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Metabolic Acidosis Mazen Kherallah, MD, FCCP Internal Medicine, Infectious Disease and Critical Care Medicine Basis of Metabolic Acidosis H+ + HCO3 H2O + CO2 (Exhaled) Added acids New A(rise in plasma AG) Loss of NaHCO3 No New A(no rise in plasma AG) Overproduction of Acids • Retention of anions in plasma (increased anion gap): – L-lactic acidosis – Ketoacidosis (-hydroxybutyric acid) – Overproduction of organic acids in GI tract (D-lactic acidosis) – Conversion of alcohol (methanol, ethylene glycol) to acids and poisonous aldehydes • Excretion of anions in the urine (normal plasma anion gap): – Ketoacidosis and impaired renal reabsorption of hydroxybutyric acid – Inhalation of toluene (hippurate) Actual Bicarbonate Loss Normal Plasma Anion Gap • Direct loss of NaHCO3 – Gastrointestinal tract (diarrhea, ileus, fistula or T-tube drainage, villous adenoma, ileal conduit combined with delivery of Cl- from urine) – Urinary tract ( proximal RTA, use of carbonic anhydrase inhibitors) • Indirect loss of NaHCO3 – Failure of renal generation of new bicarbonate (low NH4+ excretion) – Low production of NH4+ (renal failure, hyperkalemia) – Low transfer of NH4+ to the urine (medullary interstitial disease, low distal net H+ secretion) Rate of Production of Event Rate ( mmol/min) + H Comment Production of H+ Lactic acid Ketoacids 72 7.2 1 Complete anoxia 10% hypoxia Lack of insulin Toxic alcohols <1 Poisening metabolites 0-2 Lag period Lactic acid 4-8 Oxidation and glucogenesis Ketoacids 0.8 Oxidized in brain and kidney Removal of H+ Excretion of NH4+ Metabolism Metabolic Acidosis Yes No Is the AG elevated Respiratory acidosis or alkalosis No rise in AG Rise in AG= fall in HCO3 Rise in AG> fall in HCO3 Loss of NaHCO3 GI tract Urine Indirect Are the plasma ketones strongly positive Metabolic alkalosis Yes No Is hypoxemia present? Ketoacidosis No Yes Is GFR low L-lactic acidosis Yes No Plasma osmolal gap Renal failure Yes No Methanol Ethanol Ethylene glycol Type B Lactic acidosis D-lactic acidosis Other acids Diagnostic Approach to Metabolic Acidosis • Confirm that metabolic acidosis is present • Has the ventilatory system responded appropriately • Does the patient have metabolic acidosis and no increase in plasma anion gap • Has the plasma anion gap risen appropriately Patient [H+] pH PaCO2 [HCO3-] A 64 7.20 20 8 B 120 6.90 40 8 C 30 7.50 10 8 Metabolic Acidosis with Elevated Plasma Anion Gap Ketoacidosis Causes • Ketoacidosis with normal -cell function: – Hypoglycemia – Inhibition of -cell (-adrenergics) – Excessive lipolysis • Ketoacidosis with abnormal -cell function: – Insulin-dependent diabetes mellitus – Pancreatic dysfunction Ketoacids • hydroxybuturic acid: a hydroxy acid • Acetoacetate: a real ketoacid • Acetone: it is not an acid Production of Ketoacids Insulin TG Adrenaline Hormone sensitive lipase Fatty acids Glucose -GP Fatty acids Adipocyte Control of Ketoacid Production in the Liver Liver Fatty acids Acetyl-CoA Ketoacids High glucagon Low insulin Fatty acids ATP Production of Ketoacids • Ketoacids are produced at a rate of not more than 1.3 mmol/min • Maximum rate of production would be 1500- 1850 mmol/day • The brain can oxidize 750 mmol/day • The kidney will oxidize 250 mmol/day Removal of Ketoacids TG Adipocyte Fatty acids Liver Oxidation ATP Brain Oxidation 750 200 ATP H+ + HB- 400 Kidney 150 200 Ketoacids 150 and NH4 Acetone ATP in other in urine in breath organs 1500 Excretion of -HB- + NH4+ has no net acid base effect ECF H+ -HB- HCO3- HCO3+ CO2 Glutamine -HBNH4+ Excretion of -HB- + NH4+ • If NH4+ are excreted, HCO3- are added to the body, and balance for H+ and is restored. • To the degree