Electrolyte Disorders in Chronic Alcohol Use Disorder: A Case Based Approach
Biff F. Palmer, M.D. Professor of Internal Medicine University of Texas Southwestern Medical Center, Dallas Texas Case • A 52 year old homeless man presents to the emergency room complaining of weakness. He typically drinks one pint of whisky daily. He noted the onset of epigastric pain 3 days ago but continued to drink until 1 day prior to presentation, when he developed the onset of nausea and persistent vomiting. He reports having had no food intake over the last 24 hours. • PE: BP 138/90 mm Hg supine, 110/74 mm Hg standing, pulse 105 beats/minute. There is tenderness to palpation in the epigastrium but no rebound tenderness. Laboratory Data
Creatinine 1.2 mg/dl Arterial blood gas: BUN 22 mg/dl – pH 7.47
Serum electrolytes –PCO2 28 (mEq/l): – Na + 142 –K+ 3.8 – Cl 92 – HCO 3 22
Glucose 110 mg/dl Which of the following best describes the acid base disturbance in this patient?
1. Chronic respiratory alkalosis 2. Anion gap metabolic acidosis 3. Respiratory alkalosis and metabolic acidosis 4. Anion gap metabolic acidosis, respiratory alkalosis, and metabolic alkalosis Case
• Arterial pH = 7.47 142 92 22
• pCO 2 = 28 mmHg 3.8 22 1.2
Anion gap 28 • Anion gap metabolic acidosis • Metabolic alkalosis • Respiratory alkalosis Case • A man with chronic alcohol use disorder is found lying semiconscious at the bottom of a stairwell with a broken arm by his landlady, who called an ambulance to take him to the ED. + + • Labs (mEq/l): Na 137, K 3.6, Cl 90, HCO 3 15 (anion gap 32), ethanol level 150 mg/dl, glucose 38 mg/dl Which of the following best accounts for the hypoglycemia and increased anion gap? 1. Increased insulin release 2. Glycosuria secondary to ethanol induced proximal tubular dysfunction 3. Increased cellular NADH/NAD + 4. Decreased secretion of glucagon Alcohol Induced Hypoglycemia
• Occurs in chronic malnourished or weekend binge drinker, children or adolescents particularly susceptible • Variable period of fasting present (liver glycogen depleted in 14 24 hours) • Onset 5 20 hours after last ingestion • Transition from alcoholic stupor to hypoglycemia coma can be imperceptible Metabolism of Alcohol Increases the NADH/NAD + Ratio
Alcohol Acetaldehyde Ethanoldehydrogenase Acetaldehydedehydrogenase Acetate
+ NAD NADH 2 + NAD NADH 2 Increases in the NADH/NAD + Ratio Leads to Shunting of Gluconeogenic Precursors Away From Gluconeogenic Pathways
Tricarboxylic acid cycle, (Krebs cycle)
Citrate
Isocitrate Oxaloacetate + NADH + H + NAD + NAD + NADH + H Malate α Ketoglutarate NAD +
+ Fumarate NADH + H Succinyly CoA Succinate Alcohol Induced Hypoglycemia • Oxalacetate is reduced to malate • α ketoglutarate is converted to glutamate
Citrate
Isocitrate ↓ Oxaloacetate Glutamate NADH + H + NAD + NAD +
NADH + H + NADH + H + NAD + Malate ↓ α Ketoglutarate
NAD +
+ Fumarate NADH + H Succinyly CoA
Succinate ↓ Glucose
Glucose The Increased ADH/ AD + Ratio Shunts Gluconeogenic Precursors Away From Gluconeogenic Pathways ↓ Phosphoenolpyruvate
