, 92 mmol per liter; remain after correction of the anion gap owing bicarbonate, 22 mmol per liter; creatinine, 1.2 mg per deciliter (106 μmol per liter); and blood urea , 22 mg per deciliter (7.9 mmol per liter). A measurement to indirect loss of bicarbonate in the urine. How- of arterial blood gas shows a pH of 7.47 and a partial pressure of ever, bicarbonate regeneration by the will of 28 mm Hg. The acid–base disturbance and the type of fluid therapy that is usually correct the bicarbonate deficit over a period appropriate for correction of the underlying disorders are noted in Case 1 in the Supplementary Appendix. of 24 to 36 hours. Many patients with chronic alcohol-use disorder will seek alternative forms of alcohol to satisfy their addiction; therefore, clinicians should be aware of the clinical features of tends to be mild.6 Thus, severe of ingestion of other toxic (Table 1). lactic acidosis in a patient with alcohol abuse suggests the presence of other issues such as sep- Phosphorus Disturbances sis, tissue hypoperfusion, or deficiency. An increased ratio of NADH to NAD leads to Acute hypophosphatemia develops in up to 50% an inhibitory effect on hepatic gluconeogenesis of patients over the first 2 to 3 days after hospi- that predisposes patients to hypoglycemia, which talization for problems related to chronic alco- occurs in approximately one quarter of patients hol overuse.15,16 Deficits in total-body stores of with alcoholic ketoacidosis.13 Patients who present phosphorus are most often due to inadequate with hypoglycemia often have had reduced food dietary intake of phosphate-rich such as intake for 14 to 24 hours after the last ingestion meats, poultry, fish, nuts, beans, and dairy of alcohol. In such patients, hypoglycemia can products. In addition, use of , chronic be life threatening because the transition of , vomiting, or all of these may further alcoholic stupor to hypoglycemic coma may be limit phosphorus intake. imperceptible. Despite low body stores of phosphorus and Initial approaches to treating ketoacidosis in a hypophosphatemia, excretion of urinary phos- patient with chronic alcohol-use disorder should phate is usually increased because of generalized be centered on correcting any hemodynamic in- tubular dysfunction, which is most often mani- stability and terminating the ketogenic process. fested as , aminoaciduria, hypermag- The administration of 5% dextrose in 0.9% nor- nesuria, hypercalciuria, and a decreased renal mal saline will generally restore hemodynamic threshold for phosphate excretion.17 The described stability and begin to correct metabolic alkalo- tubular abnormalities may be related to dysfunc- sis, if present. Restoration of volume decreases tion of apically located transporters and to de- sympathetic-nerve output, thereby removing an creased activity of the sodium–potassium ATPase, inhibitory effect on insulin release. Dextrose con- both of which are related to structural changes tained in the intravenous fluid provides a rapid in the phospholipid bilayer of the cell mem- additional stimulus for release of insulin. Intra- brane.18,19 In addition, excretion of renal phos- venous dextrose administered at a rate of 7.0 to phate is increased in patients with metabolic 7.5 g per hour usually reverses the acidosis in 12 acidosis caused by increased mobilization of phos- to 24 hours.14 Thiamine should be administered phate from and a direct gating effect of pH before administering -containing solutions on the NaPi-2a and NaPi-2c cotransporters in the in order to decrease the risk of precipitating proximal tubule.20 These abnormalities often re- Wernicke’s encephalopathy or Korsakoff’s syn- solve over several weeks of alcohol abstinence.17 drome. Exogenous insulin should not be admin- Decreased reabsorption of phosphate can istered, since it can contribute to a decrease in also be due to the action of increased levels of

1370 n engl j med 377;14 nejm.org October 5, 2017 The New England Journal of Medicine Downloaded from nejm.org by LUIS ERNESTO GONZALEZ SANCHEZ on November 7, 2017. For personal use only. No other uses without permission. Copyright © 2017 Massachusetts Medical Society. All rights reserved. Electrolyte Disturbances in Alcohol-Use Disorder

Table 1. Characteristics of Alcohols Ingested in Patients with Chronic Alcohol-Use Disorder.