that -HB- are excreted with Na and K, a deficit of HCO3- Na and K may occur Conversion of Ketoacids to Acetone • Acetoacetate- + H+ + NADH -HB- + NAD+ • Acetoacetate- + H+ Acetone + CO2 Balance of Ketoacids NADH + H+ AcAc- NAD+ -HB- If the patient has NADH accumulation in mitochondria, such as in hypoxia and during Acetone Alcohol metabolism, the equilibrium of the (nitroprusside test)equation is displaced to the right Thus the quick test will be low Alcoholic Ketoacidosis Low ECF -adrenergics - cells Low net insulin TG + Fatty acids + Ethanol AcetylCoA Ketoacids - - Brain ATP Rate of Production of Event Rate ( mmol/min) + H Comment Production of H+ Lactic acid Ketoacids 72 7.2 1 Complete anoxia 10% hypoxia Lack of insulin Toxic alcohols <1 Poisening metabolites 0-2 Lag period Lactic acid 4-8 Oxidation and glucogenesis Ketoacids 0.8 Oxidized in brain and kidney Removal of H+ Excretion of NH4+ Metabolism Stoichiometry of ATP and O2 • The ratio of phosphorus to oxygen is 3:1 • 6 ATP can be produced per O2 • Consumption of at rest is close to 12 mmol/min • The amount of ATP needed per minute is 12 X 6, or 72 mmol/min Lactic Acid • Dead-end product of glycolysis • Produced in all tissues • Most from tissues with high rate of glycolysis, gut, erythrocytes, brain, skin, and skeletal muscles • Total of 15 to 20 mEq/kg is produced per day • Normal lactic level is maintained at 0.7-1.3 mEq/L • Eliminated in liver (50%), kidneys (25%), heart and skeletal muscles Glucose Glucose-6-ph Glucose-1-ph Glycogen ATP ADP Fructose-5-ph ATP ADP NAD+ +H3PO4 Fructose-1.6-diph 2 Glyceraldehyde-3-ph NADH+H+ 1,3 Diphosphoglycerate ADP ATP ADP Phosphoenolpyruvate 3-phosphoglycerate ATP NADH+H+ Pyruvate NAD+ Lactate- + H+ 2-phosphoglycerate Formation of Lactic Acid in the Cytosols Lactate Dehydrogenase Pyruvate + NADH + H+ Lactate + NAD 1 time 10 times Utilization of Lactic Acid Lactate itself cannot be utilized by the body, and blood Lactate levels are therefore dependent on pyruvate metabolism Pyruvate can be Utilized by Three Pathways • Conversion to acetyl-CoA and oxidization to CO2 and H2O by Krebs cycle • Transamination with glutamine to form alanine and -ketogluarate • Gluconeogenesis in the liver and kidney: Cori Cycle Gluconeognesis Oxaloacetate Glucose Glycolysis 2 Pyruvate LDH 2 Lactate + 2 ATP + 2H+ Krebs PDH CO2 + H2O + 36 ATP Transamination Alanine Lactate Dehydrogenase LDH Pyruvate + NADH + H+ Lactate + NAD (NADH) (H+) Lactate= Pyruvate X Keq ------------------NAD Keq is the equilibrium constant of LDH Glucose ADP ATP H+ + LactateNa+ + HCO3- CO2 + H2O L-Lactic Acidosis Overproduction of L-lactic Acid • Net production of L-lactic acid occurs when the body must regenerate ATP without oxygen • 1 H+ is produced per ATP regenerated from glucose • Because a patient will need to regenerate 72 mmol of ATP per minutes, As much as 72 mmol/min of H+ can be produced in case of anoxia • 2ATP2 ADP + 2 Pi + biologic work • Glucose + 2 ADP + 2 Pi 2 H+ + 2L-Lactate- + 2 ATP L-Lactic Acidosis Overproduction of L-lactic Acid • Rapid increase in metabolic rate: strenuous exercise • Increase Glycolysis • Normal Lactate/Pyruvate ratio suggest that the cause is not related to anaerobic metabolism or anoxia L-Lactic Acidosis Underutilization of L-lactic Acid • Decreased gluconeogesis: liver problems, inhibitors by drugs • Decreased Transamination: malnutrition • Decreased oxidation: anaerobic conditions, PDH problems Lactic Acidosis Type A • Severe hypoxemia • Acute circulatory shock (poor delivery of O2) • Severe anemia (low capacity of blood to carry O2) • Prolonged seizures • Exhausting exercise Type B • PDH problems: thiamin deficiency or an inborn error • Decreased gluconeogenesis, liver