PEPCK Pyruvate
↓ Oxaloacetate Citrate
Acetyl CoA Isocitrate ↓ Oxaloacetate Glutamate NADH + H + NAD + NAD + ↓ Pyruvate NADH + H + NADH + H + NAD + NADH + Malate ↓ α Ketoglutarate
NAD + NAD +
+ Lactate Fumarate NADH + H Succinyly CoA
NADH Favors reduction of pyruvate to lactate Succinate NAD + reducing availability of OAA Alcohol Induced Hypoglycemia and Ketoacidosis • Alcohol can be associated with both hypoglycemia and ketoacidosis • In patients with alcohol induced hypoglycemia (n=101)* – plasma HCO 3 <15 mEq/L in one third – plasma HCO 3 <9 mEq/L in 17% – urinary ketones frequently positive
Madison L. Advances in Metabolic Disorders, 1968 Alcoholic Ketoacidosis
• Chronic alcoholics with recent debauch, often with no alcohol in past 24 48 hours • Poor dietary intake in preceding 1 2 days • Ketoacidosis predominates, lactic acid also present • Mechanism related to increases in the NADH/NAD + ratio along with augmented free fatty acid mobilization ↓ Glucose ↑↑ Fatty acid Mobilization VLDL
Glucose Fatty acid VLDL Cytosol
Fatty Acyl CoA
Pyruvate
↓ OAA Mitochondria
↓ Pyruvate Citrate NADH + Acetyl CoA Isocitrate Glutamate Oxaloacetate NAD + NAD + NAD + NADH + H + + NADH + H + NADH + H + ↑ Lactate Malate NAD α Ketoglutarate NAD +
NADH + H + Fumarate Succinyly CoA Succinate ↓ Glucose ↑↑ Fatty acid Mobilization VLDL
Glucose Fatty acid VLDL Cytosol
Fatty Acyl CoA Malonyl CoA ACC (inhibited by glucagon, epinephrine stimulated by insulin Acetyl CoA Pyruvate ↓OAA ↓ Citrate
↓ OAA Mitochondria
↓ Pyruvate Citrate NADH + Acetyl CoA Isocitrate Glutamate Oxaloacetate NAD + NAD + NAD + NADH + H + + NADH + H + NADH + H + ↑ Lactate Malate NAD α Ketoglutarate NAD +
NADH + H + Fumarate Succinyly CoA Succinate ↓ Glucose ↑↑ Fatty acid VLDL
Glucose Fatty acid VLDL Cytosol
Fatty Acyl CoA Malonyl CoA ACC (inhibited by glucagon, epinephrine stimulated by insulin Acetyl CoA Pyruvate Fatty Acyl Carnitine ↓OAA ↓ Citrate
↓ OAA Fatty Acyl Carnitine Mitochondria Fatty Acyl CoA ↓ Pyruvate Citrate NADH + Acetyl CoA Isocitrate Glutamate PDH Oxaloacetate NAD + NAD + NAD + NADH + H + + NADH + H + NADH + H + ↑ Lactate Malate NAD α Ketoglutarate ↑ Acetoacetate NAD + NADH + NADH + H + Fumarate NAD + Succinyly CoA ↑↑ β Hydroxybutyrate Succinate Alcohol withdrawal ↓ Glycogen stores Starvation Volume depletion
Sympathetic nerve activation Lipolysis ↓ Insulin ↑ Glucagon Fatty acids
↓ Gluconeogenesis Ketogenic State Ethanol NAD NADH NADH β hydroxybutyric acid + NaHCO 3 Acetaldehyde NAD NAD NaBOH H2CO 3 NADH Acetate CO 2 and H 2O Loss through the lungs
Palmer BF, Clegg DJ. New Engl J Med. 2017;377:1368 1377 Indirect Loss of NaHCO 3 Which of the following best accounts for the hypoglycemia and increased anion gap? 1. Increased insulin release 2. Glycosuria secondary to ethanol induced proximal tubular dysfunction 3. Increased cellular ADH/ AD + 4. Decreased secretion of glucagon Therapy