Acid–Base Disturbances and Alcohol Other Features Osmolar Gap Treatment Ethanol Mixed disturbances (includ- Increased by 11 mOsm per 5% dextrose in 0.9% (normal) saline; ing anion-gap acidosis, kilogram per change of to prevent alco- normal-gap acidosis, and 50 mg per deciliter in hol withdrawal respiratory and metabolic ­alcohol concentration alkalosis) common Ethylene glycol Anion-gap metabolic acidosis Increased by 8 mOsm per Administration of fomepizole to inhib- in association with acute kilogram per change of it alcohol dehydrogenase and limit kidney injury and calcium 50 mg per deciliter in formation of toxic metabolites; crystals in urine ­alcohol concentration ­hemodialysis Methanol Anion-gap metabolic acidosis Increased by 16 mOsm per Administration of fomepizole to inhib- in association with toxic kilogram per change of it alcohol dehydrogenase and limit effects in the eye that may 50 mg per deciliter in formation of toxic metabolites; cause blindness ­alcohol concentration ­hemodialysis Isopropanol No acidosis; positive urine Increased by 8 mOsm per Conservative management and plasma ketones due kilogram per change of to presence of 50 mg per deciliter in ­alcohol concentration

circulating parathyroid hormone, the result of skeletal muscles and rhabdomyolysis, which are caused by deficiency. probably due to the presence of an underlying can also be a cause of ethanol-induced myopathy. In muscle-biopsy sam- phosphaturia. Experimental data indicate that ples obtained from patients with chronic alcohol- selective magnesium deficiency can to use disorder and from dogs that have received marked reductions in skeletal-muscle phosphate alcohol, there are significant reductions in phos- content and increases in excretion of urinary phate and magnesium content in skeletal mus- phosphate.21 Furthermore, magnesium deficiency cles; these reductions are accompanied by in- can cause a state of functional hypoparathyroid- creased amounts of sodium and chloride and a ism, and in such patients, renal resistance to the greatly increased calcium content22-24 (Table S1 effects of parathyroid hormone can increase in the Supplementary Appendix, available with plasma phosphate levels and cause an increase the full text of this article at NEJM.org). In pa- in the filtered load of phosphate, thereby con- tients with hypophosphatemia who have been tributing to inappropriate phosphaturia. abusing alcohol, a sudden decrease in the plasma Unmasking of the total-body deficit in phos- phosphate level explains the increased frequency phorus after hospital admission is multifactorial. of acute rhabdomyolysis during alcohol with- Normalization of pH in patients with ketoacido- drawal. The absence of rhabdomyolysis in healthy sis will cause an intracellular shift of phosphate. persons who hyperventilate or in patients treat- Increased intracellular pH stimulates the rate- ed for in whom a rapid limiting for glycolysis, necessitating decrease in plasma phosphate levels also devel- cellular phosphate uptake in order to phosphory- ops suggests that underlying muscle injury is re- late glucose, since intracellular stores are de- quired for the development of this complication pleted. Release of insulin after administration of and is unique to persons with chronic alcohol- glucose-containing fluids will exacerbate this use disorder. shift. In patients who have alcohol withdrawal, Hypophosphatemia also contributes to the the development of respiratory alkalosis and in- development of metabolic acidosis. Intracellular creased levels of circulating catecholamines pro- deficiency of phosphate impairs generation of vide additional stimulatory effects for the uptake triphosphate (ATP) from adenosine of cellular phosphate. diphosphate (ADP). Decreased cellular ATP stim- Hypophosphatemia leads to a variety of man- ulates phosphofructokinase activity, enhancing ifestations that may include weakness in the glycolysis and lactate production. In red cells,

n engl j med 377;14 nejm.org October 5, 2017 1371 The New England Journal of Medicine Downloaded from nejm.org by LUIS ERNESTO GONZALEZ SANCHEZ on November 7, 2017. For personal use only. No other uses without permission. Copyright © 2017 Massachusetts Medical Society. All rights reserved. The new england journal of medicine

