Electrolyte Disorders in Chronic Alcohol Use Disorder: A Case Based Approach

Transcription

1 Electrolyte Disorders in Chronic Alcohol Use Disorder: A Case Based Approach Biff F. Palmer, M.D. Biff F. Palmer, M.D. Professor of Internal Medicine University of Texas Southwestern Medical Center, Dallas Texas

2 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.

3 Laboratory Data Creatinine 1.2 mg/dl BUN 22 mg/dl Serum electrolytes (meq/l): Na K Cl - 92 HCO 3-22 Arterial blood gas: ph 7.47 P CO2 28 Glucose 110 mg/dl

4 Which of the following best describes the acidbase 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

5 Case Arterial ph = pco 2 = 28 mmhg Anion gap metabolic acidosis Metabolic alkalosis Respiratory alkalosis Anion gap 28

6 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

7 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

8 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 hours) Onset 5-20 hours after last ingestion Transition from alcoholic stupor to hypoglycemia coma can be imperceptible

9 Metabolism of Alcohol Increases the NADH/NAD + Ratio Alcohol dehydrogenase Acetaldehyde dehydrogenase Ethanol Acetaldehyde Acetate NAD + NADH 2 NAD + NADH 2

10 Increases in the NADH/NAD + Ratio Leads to Shunting of Gluconeogenic Precursors Away From Gluconeogenic Pathways Tricarboxylic acid cycle, (Krebs cycle) Citrate NADH + H + NAD + Oxaloacetate Isocitrate NAD + Malate NADH + H + α-ketoglutarate NAD + Fumarate Succinate Succinyly-CoA NADH + H +

11 Alcohol-Induced Hypoglycemia Oxalacetate is reduced to malate α-ketoglutarate is converted to glutamate Citrate Oxaloacetate NADH + H + Isocitrate NAD + Glutamate NAD + Malate NAD + NADH + H + α-ketoglutarate NADH + H + NAD + Fumarate NADH + H + Succinyly-CoA Succinate

12 Glucose Glucose Phosphoenolpyruvate The Increased ADH/ AD + Ratio Shunts Gluconeogenic Precursors Away From Gluconeogenic Pathways Pyruvate PEPCK Oxaloacetate Citrate Pyruvate NADH + Acetyl CoA Oxaloacetate Malate NADH + H + NAD + Isocitrate NAD + NADH + H + α-ketoglutarate Glutamate NAD + NADH + H + NAD + NAD + Lactate Fumarate NADH + H + Succinyly-CoA NADH NAD + Favors reduction of pyruvate to lactate reducing availability of OAA Succinate

13 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

14 Alcoholic Ketoacidosis Chronic alcoholics with recent debauch, often with no alcohol in past 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

15 Glucose Fatty acid Mobilization VLDL Glucose Fatty acid VLDL Cytosol Fatty Acyl CoA Pyruvate OAA Mitochondria Pyruvate Lactate NADH + NAD + Acetyl CoA Oxaloacetate Malate Citrate NADH + H + NAD + Isocitrate NAD + NADH + H + NAD + Glutamate NAD + α-ketoglutarate NADH + H + Fumarate NADH + H + Succinate Succinyly-CoA

16 Glucose Fatty acid Mobilization VLDL Glucose Fatty acid VLDL Cytosol Pyruvate Fatty Acyl CoA Malonyl CoA Acetyl CoA Citrate ACC (inhibited by glucagon, epinephrine stimulated by insulin OAA OAA Mitochondria Pyruvate Lactate NADH + NAD + Acetyl CoA Oxaloacetate Malate Citrate NADH + H + NAD + Isocitrate NAD + NADH + H + NAD + Glutamate NAD + α-ketoglutarate NADH + H + Fumarate NADH + H + Succinate Succinyly-CoA

17 Glucose Fatty acid VLDL Glucose Fatty acid VLDL Cytosol Pyruvate Fatty Acyl CoA Fatty Acyl Carnitine Malonyl CoA Acetyl CoA Citrate ACC (inhibited by glucagon, epinephrine stimulated by insulin OAA OAA Fatty Acyl Carnitine Mitochondria Fatty Acyl CoA Pyruvate Lactate NADH + NAD + PDH Acetyl CoA Acetoacetate NADH + NAD + β-hydroxybutyrate Oxaloacetate Malate Fumarate NAD + Citrate NADH + H + Succinate Isocitrate NAD + NADH + H + NAD + NADH + H + Glutamate NAD + α-ketoglutarate Succinyly-CoA NADH + H +