• Initial therapy is 5% dextrose in 0.9% normal saline – Restore ECF volume and stabilize hemodynamics – Provides Cl for correction of metabolic alkalosis • Volume resuscitation decreases sympathetic nerve activity • Dextrose decreases ketogenesis by stimulating insulin release and suppressing glucagon • Supplemental thiamine (100 mg intravenous or intramuscular) prior to glucose containing solutions to minimize risk of precipitating Wernicke encephalopathy or Korsakoff syndrome • Benzodiazepines to treat alcohol withdrawal. • Monitor for development of hypomagnesemia, hypophosphatemia, and hypokalemia Case • A 42 year old woman is admitted to the hospital with a several week history of increasing weakness and fatigue followed by the onset of paresthesias in the lower extremities one week ago. She normally drinks up to one pint of vodka per day but has not ingested any alcohol over the last 24 hours. Vital signs on admission show a blood pressure of 134/82 mmHg and a pulse of 110 beats per minute with no orthostatic changes. The respiratory rate is 24 per minute and she is afebrile. Physical examination shows a disheveled woman who appears visibly agitated. Laboratory Data
Creatinine 1.2 mg/dl, Mg 2+ 0.6 mg/dl BUN 35 mg/dl Ca 2+ 6.5 mg/dl Glucose 110 mg/dl PO 4 1.5 mg/dl Serum electrolytes Albumin 3.8 gm/dl (mEq/l): – Na + 140 Arterial blood gas: –K+ 2.4 • pH 7.50 – Cl 103 • P 28 CO2 – HCO 3 21 • PO 2 110 Skeletal Muscle Ion Composition in Chronic Alcohol Use Disorder Compared to Normal Persons
- 2+ + 2+ + - PO 4 Mg K Ca Na Cl
Normal 28.7 8.1 42.8 1.8 9.9 7.5 subjects
Alcohol use 20.4 5.7 35.8 6.2 25.1 12.0 disorder patients
All values are mEq per 100 mg fat free dry weight except for PO 4 which is mmol per 100 mg fat free dry weight (data extracted from 2)
Miner Electrolyte Metab 1980;4:106 112 Malabsorption • Steatorrhea • Diarrhea • Antacids
Ethanol-induced myopathy
↓K +
- ↓PO 4 General malnutrition ↓Mg 2+ Vitamin ,deficiency Dietary insufficiency
Ethanol-induced tubular dysfunction
+ - 2+ 2+ ↑K ↑PO 4 ↑Mg ↑Ca
Palmer BF, Clegg DJ. New Engl J Med. 2017;377:1368 1377 2+ Mg and FE Mg in 61 Alcoholics During 4 Weeks of Abstinence
Serum Mg 2+ (mEq/l) Fractional excretion of Mg 2+ 1,8 3,5 1,7∗ 1.8 3.5 1,6 1,57 3 3.0
2,5 1,4 ∗ 1,4 2.5 1.4 2 2.0
1,5 1.5
1 1.0 1.0 1 1 4 7 28 1 4 7 28 114 4 7 7 28 28 Days Days
∗ p<0.02 vs day 1 De Marchi et al., NEJM 329:1927,1993 Malabsorption • Steatorrhea • Diarrhea • Antacids
Ethanol-induced myopathy
2+ ↓K + ↓Mg - ↓PO 4 ↓PO - 4 ↓K + General malnutrition ↓Mg 2+ Vitamin ,deficiency Dietary insufficiency
Ethanol-induced tubular dysfunction
+ - 2+ 2+ ↑K ↑PO 4 ↑Mg ↑Ca
Palmer BF, Clegg DJ. New Engl J Med. 2017;377:1368 1377 Intracellular Mg ++ Decreases K + Secretion via ROMK Channel in CCD
Principal Cell Lumen Interstitium
ENaC 3Na + 3Na + + + Na Na 2K + 2K + ROMK + K+ K Mg ++
J Am Soc Nephrol 18:2649, 2007 Parathyroid glands Malabsorption • Steatorrhea ↓Ca 2+ • Diarrhea + • Antacids ↓PTH release PTH resistance Ethanol-induced Functional myopathy hypoparathyroidism
2+ ↓K + ↓Mg ↓K + ↓PO - 4 - ↓PO 4 General malnutrition ↓Mg 2+ Vitamin ,deficiency Dietary insufficiency
Ethanol-induced tubular dysfunction