cellular phosphate deficiency lowers the content parathyroid hormone; this explains the persistence of 2,3-diphosphoglycerate, and reductions in the of hypocalcemia until the magnesium deficit is level of 2,3-diphosphoglycerate increase the af- repaired. Hypocalcemia will correct in minutes finity of hemoglobin for by shifting the to hours after the restoration of normal concen- oxygen disassociation curve to the left, thereby trations of plasma magnesium. Residual high predisposing the patient to tissue ischemia and plasma concentrations of ethanol also limit the increasing lactic acid production. As phosphate hypercalcemic response to parathyroid hormone. shifts into cells, levels of urinary phosphate de- Vitamin D deficiency should be considered as crease, reducing the buffering capacity of the a contributing factor in patients with hypocalce- kidneys for hydrogen secretion, although this mia. Risk factors include poor dietary intake of effect tends to be mild. vitamin D, lack of exposure to sunlight, and di- rect effects of alcohol on vitamin D metabolism Magnesium and Calcium or decreased absorption in patients with alcohol- Disturbances related steatorrhea. Rhabdomyolysis can cause hypocalcemia owing to the deposition of calcium Hypomagnesemia occurs in almost one third of phosphate in injured muscle tissue. patients with chronic alcohol-use disorder.17,25 In acutely ill hospitalized patients, the plasma mag- Potassium Disturbances nesium concentration typically decreases from normal or only slightly reduced values to severely occurs in nearly 50% of hospital- reduced levels over several days, unmasking total- ized patients with chronic alcohol-use disorder.17,26 body depletion of magnesium (Table 2). De- As with magnesium and phosphorus, plasma creased body stores of magnesium result from potassium concentrations may be normal or insufficient consumption of magnesium-enriched only slightly reduced on admission, only to de- foods, such as leafy vegetables, nuts, and crease over several days because of an inward meats. In addition, gastrointestinal absorption cellular shift that unmasks decreased total-body is decreased in patients with chronic diarrhea stores. Potassium deficiency results from inade- or steatorrhea, the latter of which causes the quate intake and gastrointestinal losses due to formation of fatty acid–magnesium complexes. diarrhea. Urinary losses also contribute and are Losses of renal magnesium are present owing to multifactorial. Vomiting and ketoacidosis lead to reversible ethanol-induced tubular dysfunction. increased loss of urinary potassium that is due Although selective magnesium deficiency can to the coupling of increased mineralocorticoid lead to renal phosphate wasting, the reverse is levels and increased delivery of sodium to the also true. Selective depletion of phosphate from distal nephron (Table S2 in the Supplementary skeletal muscle leads to reductions in the mag- Appendix). Increased sodium delivery is due to nesium and ATP content in muscle; this accounts the nonreabsorbable anion effect of bicarbonate for the frequent coexistence of these disorders.22-24 in patients with vomiting and of ketoacid salts The development of hypomagnesemia after in patients with alcoholic ketoacidosis.27 admission to the hospital is due to the intracel- Coexistent magnesium deficiency also causes lular shift brought about by correction of acido- inappropriate kaliuresis. Under normal circum- sis and administration of glucose-containing stances, intracellular magnesium blocks the ROMK fluids leading to insulin release. Increased cate- channels, which are located on the apical mem- cholamines and respiratory alkalosis accompa- brane of the distal nephron and limit outward nying alcohol withdrawal also contribute to the potassium secretion from the distal tubular intracellular shift. cells.28 Magnesium deficiency reduces intracellu- The clinical manifestations of hypomagnese- lar magnesium, which releases the magnesium- mia are primarily neuromuscular irritability man- mediated inhibition of ROMK channels, thus ifested by weakness, tremors, and a positive accounting for potassium wasting.

Trousseau’s sign. Magnesium depletion suppress- Stimulation of β2-adrenergic receptors in skel- es release and induces peripheral resistance to etal muscle because of autonomic hyperactivity

1372 n engl j med 377;14 nejm.org October 5, 2017 The New England Journal of Medicine Downloaded from nejm.org by LUIS ERNESTO GONZALEZ SANCHEZ on November 7, 2017. For personal use only. No other uses without permission. Copyright © 2017 Massachusetts Medical Society. All rights reserved. Electrolyte Disturbances in Alcohol-Use Disorder