18 Glycogen stores Alcohol withdrawal Starvation Volume depletion Gluconeogenesis Ethanol Acetaldehyde Acetate NAD NADH NAD NADH Sympathetic nerve activation Insulin Glucagon Ketogenic State NADH NAD Fatty acids Lipolysis β-hydroxybutyric acid + NaHCO 3 NaBOH H 2 CO 3 CO 2 and H 2 O Loss through the lungs Palmer BF, Clegg DJ. New Engl J Med. 2017;377: Indirect Loss of NaHCO 3

19 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

20 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

21 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.

22 Laboratory Data Creatinine 1.2 mg/dl, BUN 35 mg/dl Glucose 110 mg/dl Serum electrolytes (meq/l): Na K Cl HCO 3-21 Mg mg/dl Ca mg/dl PO mg/dl Albumin 3.8 gm/dl Arterial blood gas: ph 7.50 P CO2 28 PO 2 110

23 Skeletal Muscle Ion Composition in Chronic Alcohol Use Disorder Compared to Normal Persons PO 4 - Mg 2+ K + Ca 2+ Na + Cl - Normal subjects Alcohol use 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:

24 Malabsorption Steatorrhea Diarrhea Antacids Ethanol-induced myopathy K + PO 4 - General malnutrition Vitamin,deficiency Dietary insufficiency Mg 2+ Ethanol-induced tubular dysfunction K + PO 4 - Mg 2+ Ca 2+ Palmer BF, Clegg DJ. New Engl J Med. 2017;377:

25 Mg 2+ and FE Mg in 61 Alcoholics During 4 Weeks of Abstinence 1,8 Serum Mg 2+ (meq/l) ,4 1,57 1,4 1,6 1,7 3, , Fractional excretion of Mg 2+ 1, Days Days p<0.02 vs day 1 De Marchi et al., NEJM 329:1927,1993

26 Malabsorption Steatorrhea Diarrhea Antacids Ethanol-induced myopathy General malnutrition Vitamin,deficiency Dietary insufficiency K + Mg 2+ PO - 4 PO 4 - Mg 2+ K + 4 Ethanol-induced tubular dysfunction K + PO 4 - Mg 2+ Ca 2+ Palmer BF, Clegg DJ. New Engl J Med. 2017;377:

27 Intracellular Mg ++ Decreases K + Secretion via ROMK Channel in CCD Lumen Principal Cell Interstitium ENaC + 3Na + Na + 3Na Na + 2K + 2K + ROMK K + Mg ++ K + J Am Soc Nephrol 18:2649, 2007

28 Malabsorption Steatorrhea Diarrhea Antacids Ethanol-induced myopathy Parathyroid glands PTH release + Functional hypoparathyroidism PTH resistance Ca 2+ General malnutrition Vitamin,deficiency Dietary insufficiency K + Mg 2+ PO - 4 Mg 2+ K + PO - 4 Ethanol-induced tubular dysfunction K + PO 4 - Mg 2+ Ca 2+ Palmer BF, Clegg DJ. New Engl J Med. 2017;377:

29 PTH is Inappropriately Low in Hypocalcemic Hypomagnesemic Patients Serum ipth pg/ml Normal Undetectable Serum calcium (mg/dl) Clin Endocrinol 5:200, 1976

30 Effect of IV Mg 2+ on Serum Mg +2, Ca 2+, and ipth in a Hypocalcemic Magnesium Deficient Patient Ca 2+ mg/dl Mg ++ 8 meq IV Mg 2+ mg/dl PTH pg/ml Minutes J Clin Endo Metab 47:800,1978

31 Electrolyte Disturbances Often Become More Severe After Admission to the Hospital

32 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

33 Laboratory Examination Na + 130, K + 2.8, Cl - 90, HCO 3-16, (anion gap = 24) Urine and serum ketones are positive PO mg/dl, Ca mg/dl, Mg mg/dl

34 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

35 Change in Mg 2+ and ph after Withdrawal of ETOH in Patient with Chronic Alcohol Use Disorder 1,7 1, Serum Mg 2+ (meq/l) 1,5 1,4 1,3 Mg , ,1 Arterial ph Hours Ann NY Acad Aci 1973;215:235