failure, biguanide, alcohol • Excessive formation of lactic acid: malignant cells, low ATP, inhibition of mitochondrial generation of ATP: cyanide, uncoupling oxidation and phosphorylation, alcohol intoxication Lactic Acidosis in Sepsis • • • • Normal lactate/Pyruvate ratio Increasing Do2 Does not reduce lactate level Inhibition of pyruvate dehydrogenase Increase pyruvate production by increased aerobic glycolysis • Hypoxia and hypoperfusion Ethanol-Induced Metabolic Acidosis Acetaldehyde Ethanol NAD+ L-Lactate NADH + H+ Pyruvate Decreasing Rate of Metabolism in Specific Organs Organ Strategy Brain Anesthetics Sedatives Lower GFR Lower Na pumping Paralytic agents Kidney Muscles Organic Acid Load from the GI Tract D-Lactic Acidosis • Bacteria in GI tract that convert cellulose into organic acids: – Butyric acid: provide ATP to colon – Propionic acid and D-lactic acid – Acetic acid • Total of 300 mmol of organic acids is produced each day: 60% acetic acid, 20% propionic and dlactic acids, and 20% butyric acid Organic Acid Load from the GI Tract D-Lactic Acidosis • Slow GI transit lead to bacterial growth: blind loop, obstruction, drugs decreasing GI motility • A change in bacterial flora secondary to antibiotic usage : large population of bacteria producing D-lactic • Feeding with carbohydrate-rich food will aggravate D-lactic acidosis in patients with GI bacterial overgrowth Metabolic Acidosis Caused by Toxins Alcohol Aldehyde Carboxylic Acid Alcohol dehydrogenase Aldehyde dehydrogenase Ethanol Acetaldehyde Acetic acid Methanol Formaldehyde Formic acid Ethylene glycol Glycoaldehyde Glycolic acid Oxalic acid Ethanol Methanol Ethylene Glycol + Isopropanol CNS depressant Convulsion + + + + + + Odor + - - Acetone Respiratory acidosis, ketoacidosis + Severe metabolic acidosis +++ Severe metabolic acidosis +++ Mild metabolic acidosis Osmo gap + + + + Oxalate crystaluria Symptoms onset Lethal dose - - - 30 minutes 12-48 hr ++ hypocalcemia 30 min-12 h Rapid 5-8 g/kg 1-5 g/kg 1.5 g/Kg 3-4 g/kg 350-500 80 200 400 HD ETOH, HD ETOH, HCO3, HD HD, HCO3 Blood gases AG Lethal blood level Special treatment + + Basis of Metabolic Acidosis H+ + HCO3 H2O + CO2 (Exhaled) Added acids New A(rise in plasma AG) Loss of NaHCO3 No New A(no rise in plasma AG) Metabolic Acidosis With Normal Plasma Anion Gap Normal Renal Response to Acidemia • Reabsorb all the filtered HCO3• Increase new HCO3- generation by increasing the excretion of NH4+ in the urine Renal Tubular Acidosis • Inability of the kidney to reabsorb the filtered HCO3• Inability of the kidney to excrete NH4+ Metabolic Acidosis with Normal Plasma Anion Gap • Excessive excretion of NH4+ • Increased renal excretion of HCO3• Low excretion of NH4+ Increased Renal Excretion of NH4 + Negative Urine Net Charge/High Urine Osmolal Gap • • • • • • Gastrointestinal Loss of HCO3Acid ingestion Acetazolamide ingestion Recovery from chronic hypocapnea Expansion acidosis Overproduction of acids with the rapid excretion of their conjugate base: Toluene Diarrhea • Should be more than 4 liters per day • Normal kidney can generate 200 mmol of HCO3 as a result of enhanced excretion of NH4 • Normal anion gap with acidosis and negative urine net charge and increased osmolality An 80-year-old man with pyelonephritis, developed diarrhea after a course of antibiotics, what is the diagnosis? Plasma Na K CL HCO3 H pH 134 2.8 115 10 62 7.20 Urine Na K CL Osmo Urea pH 10 40 100 800 300 5.9 Acid Ingestion Anion of the Acid is Cl• • • • HCl NH4Cl Lysine-HCl Arginine-HCl Acetazolamide Ingestion • Inhibition of carbonic anhydrase • Bicarbonaturia • Metabolic acidosis with loss of bicarbonate in the urine • Normal anion gap Recovery from Chronic