Metabolic Acidosis

1. Metabolic Acidosis Mazen Kherallah, MD, FCCP Internal Medicine, Infectious Disease and Critical Care Medicine

2. Basis of Metabolic Acidosis H+ + HCO3- H2O + CO2 (Exhaled) Added acids Loss of NaHCO3 New A- No New A- (rise in plasma AG) (no rise in plasma AG)

3. 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)

4. Actual Bicarbonate LossNormal 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)

5. Rate of Production of H+

6. Is hypoxemia present? Plasma osmolal gap

7. 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

9. Metabolic Acidosis with Elevated Plasma Anion Gap

10. KetoacidosisCauses • Ketoacidosis with normal -cell function: • Hypoglycemia • Inhibition of -cell (-adrenergics) • Excessive lipolysis • Ketoacidosis with abnormal -cell function: • Insulin-dependent diabetes mellitus • Pancreatic dysfunction

11. Ketoacids •  hydroxybuturic acid: a hydroxy acid • Acetoacetate: a real ketoacid • Acetone: it is not an acid

12. Production of Ketoacids Insulin TG Adrenaline Hormone sensitive lipase Glucose -GP Fattyacids Fatty acids Adipocyte

13. Control of Ketoacid Production in the Liver Liver Fatty acids Acetyl-CoA Ketoacids High glucagon Low insulin Fatty acids ATP

14. 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

15. Removal of Ketoacids Oxidation ATP Brain TG Fatty acids Liver Oxidation ATP Adipocyte 1500 750 200 Kidney H+ +  HB- 400 150 200 Ketoacids and NH4 in urine 150 Acetone in breath ATP in other organs

16. Excretion of -HB- + NH4+has no net acid base effect ECF HCO3- HCO3- + CO2 H+ -HB- Glutamine -HB- NH4+

17. 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

18. Conversion of Ketoacids to Acetone • Acetoacetate- + H+ + NADH  -HB- + NAD+ • Acetoacetate- + H+ Acetone + CO2

19. Balance of Ketoacids NADH + H+ NAD+ AcAc- -HB- If the patient has NADH accumulation in mitochondria, such as in hypoxia and during Alcohol metabolism, the equilibrium of the equation is displaced to the right Thus the quick test will be low Acetone (nitroprusside test)

20. Alcoholic Ketoacidosis Low ECF -adrenergics -  cells Low net insulin + Acetyl- CoA + TG Ketoacids Fatty acids - Ethanol Brain ATP -

21. Rate of Production of H+

22. 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

23. 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

24. Glucose Glucose-6-ph Glucose-1-ph Glycogen ATP ADP Fructose-5-ph ATP ADP NAD+ +H3PO4 NADH+H+ Fructose-1.6-diph 2 Glyceraldehyde-3-ph 1,3 Diphosphoglycerate ADP ATP ADP ATP 3-phosphoglycerate Phosphoenolpyruvate Pyruvate 2-phosphoglycerate NADH+H+ NAD+ Lactate- + H+

25. Formation of Lactic Acid in the Cytosols Lactate Dehydrogenase Pyruvate + NADH + H+  Lactate + NAD 1 time 10 times

26. Utilization of Lactic Acid Lactate itself cannot be utilized by the body, and blood Lactate levels are therefore dependent on pyruvate metabolism

27. 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

28. Gluconeognesis Oxaloacetate Glucose Glycolysis Krebs 2 Pyruvate CO2 + H2O + 36 ATP PDH LDH Transamination Alanine 2 Lactate + 2 ATP + 2H+

29. Lactate Dehydrogenase LDH Pyruvate + NADH + H+ Lactate + NAD (NADH) (H+) Lactate= Pyruvate X Keq ------------------- NAD Keq is the equilibrium constant of LDH

30. Glucose ADP ATP - H+ + Lactate- Na+ + HCO3- CO2 + H2O

31. L-Lactic AcidosisOverproduction 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 • 2ATP2 ADP + 2 Pi + biologic work • Glucose + 2 ADP + 2 Pi  2 H+ + 2L-Lactate- + 2 ATP

32. L-Lactic AcidosisOverproduction 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

33. L-Lactic AcidosisUnderutilization of L-lactic Acid • Decreased gluconeogesis: liver problems, inhibitors by drugs • Decreased Transamination: malnutrition • Decreased oxidation: anaerobic conditions, PDH problems

34. Severe hypoxemia Acute circulatory shock (poor delivery of O2) Severe anemia (low capacity of blood to carry O2) Prolonged seizures Exhausting exercise 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 Type A Type B

35. 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

36. Ethanol-Induced Metabolic Acidosis Acetaldehyde Ethanol NADH + H+ NAD+ L-Lactate Pyruvate

37. Decreasing Rate of Metabolism in Specific Organs

38. Organic Acid Load from the GI TractD-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 d-lactic acids, and 20% butyric acid

39. Organic Acid Load from the GI TractD-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

40. Metabolic Acidosis Caused by Toxins

42. Basis of Metabolic Acidosis H+ + HCO3- H2O + CO2 (Exhaled) Added acids Loss of NaHCO3 New A- No New A- (rise in plasma AG) (no rise in plasma AG)

43. Metabolic Acidosis With Normal Plasma Anion Gap

44. Normal Renal Response to Acidemia • Reabsorb all the filtered HCO3- • Increase new HCO3- generation by increasing the excretion of NH4+ in the urine

45. Renal Tubular Acidosis • Inability of the kidney to reabsorb the filtered HCO3- • Inability of the kidney to excrete NH4+

46. Metabolic Acidosis with Normal Plasma Anion Gap • Excessive excretion of NH4+ • Increased renal excretion of HCO3- • Low excretion of NH4+

47. Increased Renal Excretion of NH4+Negative Urine Net Charge/High Urine Osmolal Gap • Gastrointestinal Loss of HCO3- • Acid ingestion • Acetazolamide ingestion • Recovery from chronic hypocapnea • Expansion acidosis • Overproduction of acids with the rapid excretion of their conjugate base: Toluene

48. 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

49. An 80-year-old man with pyelonephritis, developed diarrhea after a course of antibiotics, what is the diagnosis?

50. Acid IngestionAnion of the Acid is Cl- • HCl • NH4Cl • Lysine-HCl • Arginine-HCl