36 Malabsorption Steatorrhea Diarrhea Antacids Ethanol-induced myopathy Parathyroid glands PTH release + Functional hypoparathyroidism PTH resistance Ca 2+ General malnutrition Vitamin,deficiency Dietary insufficiency Unmasking of body deficits due to intracellular shift K + Mg 2+ Insulin release after D5W Correction of metabolic acidosis K + Onset of alcohol withdrawal PO - 4 Respiratory alkalosis Increased β-adrenergic tone PO - 4 Mg 2+ Ethanol-induced tubular dysfunction K + PO 4 - Mg 2+ Ca 2+

37 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

38 Magnesium Reabsorption in the Thick Limb Filtrate flow +15 mv Thick Ascending Limb Cell Interstitium -50 mv 0 mv Claudins-16,19 Ca 2+, Mg 2+ 3Na + 2K + Na + K + K + 2Cl - K + Mg 2+ Receptor Cl -

39 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 ( mmol or 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

40 Malabsorption Steatorrhea Diarrhea Antacids Ethanol-induced myopathy Parathyroid glands PTH release + Functional hypoparathyroidism PTH resistance Ca 2+ General malnutrition Vitamin,deficiency Dietary insufficiency Unmasking of body deficits due to intracellular shift K + Mg 2+ Insulin release after D5W Correction of metabolic acidosis K + Onset of alcohol withdrawal PO - 4 Respiratory alkalosis Increased β-adrenergic tone PO - 4 Mg 2+ Ethanol-induced tubular dysfunction K + PO 4 - Mg 2+ Ca 2+ H 2 O excretion Na +

41 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

42 Laboratory Data Creatinine 0.5 mg/dl, BUN 8 mg/dl Glucose 140 mg/dl Serum electrolytes (meq/l): Na + 94 K Cl - 65 HCO 3-25 Mg mg/dl Spot urine studies (meq/l) Na + <15 Cl - <10 UA: SG 1.002, + ketones U Osm 61 mosm/kg P Osm 200 mosm/kg

43 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

44 Beer content Na + <2 meq/l K meq/l Beer Potomania Assume Beer consumption of 5 liters Na + intake 10 mm K + intake 50 mm Obligatory urea excretion 80 mm/d }200 mosm If Uosm is 50 mosm/l, then 1 liter positive water balance ensues (200/50 = 4L)

45 Which one of the following is the mostly likely etiology for the hyponatremia? 1. Beer potomania 2. Thiazide diuretic 3. SSRI 4. Volume depletion

46 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 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 meq/l, K meq/l Urine osmolality: 50 mosm/kg Urine Na + 10 meq/l

47 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

48 ARS: Which one of the following is the most appropriate therapy? % 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

49 Time Course in Case Na + Na + Na + 8 hours 6 hours

50 Correcting Hyponatremia Acute Chronic 120 Rapid correction 140 l osmoles l osmoles Decreased osmoles Decreased osmoles Osmotic demyelination syndrome

51 Treating Chronic Hyponatremia Limits not to be exceeded to avoid iatrogenic injury < 10 meq/l per 24 hour <18 meq/l per 48 hour <20 meq/l per 72 hour Actual goals should be more modest 6-8 meq/l per 24 hour meq/l per 48 hour meq/l per 72 hour Semin Nephrol 29: , 2009

52 Risk Factors for Osmotic Demyelination Chronic hyponatremia Alcoholism Malnutrition Liver disease Burns Hypokalemia Serum Na + <105 meq/l

53 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 a + where it is now 4. Correct to a serum Na + of 115 meq/l by 0.5 meq/l/hr

54 Which one of the following is the most appropriate therapy? % 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

55 Case 59 yo woman with history of heavy ETOH use presents with severe weakness, poor appetite and decrease in oral intake Meds: losartan/hctz 100/12.5 mg daily, naproxen 220 mg twice daily Am J Kidney Ds 55: , < Mg 2+ : 1.9 Serum osm: 201 Urine osm: 546 U Na 22 U K ph 7.66, pco 2 34, po 2 87

56 Treatment and Course Initial treatment: 300 ml 0.9% NaCl, 800 ml fluid restriction, 430 meq/l KCL in 24 hours in S na = 17 meq/l in 24 h Am J Kidney Ds 55: , 2010