Hypocapnea • During hyperventilation and hypocanea, the low PCO2 will be compensated by decreased bicarbonate • If the stimulus for hyperventilation and hypocapnea resolved, the lag period before the bicarbonate is corrected will give metabolic acidosis Expansion Acidosis Condition ECF volume [HCO3] HCO3 content Normal 15 24 360 Contracted ECF 10 24 240 Restored ECF 15 16 240 Metabolic Acidosis Caused by Toxins Normal Plasma Osmolal Gap Toluene (Glue Sniffing) Toluene Benzyl alcohol Benzoate- + H+ Glycine Hippurate+ H+ Glutamine HCO3+ NH4+ To urine along with Na, K, NH4 H2O + CO2 to exhaled air Excessive Excretion of HCO3- Inadequate Indirect Reabsorption of filtered HCO3HCO3- Na+ Na+ HCO3- Na H+ H2CO3 H+ + HCO3CA CA CO2 + H2O HCO3- Indirect Reabsorption of HCO3Using the Transport of NH4+ Excessive Excretion of HCO3- Inadequate Indirect Reabsorption of filtered HCO3- Proximal RTA • • • • • • A defect in proximal H+ secretion Excretion of NaHCO3 in the urine Metabolic acidosis and no increase in AG Bicarbonaturia at onset Decreased filtered bicarbonate Decreased Bicarbonaturia Excessive Excretion of HCO3- Inadequate Indirect Reabsorption of filtered HCO3- Proximal RTA Filtered proximal Distal reabsorption delivery Hco3 Excretion NH4 excretion Normal 4500 4000 500 0 30 Proximal RTA, onset 4500 3000 1500 >100 0 Proximal RTA, established 3600 3000 600 0 20 Indirect Reabsorption of HCO3Using the Transport of NH4+ Reduced Renal Excretion of NH4+ Distal RTA • Reduced excretion of NH4+ • Failure to regenerate the needed HCO3 • Decreased [NH3] in the medullary interstitium: high urine pH • Decreased transfer of NH3 to the lumen of the collecting duct Metabolic Acidosis Normal AG Na+K > Cl Cl > Na+K What is the urine osmolal gap GI loss Acetazolamide After hypocapnea HCl,NH4Cl,CaCl2 < 100 =RTA > 250 What is the plama K? Occult overproduction of acid Hyperkalemia Aldosterone problem Type IV Hypokalemia What is the urine pH? <5 >6 NH3 problem H+ secretion problem Metabolic Acidosis in Renal Failure • Normal AG acidosis results from failure of the kidney to generate new HCO3- from a reduced rate of synthesis and excretion of NH4+ • Increased AG acidosis results from the reduced GFR, with accumulation of anions: HPO4 Ken Has a Drinking Problem • 26 year old man consumed an excessive quantity of alcohol during the past week, in the last 2 days he has been eaten little and has vomited on many occasions. • He has no history of DM • P.E. revealed marked ECF contraction, alcohol is detected in his breath Blood Plasma Glucose 90 Na 140 BUN 28 K 3.0 pH 7.30 Cl 93 H 50 HCO3 15 PaCO2 30 Ketones Strongly positive Ken Has a Drinking Problem • Large Na deficit due to renal Na excretion dragged out by HCO3 from vomiting • Hypokalemia results from excessive loss of K in the urine due to hyperaldpsteronism secondary to ECF contraction and because of bicarbonturia • Metabolic acidosis with high anion gap of 20 • AG is grater than the fall in plasma bicarbonate 20>10 • Alcoholic ketoacidosis secondary to relative insulin deficiency plus L-lactic acidosis secondary to low ECF and ethanol Alcoholic Ketoacidosis Low ECF -adrenergics - cells Low net insulin TG + Fatty acids + Ethanol AcetylCoA Ketoacids - - Brain ATP An Unusual Case of Ketoacidosis • A 21-year-old woman has had DM for 2 years and requires insulin. Six months ago, she presented with lethargy, malaise, headache, and metabolic acidosis with normal plasma anion gap, her complaints and the acid-base disturbance have persisted for 6 months. She denies taking acetazolamide, halides, or HCl equivalents • While taking her usual 34 units of insulin per day, she frequently had glycosuria and ketonuria but no major increase in AG