Table 2. Electrolyte Disturbances in Chronic Alcohol-Use Disorder.*

Disturbance Mechanism or Cause Comment Treatment Acid–base Alcoholic ketoacidosis Anion-gap metabolic acidosis due Increased NADH:NAD ratio ­favors Administer 5% dextrose in 0.9% to decrease in insulin:glucagon formation of β-hydroxybutyric (normal) saline and treat ratio acid other disorders if present Lactic acidosis Increased NADH:NAD ratio due Average lactate level 3 mmol per Administer 5% dextrose in 0.9% to ethanol metabolism ­liter; consider sepsis or thiamine (normal) saline and treat deficiency with higher levels other disorders if present Hyperchloremic normal-gap Indirect loss of bicarbonate due Regeneration of bicarbonate by kid- Provide conservative man­ metabolic acidosis to loss of ketoacid salts in urine neys repairs deficit agement Vomiting Increase in anion gap greater than Restore volume of extracellular decrease in bicarbonate con­ fluid with chloride-containing centration when combined with fluids, correct hypokalemia alcoholic ketoacidosis Respiratory alkalosis Alcohol withdrawal, chronic liver Often the primary disorder in a Administer benzodiazepines disease, pain, sepsis mixed acid–base disturbance for alcohol withdrawal; treat underlying disorders Hypophosphatemia Alcohol-induced urinary loss, mag- Muscle weakness, rhabdomyolysis, Oral supplements preferred; for nesium deficiency, acidemia, tissue ischemia, hemolysis, complications, administer increased parathyroid hormone ­cardiac dysfunction; urine phos- 42–67 mmol phosphate level, nutritional deficiency, phate excretion >100 mg/24 hr over 6–9 hr, not to exceed ­decrease in gastrointestinal or fractional excretion ≥5% indi- 90 mmol/day to avoid de- ­absorption, cellular shift due cates renal wasting crease in calcium and to insulin release, respiratory ­magnesium levels alkalosis, β2-adrenergic stimu- lation Hypomagnesemia Alcohol-induced urinary loss, Persistent renal wasting can last Oral supplements preferred; phosphate deficiency, nutri- several weeks, accounting for ­intravenous magnesium tional deficiency, decreased ­recurrence of hypomagnesemia ­indicated in patients with gastrointestinal absorption, after initial correction; urinary ­ or neuromus­ cellular shift due to insulin magnesium excretion >25 mg/ cular irritability ­release, respiratory alkalosis, 24 hr or fractional excretion >2% β2-adrenergic stimulation indicates renal wasting Hypocalcemia† Decrease in parathyroid hormone Correct for a low albumin concen- Correct the magnesium deficit; level and resistance due tration as follows: corrected correct the deficiency in to magnesium deficiency, ­calcium = serum calcium in mg/dl ­vitamin D alcohol-induced urinary loss, + [0.8 × (4.0 − serum albumin in vitamin D deficiency g/dl)]; bicarbonate therapy can decrease ionized fraction Hypokalemia Urinary loss due to coupling of in- A low or normal potassium level in Oral supplements preferred; for creased distal sodium delivery patients with rhabdomyolysis complications, administer and increased aldosterone level, suggests significant underlying intravenous potassium chlo- magnesium deficiency, diarrhea, total-body deficit of potassium; ride at 10–20 mmol/hr; ad- cellular shift due to insulin re- urinary potassium >30 mmol/ minister potassium before lease, correction of acidosis, 24 hr or urinary potassium: bicarbonate in patients with respiratory alkalosis, β2- creatinine ratio >13 (in millimoles acidemia adrenergic stimulation of potassium per gram of creati- nine) indicates renal wasting Hyponatremia Increased release of Increased risk of osmotic demyelin- Restore volume and increase due to volume depletion‡; ation protein intake; limit rate of ­decreased solute excretion correction to 6–8 mmol in in first 24 hr, to slow rate with 5% dextrose in water, desmo- pressin, or both

* To convert the values for phosphate to millimoles per liter, multiply by 0.3229. NAD denotes oxidized nicotinamide adenine dinucleotide. † Hypercalcemia can be present in patients with volume contraction and quickly resolves after volume resuscitation. ‡ Baroreceptor-independent factors leading to increased vasopressin may be present. These factors include pain, nausea, and the use of med- ications such as selective serotonin reuptake inhibitors.

n engl j med 377;14 nejm.org October 5, 2017 1373 The New England Journal of Medicine Downloaded from nejm.org by LUIS ERNESTO GONZALEZ SANCHEZ on November 7, 2017. For personal use only. No other uses without permission. Copyright © 2017 Massachusetts Medical Society. All rights reserved. The new england journal of medicine