+ - 2+ 2+ ↑K ↑PO 4 ↑Mg ↑Ca
Palmer BF, Clegg DJ. New Engl J Med. 2017;377:1368 1377 PTH is Inappropriately Low in Hypocalcemic Hypomagnesemic Patients
900 800 • 700 600 • 500 • Normal 400 • • 300 • • • Serum iPTH pg/ml pg/ml iPTHiPTH Serum Serum 200 • 100 •• • • Undetectable 0 • 0 2 4 6 8 10 12 14 Serum calcium (mg/dl)
Clin Endocrinol 5:200, 1976 Effect of IV Mg 2+ on Serum Mg +2 , Ca 2+ , and iPTH in a Hypocalcemic Magnesium Deficient Patient
8 Mg ++ 8 mEq IV
7 mg/dl 2+ Ca 6 0 1 2 5
3
2 mg/dl mg/dl 2+ Mg 1 0 1 2 5
1300 PTH pg/ml
900
500
100 0 1 2 5 Minutes J Clin Endo Metab 47:800,1978 Electrolyte Disturbances Often Become More Severe After Admission to the Hospital Ethanol and Hypomagnesemia
• 47 year old man presents with new onset ascites. His history is significant for heavy alcohol use over the last several years. His last drink was approximately 12 hours ago • Physical exam: BP 110/70, P110, RR 28 • Spider angiomas, shifting dullness, 2+ peripheral edema Laboratory Examination
+ + • Na 130, K 2.8, Cl 90, HCO 3 16, (anion gap = 24) • Urine and serum ketones are positive 2+ 2+ • PO 4 1.5 mg/dl, Ca 6.5 mg/dl, Mg 1.6 mg/dl Hospital Course
• The patient is admitted and treated with thiamine, folic acid and multivitamins followed by maintenance fluids with D5 1/2NS. • Approximately 12 hours after admission the patient is noted to be restless and agitated • The Mg 2+ is now 0.8 mg/dl Change in Mg 2+ and pH after Withdrawal of ETOH in Patient with Chronic Alcohol Use Disorder
1,7
1,6 7.50 Mg 2+ 1,5 mEq/L) (( 1,4 7.46 2+
1,3 Serum Mg Serum 1,2 7.42
1,1 Arterial pH
1 7.38 0 8 16 32 40 Hours Ann NY Acad Aci 1973;215:235 Parathyroid glands Malabsorption • Steatorrhea ↓Ca 2+ • Diarrhea + • Antacids ↓PTH release PTH resistance Ethanol-induced Functional myopathy hypoparathyroidism
Unmasking of body deficits due to intracellular shift 2+ + ↓Mg ↓K Insulin release after D5W Correction of metabolic acidosis ↓K + - Onset of alcohol withdrawal ↓PO • Respiratory alkalosis 4 - • Increased β adrenergic tone ↓PO 4 General malnutrition ↓Mg 2+ Vitamin ,deficiency Dietary insufficiency
Ethanol-induced tubular dysfunction
+ - 2+ 2+ ↑K ↑PO 4 ↑Mg ↑Ca Treatment of Hypomagnesemia
• The patient is given several doses of IV Mg 2+ over the next 24 hours and repeat measurement shows the Mg 2+ has increased to 2.1 mg/dl. • 36 hours later the Mg 2+ has once again decreased to 0.9 mg/dl Magnesium Reabsorption in the Thick Limb
Filtrate flow Thick Ascending Limb Cell +15 mV Interstitium 50 mV 0 mV Claudins 16,19
Ca 2+ , Mg 2+ 3Na + 2K + Na + K+ K+ 2Cl
K+
Mg 2+ Receptor
Cl Treatment • In addition to thiamine and folate, 1 liter of 5% glucose in
0.45% saline to which has been added 20 mmol KPO 4, 20 mEq KCl, and 4 ml of 50% MgSO4 (16 mEq Mg 2+ ) every eight hours for several days • Mg 2+ is required for coexisting hypokalemia and hypocalcemia • Most IV Mg 2+ is lost in the urine, so oral Mg 2+ is best in the asymptomatic patient or when Mg 2+ is ≥ 1.0 mg/dl – Magnesium chloride and magnesium lactate tablets contain 5 7 mEq (2.5 3.5 mmol or 60 84 mg) of magnesium per tablet. – Two to four tablets daily are generally well tolerated and are not associated with diarrhea • Replete circulatory volume in such patients and monitor for rhabdomyolysis Parathyroid glands Malabsorption • Steatorrhea ↓Ca 2+ • Diarrhea + • Antacids ↓PTH release PTH resistance Ethanol-induced Functional myopathy hypoparathyroidism