Plasma Urea 20 Na 136 Creatinine 0.9 K 2.9 Glucose 190 Cl 103 pH 7.35 HCO3 19 H 45 AG 14 PaCO2 35 -HB 2.2 Urine Glucose 5 Na 47 Urea 50 K 60 pH 5.3 Cl 13 Osmolality 680 An Unusual Case of Ketoacidosis • Metabolic acidosis with mildly elevated AG and positive urine net charge suggest RTA secondary of low proximal or distal H secretion associated with hypokalemia • Do you agree? An Unusual Case of Ketoacidosis • Calculated osmolality is 269 and osmolal gap is 411 indicating the presence of a large number of unmeasured osmoles • NH4 was 120 mmol/L in the urine indicating normal response to acidosis • -HB acid level is 234 mmol/L • Thus acidosis was not evident because of marked ketonuria Gluconeognesis Oxaloacetate Glucose Glycolysis 2 Pyruvate LDH 2 Lactate + 2 ATP + 2H+ Krebs PDH CO2 + H2O + 36 ATP Transamination Alanine Excretion of -HB- + NH4+ • If NH4+ are excreted, HCO3- are added to the body, and balance for H+ and is restored. • To the degree that -HB- are excreted with Na and K, a deficit of HCO3- Na and K may occur A Stroke of Bad Luck • 42 year old man has hypertension and rare alcohol binges, last night he consumed half a bottle of whiskey. This morning he was found unconscious and has intracerebral hemorrhage. There was no ECF volume contraction • Laboratory results now and after 2 hours with no change. Plasma pH 6.96 Glucose 162 PaCO2 11 Urea 14 HCO3 3 Creatinine 0.8 AG 42 Osmolality 305 Na 139 Ethanol 20 K 6.8 Ketones moderate A Stroke of Bad Luck Alcoholic Ketoacidosis • Metabolic acidosis with elevation of 30 due to overproduction of acid • L-lactic acid level was 7 mmol/L • -HB level was 16 mmol/L • The rest would be Acetoacetate and probably D-lactic acid A Superstar of Severe Acidosis • A patient walked into the emergency room because of SOB • PE revealed near normal ECF volume and hyperventilation • His GFR was normal • pH 6.79, PCO2 9, HCO3 1, AG 46, normal osmolal gap What is the diagnosis? • • • • • • Diabetic ketoacidosis Alcoholic ketoacidosis Type A lactic acidosis Type B lactic acidosis D-Lactic acidosis Toxins Type B Lactic Acidosis • Low rate of acid production, otherwise acidosis would have killed the patient • Normal ECF volume rules out DKA and AKA • No history of GI problem rules out D-lactic acidosis • L-Lactic acid level was higher than 30 mmol/L and the patient was taking metformin for the treatment of NIDDM Acute Popsicle Overdose • 56 year old man developed diarrhea while traveling abroad for several months. He took antibiotics an a GI motility depressant, he consumed many popsicles to quench his thirst. • Condition deteriorated and presented with confusion and poor coordination Acute Popsicle Overdose Plasma Urine PH 7.20 5.2 PaCO2 25 No data HCO3 10 0 AG 19 101 Osmolal gap 0 No data Albumin 38 No data Ketoacids Negative Negative D-Lactic Acidosis • Metabolic acidosis with elevated AG of 7 and decreased HCO3 of 15 indicating: • Mixed type metabolic acidosis: increased AG (overproduction of acid) and normal AG (bicarbonate loss in diarrhea) • D-Lactic acid was 10 mmol/L • Bacteria in the GI were fed sugar from the popsicles and started producing D-Lactic acids plus CNS toxins The Kidneys Are Seeing Red • 27 year old patient noticed progressive weakness when climbing stairs during the past several months. There was no diarrhea or evidence of problem in the GI tract. There was no special findings in the physical examination Plasma Urine pH 7.32 7.3 HCO3 17 - PCO2 32 - Na 140 57 K 2.7 32 Cl 115 82 Creatinine 0.8 7 Osmolality 290 350 Distal RTA • Normal AG metabolic acidosis • Low rate of NH4 excretion • Little excretion of HCO3 in urine following bicarbonate therapy, rules out proximal RTA • The diagnosis is distal RTA