and increased pH due to respiratory alkalosis per liter]). In such patients, administration of 42 contribute to the development of hypokalemia to 67 mmol of phosphate over a 6-to-9-hour after admission to the hospital. Insulin release period, but not exceeding 90 mmol per day, is also contributes to the intracellular shift, an ef- appropriate.30,31 fect that is independent of glucose transport. Close monitoring is required, since intrave- Coexistent phosphate depletion limits insulin nous phosphate therapy can be complicated by release in response to glucose, attenuating the clinically symptomatic hypocalcemia. This risk effect on potassium. is magnified among patients with hypomagne- The most serious manifestation of hypokale- semia, in whom suppressed parathyroid hormone mia is cardiac toxicity, which ranges from asymp- release removes a defense against further de- tomatic electrocardiographic changes to poten- creases in the level of calcium. An initial therapy tially life-threatening arrhythmias. Skeletal-muscle in patients with multiple electrolyte deficiencies toxicity and acute myopathy can occur and are is a solution of 1 liter of 5% dextrose in 0.45% characterized by severe weakness without muscle saline to which is added 20 mmol of potassium pain, tenderness, or swelling. Patients with chron- phosphate and 4 ml of 50% ic alcohol-use disorder often have severe hypoka- (8 mmol of magnesium) administered over a lemia, and many symptoms resolve after potas- period of 8 hours. When magnesium is admin- sium repletion.29 However, can istered intravenously, only a small portion of each precipitate acute rhabdomyolysis, which is heralded dose is retained, and most is excreted in the by the abrupt onset of muscle pain, swelling, urine, since the renal threshold for magnesium and weakness associated with marked elevation excretion is close to the normal plasma concen- of plasma kinase levels and myoglobin- tration. For this reason, as as the persistent uria. In such patients, skeletal-muscle necrosis renal leak due to effects of alcohol that last and subsequent release of potassium is a common several weeks, repeated oral dosing may be re- cause of hyperkalemia. Normal plasma potassi- quired to repair the total-body deficit. um concentrations in patients with rhabdomyoly- sis should arouse suspicions that depletion of Dysnatremias total-body potassium is the underlying cause. Acute ingestion of alcohol induces a water diure- Treatment of Patients sis owing to suppression of circulating vasopres- with Multiple Electrolyte sin levels, predisposing patients to Deficiencies and hypernatremia.32,33 This suppressive effect is absent with repeated exposure or prolonged con- The interplay in phosphorus, magnesium, calcium, tinuous exposure. In these patients, vasopressin and potassium in hospitalized pa- levels increase, resulting in increased urine osmo- tients with chronic alcohol use explains why lality and decreased clearance of free water. As a some, if not all, of these are depleted result, hyponatremia is a common disorder that (Fig. 2). Management should focus on providing occurs in as many as 17% of patients with oral supplementation of the relevant electrolytes chronic alcohol-use disorder.34 Increased levels whenever possible (Box 2). of vasopressin result from factors that override Oral preparations of sodium and potassium the inhibitory effect of alcohol such as increased phosphate containing 30 to 80 mmol of phos- , nausea, pain, and decreased phate can be administered daily in divided doses, effective circulatory volume. and they can be supplemented with , which The approach to hyponatremia in patients is an excellent source of calcium and potassium with chronic alcohol-use disorder is no different and contains approximately 35 mmol per liter of from that used in other patients. Successful phosphorus. Intravenous phosphate repletion may evaluation of the patient requires knowing be necessary in patients who have life-threaten- whether hyponatremia indicates a hypo-osmolar ing manifestations of hypophosphatemia (includ- state, determining whether the ability of the ing muscle weakness, rhabdomyolysis, respira- kidneys to dilute urine is intact, and assessing tory failure, and hemolytic anemia) and in those the volume status of the patient.35 Since alcohol with severe reductions in the plasma phosphate consumption is associated with elevated levels of concentration (<1.0 mg per deciliter [<0.32 mmol plasma triglycerides, pseudohyponatremia must

1374 n engl j med 377;14 nejm.org October 5, 2017 The New England Journal of Medicine Downloaded from nejm.org by LUIS ERNESTO GONZALEZ SANCHEZ on November 7, 2017. For personal use only. No other uses without permission. Copyright © 2017 Massachusetts Medical Society. All rights reserved. Electrolyte Disturbances in Alcohol-Use Disorder

Ethanol-induced ↓Ca2+ Malabsorption myopathy Steatorrhea PTH resistance Diarrhea Antacids ↓PTH release ↓K+ _ ↓PO4 Functional ↓Mg2+

+ 2+ _ ↓K ↓Mg ↓PO4 Unmasking of total-body deficits due to intracellular shift Insulin release after D5W Correction of metabolic acidosis General malnutrition Onset of alcohol withdrawal Vitamin deficiency (respiratory alkalosis, increased Dietary insufficiency β2-adrenergic tone)

Volume depletion, Ethanol-induced alcohol withdrawal, tubular dysfunction pain, and nausea

2+ Low solute intake ↑Ca (beer potomania) _ ↑K+ ↑PO ↑Mg2+ Nonosmotic 4 release of vasopressin + ↓H2O excretion ↓Na

Figure 2. Total-Body Deficits in Chronic Alcohol-Use Disorder. Patients with chronic alcohol-use disorder may have total-body deficits of phosphate, potassium, magnesium, and calcium owing to nutritional deficiencies and decreased gastrointestinal absorption, as well as tubular dysfunction due to chronic alcohol exposure. On clinical presentation, these deficits are revealed as a result of intracellular shift due to increased adrenergic tone and development of respiratory alkalosis, which characterize the onset of alcohol withdrawal, release of insulin after administration of glucose-containing fluids, and correction of metabolic acidosis. Tubular dysfunction can last several weeks after abstinence; this explains the redevelopment of hypomagnesemia and other electrolyte disorders after normalization of plasma values with supplementation in the first several days after hospitalization. Low solute intake and nonosmotic release of vasopressin account for hyponatremia in these patients. D5W denotes 5% dextrose, and PTH parathyroid hormone.