57 Potential Mechanism for Increased in Serum Na + following K + Repletion Serum [Na + ] ~ Na + E + K + E body water K + K + + Na + Buffered H + Osm H 2 O = Serum [Na + ]

58 Malabsorption Steatorrhea Diarrhea Antacids Ethanol-induced myopathy Parathyroid glands PTH release + Functional hypoparathyroidism PTH resistance Ca 2+ General malnutrition Vitamin,deficiency Dietary insufficiency Unmasking of body deficits due to intracellular shift K + Mg 2+ Insulin release after D5W Correction of metabolic acidosis K + Onset of alcohol withdrawal PO - 4 Respiratory alkalosis Increased β-adrenergic tone PO - 4 Mg 2+ Ethanol-induced tubular dysfunction Volume depletion, alcohol withdrawal, pain, nausea Low solute intake (Beer potomania) K + PO 4 - Mg 2+ Ca 2+ Non-osmotic release of vasopressin H 2 O excretion Na +

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60 Case A 32 year old man is brought to the emergency department because he became agitated and combative over the last 12 hours. His friend explains that the patient is into alcohol and all kinds of different inhalants and IV drugs, but cannon specify any substances that the patient may have used today. The patient is uncooperative and tachypneic but appears to be in generally good health.

61 Laboratory Data Creatinine 0.9 mg/dl BUN 6 mg/dl Serum electrolytes (meq/l): Na K Cl HCO 3-20 Glucose 182 mg/dl 325 mosm/kg S osm Arterial blood gas: ph 7.55 P CO2 21 Serum ketones positive 1:64 dilution Urine ketones 4+ Urine glucose 1+

62 ARS: Which of the following best describes the acid-base disturbance in this patient? 1. Acute respiratory alkalosis 2. Anion gap metabolic acidosis 3. Respiratory alkalosis and normal gap metabolic acidosis 4. Anion gap metabolic acidosis, respiratory alkalosis, and metabolic alkalosis

63 ARS: Which of the following is the most likely cause of this clinical syndrome? 1. Diabetic ketoacidosis 2. Alcoholic ketoacidosis 3. Isopropyl alcohol ingestion 4. Methanol ingestion 5. Toluene inhalation

64 Case Arterial ph = pco 2 = 21 mmhg Respiratory alkalosis Anion gap 9 Is this acute or chronic?

65 Respiratory Acid Base Disorders Acute respiratory acidosis For every 10 mmhg rise in pco 2 the HCO 3- increases by 1 meq/l Chronic respiratory acidosis For every 10 mmhg rise in pco 2 the HCO 3 - increases by meq/l Acute respiratory alkalosis For every 10 mmhg fall in pco 2 the HCO 3- decreases by 2 meq/l Chronic respiratory alkalosis For every 10 mmhg decrease in pco 2 the HCO 3 - decreases by 5 meq/l Palmer BF. Prim Care Jun;35(2):

66 Laboratory Data Serum electrolytes (meq/l): Na K Cl HCO 3-20 Arterial blood gas: ph 7.55 P CO2 21 Symptoms began 12 hours ago, so the patient has acute respiratory alkalosis For each 10 mmhg decrease in P CO2 the HCO 3- should decrease by 2 Osmolar gap = 35 What accounts for the osmolar gap, positive serum and urine ketones, with no evidence of metabolic acidosis?

67 Which of the following is the most likely cause of this clinical syndrome Isopropyl alcohol ingestion Found in rubbing alcohol, solvent, and deicers Metabolized by alcohol dehydrogenase to acetone Increased osmolar gap, ketonuria, acetone on the breath in the absence of metabolic acidosis Level >400 mg/dl life threatening

68 Which of the following best describes the acidbase disturbance in this patient? 1. Acute respiratory alkalosis 2. Anion gap metabolic acidosis 3. Respiratory alkalosis and normal gap metabolic acidosis 4. Anion gap metabolic acidosis, respiratory alkalosis, and metabolic alkalosis

69 Which of the following is the most likely cause of this clinical syndrome? 1. Diabetic ketoacidosis 2. Alcoholic ketoacidosis 3. Isopropyl alcohol ingestion 4. Methanol ingestion 5. Toluene inhalation

70