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Metabolic Acidosis Mazen Kherallah, MD, FCCP

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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 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)

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

8

9 Metabolic Acidosis with Elevated Plasma Anion Gap

10 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

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 Fatty acids Fatty acids Adipocyte

13 Control of Ketoacid Production in the 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 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
Adipocyte 1500 Oxidation ATP 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 AcAc- -HB- NADH + H+ NAD+
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 + TG + Acetyl- CoA Fatty acids Ketoacids - 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 mEq/L Eliminated in liver (50%), kidneys (25%), heart and skeletal muscles

24 Glucose Glucose-6-ph Glucose-1-ph Glycogen Fructose-5-ph
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 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 Glucose Oxaloacetate 2 Pyruvate CO2 + H2O + 36 ATP 2 Lactate + 2 ATP +
Gluconeognesis Glucose Oxaloacetate Glycolysis Krebs 2 Pyruvate CO2 + H2O + 36 ATP PDH LDH Transamination 2 Lactate + 2 ATP + Alanine 2H+

29 Pyruvate + NADH + H+  Lactate + NAD
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 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 2ATP2 ADP + 2 Pi + biologic work Glucose + 2 ADP + 2 Pi  2 H+ + 2L-Lactate- + 2 ATP

32 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

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

34 Lactic Acidosis Severe hypoxemia
Type A Type B 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

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 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 d-lactic acids, and 20% butyric acid

39 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

40 Metabolic Acidosis Caused by Toxins

41

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 Ingestion Anion of the Acid is Cl-
HCl NH4Cl Lysine-HCl Arginine-HCl

51 Acetazolamide Ingestion
Inhibition of carbonic anhydrase Bicarbonaturia Metabolic acidosis with loss of bicarbonate in the urine Normal anion gap

52 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

53 Expansion Acidosis

54 Metabolic Acidosis Caused by Toxins Normal Plasma Osmolal Gap Toluene (Glue Sniffing)
Benzyl alcohol Benzoate- + H+ Glycine To urine along with Na, K, NH4 Hippurate- + H+ H2O + CO2 to exhaled air HCO3- + NH4+ Glutamine

55 Excessive Excretion of HCO3- Inadequate Indirect Reabsorption of filtered HCO3-
HCO Na+ HCO Na H2CO3 Na+ H+ + HCO3- CO2 + H2O H+ HCO3- CA CA

56 Indirect Reabsorption of HCO3- Using the Transport of NH4+

57 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

58 Excessive Excretion of HCO3- Inadequate Indirect Reabsorption of filtered HCO3- Proximal RTA

59 Indirect Reabsorption of HCO3- Using the Transport of NH4+

60 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

61 What is the urine pH?

62 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

63 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

64

65 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

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

67 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

68

69

70 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?

71 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

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

73 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

74 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.

75

76 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

77 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

78 What is the diagnosis? Diabetic ketoacidosis Alcoholic ketoacidosis
Type A lactic acidosis Type B lactic acidosis D-Lactic acidosis Toxins

79 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

80 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

81 Acute Popsicle Overdose

82 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

83 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

84

85 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


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