be ruled out; however, clinically significant pseu- Box 2. A 42-year-old woman is admitted to the hospital with a history dohyponatremia would be a consideration only of several weeks of increasing weakness and fatigue followed by the onset with triglyceride levels greater than 1500 mg per of paresthesias in the legs 1 week before admission. deciliter (17 mmol per liter). Beer potomania refers to a vasopressin-inde- She normally drinks up to 1 pint of vodka per day but has not ingested any alcohol over the past 24 hours. Vital signs on admission show a blood pressure pendent mechanism of hyponatremia in persons of 134/82 mm Hg and a pulse rate of 110 beats per minute and no orthostatic who drink large quantities of beer without ade- changes. The respiratory rate is 24 breaths per minute, and she is afebrile. quate food intake. Low excretion of urinary Physical examination shows a disheveled woman who appears visibly agitated. Her laboratory values are as follows: sodium, 140 mmol per liter; potassium, solute limits excretion of renal water, since sol- 2.4 mmol per liter; chloride, 103 mmol per liter; bicarbonate, 21 mmol per liter; ute excretion determines the upper limits for the creatinine, 1.2 mg per deciliter (106 μmol per liter); blood urea nitrogen, 35 mg volume of renal water loss.36 Beer has a very low per deciliter (12.5 mmol per liter); calcium, 6.5 mg per deciliter (1.62 mmol per liter); magnesium, 0.6 mg per deciliter (0.24 mmol per liter); phosphate, sodium and protein content, and unless it is 1.5 mg per deciliter (0.48 mmol per liter); and albumin, 3.8 g per deciliter. A ingested with food, it provides little solute for measurement of arterial blood gas obtained while the patient was breathing am- excretion in the urine. bient air showed a pH of 7.50, a partial pressure of carbon dioxide of 28 mm Hg, and partial pressure of oxygen of 110 mm Hg. The acid–base disturbance and Laboratory findings in patients with beer the type of fluid therapy that is appropriate for correction of the underlying potomania include severe hyponatremia (plasma disorders are noted in Case 2 in the Supplementary Appendix. sodium concentration, <110 mmol per liter),

n engl j med 377;14 nejm.org October 5, 2017 1375 The New England Journal of Medicine Downloaded from nejm.org by LUIS ERNESTO GONZALEZ SANCHEZ on November 7, 2017. For personal use only. No other uses without permission. Copyright © 2017 Massachusetts Medical Society. All rights reserved. The new england journal of medicine

40 Box 3. A 52-year-old man who typically drinks 15 to 20 per day presents in a 24-hour period. Administration of 5% dex- to the emergency department with a history of nausea over the past 48 hours. trose in water, administered either with or with- out desmopressin, slows the rate of correction He has had no food intake over the past 2 days but has continued to drink the and, if needed, can be used to lower the plasma same amount of beer each day. On physical­ examination, he has difficulty fol- lowing commands. His laboratory values on admission are as follows: sodi- sodium level again in patients in whom overcor- um, 110 mmol per liter; chloride, 78 mmol per liter; potassium, 3.9 mmol per rection has already occurred. liter; bicarbonate, 22 mmol per liter; creatinine, 0.7 mg per deciliter (62 μmol per liter); blood urea nitrogen, 4 mg per deciliter (1.4 mmol per liter); spot uri- nary sodium, 12 mmol per liter; and urine osmolality, 234 mOsm per kilogram Conclusions of water. He receives thiamine followed by 1 liter of 5% dextrose in 0.9% normal saline. The urine output during the first 5 hours after presentation is 3.2 liters. An array of acid–base disorders and electrolyte The acid–base disturbance and the type of fluid therapy that is appropriate for correction of the underlying disorders are noted in Case 3 in the Supplementary disorders can occur in patients with chronic Appendix. alcohol-use disorder, irrespective of their social circumstances. Thus, these disorders are not con- fined to unfortunate patients with malnutrition hypokalemia, low blood urea nitrogen levels and intercurrent illness, but rather they can be (indicating low protein intake), and a maximally encountered in well-nourished patients who are dilute urine (<100 mOsm per kilogram of water). abusing alcohol, since alcohol ingestion itself is In some patients, the urine osmolality may be directly involved in the underlying pathophysio- higher than 100 mOsm per kilogram owing to logical features of these derangements. coexistent nonosmotic release of vasopressin Treatment of the underlying cause of hospital caused by volume depletion, alcohol withdrawal, admission will unmask the disturbances that nausea, or medications (see Box 3). have been described in this review. Furthermore, Administration of solute, either as sodium electrolyte disturbances that are present may be chloride in intravenous fluids or refeeding com- corrected initially, but owing to the deleterious bined with fluid restriction, typically results in a effects of alcohol on renal tubular function, they brisk diuresis in patients with beer potomania. may reappear within days after the initial correc- Rapid correction of the ensuing hyponatremia is tion. Understanding the pathophysiological fea- problematic because osmotic demyelination oc- tures of electrolyte disorders related to alcohol curs in approximately 18% of patients.37 Hypo- abuse should help physicians to implement ap- kalemia and hypophosphatemia are risk factors propriate and avoid the potential toxic for this complication.38,39 To minimize the risk, effects of these abnormalities in their patients. the therapeutic goal is to limit correction of the Disclosure forms provided by the authors are available with plasma sodium level to between 4 and 6 mmol the full text of this article at NEJM.org.