Unmasking of body deficits due to intracellular shift 2+ + ↓Mg ↓K Insulin release after D5W Correction of metabolic acidosis ↓K + - Onset of alcohol withdrawal ↓PO • Respiratory alkalosis 4 - • Increased β adrenergic tone ↓PO 4 General malnutrition ↓Mg 2+ Vitamin ,deficiency Dietary insufficiency
Ethanol-induced tubular dysfunction
+ - 2+ 2+ ↑K ↑PO 4 ↑Mg ↑Ca + ↓ H 2O excretion ↓Na Case • A 44 year old woman with a history of heavy beer drinking visits her PCP and is started on a thiazide diuretic for hypertension and an SSRI for depression. Two weeks after starting these medications, she develops progressive weakness and lethargy, and for the next several days she experiences multiple falls. • PE: BP 110/80 pulse 88, no orthostatic changes, she is disoriented by no focal neurologic deficits Laboratory Data
Creatinine 0.5 mg/dl, BUN 8 mg/dl Spot urine studies (mEq/l) – Na + <15 Glucose 140 mg/dl Serum electrolytes – Cl <10 (mEq/l): – Na + 94 UA: SG 1.002, + ketones –K+ 2.0 – Cl 65 UOsm 61 mOsm/Kg – HCO 3 25 Mg 2+ 1.4 mg/dl
POsm 200 mOsm/Kg ARS: Which one of the following is the mostly likely etiology for the hyponatremia?
1. Beer potomania 2. Thiazide diuretic 3. SSRI 4. Volume depletion Beer Potomania
• Beer content – Na + <2 mEq/L –K+ 10 12 mEq/L • Assume Beer consumption of 5 liters – Na + intake 10 mM –K+ intake 50 mM } 200 mOsm – Obligatory urea excretion 80 mM/d • If Uosm is 50 mOsm/L, then 1 liter positive water balance ensues (200/50 = 4L) Which one of the following is the mostly likely etiology for the hyponatremia?
1. Beer potomania 2. Thiazide diuretic 3. SSRI 4. Volume depletion Case
• Eight hours later she arrives at a city hospital ED where admission lab work shows the serum Na + has increased from 94 to is 97 mEq/l and the serum is K + 2.4 mEq/l. She is given 0.9% NaCl with 40 mEq/L KCl at 250 ml/hr and 40 mEq/l of KCl orally. • Six hours after arrival in the ED she is transferred to the ICU where additional laboratory work are obtained: • Serum Na + 107 mEq/l, K + 2.7 mEq/l • Urine osmolality: 50 mOsm/kg • Urine Na + 10 mEq/l ARS: Which one of the following is the goal of therapy?
1. Correct to a serum Na + of 120 mEq/L by 1 mEq/L/hr 2. Correct to a serum Na + of 115 mEq/L by 1 mEq /L/ hr 3. Keep the serum Na + where it is now 4. Correct to a serum Na + of 115 mEq/L by 0.5 mEq/L/hr ARS: Which one of the following is the most appropriate therapy?
1. 0.45% saline to match urine output 2. D5W to match urine output 3. Isotonic saline to match urine output 4. 3% saline at 50 ml/hr Time Course in Case
Na + Na + Na + 8 hours 6 hours
94 97 107 Correcting Hyponatremia
Rapid Acute Chronic correction 140 120 120 140