References 1. Kessler RC, McGonagle KA, Zhao S, alcoholic men. Alcohol Alcohol 2014;​49:​ 11. Foster DW, McGarry JD. The meta- et al. Lifetime and 12-month prevalence 618-25. bolic derangements and treatment of dia- of DSM-III-R psychiatric disorders in the 6. Halperin ML, Hammeke M, Josse RG, betic ketoacidosis. N Engl J Med 1983;​ United States: results from the National Jungas RL. Metabolic acidosis in the alco- 309:​159-69. Comorbidity Survey. Arch Gen Psychiatry holic: a pathophysiologic approach. Metab- 12. Palmer BF, Clegg DJ, Taylor SI, Weir 1994;51:​ 8-19.​ olism 1983;32:​ 308-15.​ MR. Diabetic ketoacidosis, sodium glu- 2. Muller A. Alcohol consumption and 7. Zhong W, Zhao Y, Tang Y, et al. cose transporter-2 inhibitors and the kid- community hospital admissions in the Chronic alcohol exposure stimulates adi- ney. J Diabetes Complications 2016;​30:​ United States: a dynamic regression analy- pose tissue lipolysis in mice: role of re- 1162-6. sis, 1950-1992. Addiction 1996;​91:​231- verse triglyceride transport in the patho- 13. Madison LL, Lochner A, Wulff J. 42. genesis of alcoholic steatosis. Am J Pathol Ethanol-induced hypoglycemia. II. Mech- 3. Wrenn KD, Slovis CM, Minion GE, 2012;​180:​998-1007. anism of suppression of hepatic gluco- Rutkowski R. The of alcoholic 8. Palmer BF, Clegg DJ. Electrolyte and neogenesis. Diabetes 1967;16:​ 252-8.​ ketoacidosis. Am J Med 1991;​91:​119-28. acid–base disturbances in patients with 14. Miller PD, Heinig RE, Waterhouse C. 4. Elisaf M, Merkouropoulos M, Tsianos diabetes mellitus. N Engl J Med 2015;​373:​ Treatment of alcoholic acidosis: the role EV, Siamopoulos KC. Acid-base and elec- 548-59. of dextrose and phosphorus. Arch Intern trolyte abnormalities in alcoholic patients. 9. Fulop M, Hoberman HD. Alcoholic Med 1978;138:​ 67-72.​ Miner Electrolyte Metab 1994;​20:​274-81. detosis. Diabetes 1975;24:​ 785-90.​ 15. Elisaf MS, Siamopoulos KC. Mecha- 5. Yokoyama A, Yokoyama T, Mizukami 10. Palmer BF. Evaluation and treatment nisms of hypophosphataemia in alcoholic T, et al. Alcoholic : prevalence, de- of respiratory alkalosis. Am J Kidney Dis patients. Int J Clin Pract 1997;​51:​501-3. terminants, and ketohepatitis in Japanese 2012;60:​ 834-8.​ 16. Stein JH, Smith WO, Ginn HE. Hypo-

1376 n engl j med 377;14 nejm.org October 5, 2017 The New England Journal of Medicine Downloaded from nejm.org by LUIS ERNESTO GONZALEZ SANCHEZ on November 7, 2017. For personal use only. No other uses without permission. Copyright © 2017 Massachusetts Medical Society. All rights reserved. Electrolyte Disturbances in Alcohol-Use Disorder

phosphatemia in acute . Am J Knochel JP. Derangements of muscle com- response of arginine vasopressin to intra- Med Sci 1966;252:​ 78-83.​ position, ion transport, and oxygen con- venous ethanol and hypertonic saline in 17. De Marchi S, Cecchin E, Basile A, Ber- sumption in chronically alcoholic dogs. man: the impact of aging. J Gerontol 1978;​ totti A, Nardini R, Bartoli E. Renal tubu- Am J Physiol 1984;​246:​F700-F709. 33:39-47.​ lar dysfunction in chronic alcohol abuse 25. Elisaf M, Bairaktari E, Kalaitzidis R, 34. Elisaf M, Kalaitzidis R. Metabolic ab- — effects of abstinence. N Engl J Med Siamopoulos KC. Hypomagnesemia in normalities in alcoholic patients: focus on 1993;329:​ 1927-34.​ alcoholic patients. Alcohol Clin Exp Res acid base and electrolyte disorders. J Alco- 18. Parenti P, Giordana B, Hanozet GM. 1998;​22:​134. hol Drug Depend 2015;​3:​185. In vitro effect of ethanol on sodium and 26. Elisaf M, Liberopoulos E, Bairaktari E, 35. Palmer BF. Diagnostic approach and glucose transport in rabbit renal brush Siamopoulos K. Hypokalaemia in alco- management of inpatient hyponatremia. border membrane vesicles. Biochim Bio- holic patients. Drug Alcohol Rev 2002;​21:​ J Hosp Med 2010;​5:​Suppl 3:​S1-S7. phys Acta 1991;1070:​ 92-8.​ 73-6. 36. Berl T. Impact of solute intake on 19. Rothman A, Proverbio T, Proverbio F. 27. Palmer BF, Clegg DJ. Physiology and urine flow and water excretion. J Am Soc Inhibitory effect of ethanol on the Na(+)- pathophysiology of potassium homeosta- Nephrol 2008;​19:​1076-8. ATPase activity of rat kidney proximal tu- sis. Adv Physiol Educ 2016;​40:​480-90. 37. Sanghvi SR, Kellerman PS, Nanovic L. bular cell plasma membranes. Physiol Res 28. Huang CL, Kuo E. Mechanism of hypo- Beer potomania: an unusual cause of hypo- 1996;45:​ 205-11.​ kalemia in magnesium deficiency. J Am natremia at high risk of complications 20. Curthoys NP, Moe OW. Proximal tu- Soc Nephrol 2007;​18:​2649-52. from rapid correction. Am J Kidney Dis bule function and response to acidosis. 29. Rubenstein AE, Wainapel SF. Acute 2007;50:​ 673-80.​ Clin J Am Soc Nephrol 2014;​9:​1627-38. hypokalemic myopathy in alcoholism: 38. Bähr M, Sommer N, Petersen D, 21. Cronin RE, Ferguson ER, Shannon WA a clinical entity. Arch Neurol 1977;​34:​553-5. ­Wiethölter H, Dichgans J. Central pontine Jr, Knochel JP. Skeletal muscle injury after 30. Miller DW, Slovis CM. Hypophospha- myelinolysis associated with low potassi- magnesium depletion in the dog. Am J temia in the emergency department thera- um levels in alcoholism. J Neurol 1990;​ Physiol 1982;243:​ F113-F120.​ peutics. Am J Emerg Med 2000;​18:​457-61. 237:275-6.​ 22. Anderson R, Cohen M, Haller R, Elms J, 31. Felsenfeld AJ, Levine BS. Approach to 39. Falcone N, Compagnoni A, Meschini Carter NW, Knochel JP. Skeletal muscle treatment of hypophosphatemia. Am J Kid- C, Perrone C, Nappo A. Central pontine phosphorus and magnesium deficiency in ney Dis 2012;​60:​655-61. myelinolysis induced by hypophosphate- alcoholic myopathy. Miner Electrolyte 32. Eisenhofer G, Johnson RH. Effect of mia following Wernicke’s encephalopathy. Metab 1980;​4:​106-12. ethanol ingestion on plasma vasopressin Neurol Sci 2004;24:​ 407-10.​ 23. Haller RG, Knochel JP. Skeletal mus- and water balance in humans. Am J Physiol 40. Sterns RH, Silver SM. Complications cle disease in alcoholism. Med Clin North 1982;​242:​R522-R527. and management of hyponatremia. Curr Am 1984;68:​ 91-103.​ 33. Helderman JH, Vestal RE, Rowe JW, Opin Nephrol Hypertens 2016;25:​ ​114-9. 24. Ferguson ER, Blachley JD, Carter NW, Tobin JD, Andres R, Robertson GL. The Copyright © 2017 Massachusetts Medical Society.

images in clinical medicine The Journal welcomes consideration of new submissions for Images in Clinical Medicine. Instructions for authors and procedures for submissions can be found on the Journal’s website at NEJM.org. At the discretion of the editor, images that are accepted for publication may appear in the print version of the Journal, the electronic version, or both.

n engl j med 377;14 nejm.org October 5, 2017 1377 The New England Journal of Medicine Downloaded from nejm.org by LUIS ERNESTO GONZALEZ SANCHEZ on November 7, 2017. For personal use only. No other uses without permission. Copyright © 2017 Massachusetts Medical Society. All rights reserved.