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Metabolic Acidosis
Mazen Kherallah, MD, FCCPInternal Medicine, Infectious Disease
and Critical Care Medicine
Basis of Metabolic Acidosis
H+ + HCO3- H2O + CO2
Added acids
Loss ofNaHCO3
New A- No New A-(rise in plasma AG) (no rise in plasma AG)
(Exhaled)
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 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)
Rate of Production of H+
Event Rate( mmol/min)
Comment
Production of H+
Lactic acid 72 Complete anoxia
7.2 10% hypoxia Ketoacids 1 Lack of insulin
Toxic alcohols <1 Poisening metabolites
Removal of H+
Excretion of NH4+ 0-2 Lag period
Metabolism
Lactic acid 4-8 Oxidation and glucogenesis
Ketoacids 0.8 Oxidized in brain and kidney
L oss o f N aH C O 3G I trac t
U rin eIn d irec t
N o rise in A G
K etoac id os is
Y es
R en a l fa ilu re
Y es
M eth an o lE th an o l
E th ylen e g lyco l
Y es
Typ e B L ac tic ac id os isD -lac tic ac id os is
O th er ac id s
N o
N o
Is G F R low
N o
L -lac tic ac id os is
Y es
N o
A re th e p lasm aketon es s tron g ly
p os it ive
R ise in A G =fa ll in H C O 3
M etab o lic a lka los is
R ise in A G >fa ll in H C O 3
Is th e A Ge leva ted
Y es
R esp ira to ryac id os is o r a lka los is
N o
M etab o lic A c id os is
Plasma osmolal gap
Is hypoxemia present?
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
KetoacidosisCauses
• 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
TG
Fatty acids
Hormone sensitive lipase
Fatty acids
Adrenaline
Insulin
-GP
Glucose
Adipocyte
Control of Ketoacid Production in the Liver
Fatty acids Acetyl-CoA Ketoacids
Fatty acids ATPHigh glucagonLow insulin
Liver
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 Fattyacids
Liver
H+ + HB-
ATP in other organs
OxidationATPBrain
750
400Kidney
Oxidation ATP
Ketoacidsand NH4in urine
1500
150Acetonein breath
200
Adipocyte
200
150
Excretion of -HB- + NH4+
has no net acid base effect
H+
-HB-
HCO3-
+CO2
ECF
-HB-
NH4+
HCO3-
Glutamine
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
AcAc-
NADH + H+ NAD+
-HB-
Acetone(nitroprusside test)
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 rightThus the quick test will be low
Alcoholic Ketoacidosis
TGAcetyl-
CoA
BrainATP
cells
Fatty acids
Low ECF-adrenergics
-
Low net insulin
+ + Ketoacids
Ethanol -
-
Rate of Production of H+
Event Rate( mmol/min)
Comment
Production of H+
Lactic acid 72 Complete anoxia
7.2 10% hypoxia Ketoacids 1 Lack of insulin
Toxic alcohols <1 Poisening metabolites
Removal of H+
Excretion of NH4+ 0-2 Lag period
Metabolism
Lactic acid 4-8 Oxidation and glucogenesis
Ketoacids 0.8 Oxidized in brain and kidney
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-1-phGlucose-6-ph
Fructose-5-ph
Fructose-1.6-diph
2 Glyceraldehyde-3-ph
Glycogen
1,3 Diphosphoglycerate
3-phosphoglycerate
2-phosphoglycerate
Phosphoenolpyruvate
Pyruvate
Lactate- + H+
NADH+H+
NAD+
NAD+ +H3PO4
NADH+H+
ATPADP
ATP
ADP
ADPATP
ADP
ATP
Formation of Lactic Acid in the Cytosols
Pyruvate + NADH + H+ Lactate + NAD
Lactate Dehydrogenase
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
Glucose
2 Pyruvate
2 Lactate + 2 ATP +
CO2 + H2O + 36 ATP
Alanine
Oxaloacetate
2H+
KrebsPDH
LDH
Gluconeognesis
Transamination
Glycolysis
Lactate= Pyruvate X Keq -------------------(NADH) (H+)
NAD
Keq is the equilibrium constant of LDH
Pyruvate + NADH + H+ Lactate + NADLactate Dehydrogenase LDH
Glucose
H+ + Lactate-
Na+ + HCO3- CO2 + H2O
-
ADP
ATP
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
• 2ATP2 ADP + 2 Pi + biologic work• Glucose + 2 ADP + 2 Pi 2 H+ + 2L-Lactate- + 2 ATP
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
L-Lactic AcidosisUnderutilization of L-lactic Acid
• Decreased gluconeogesis: liver problems, inhibitors by drugs
• Decreased Transamination: malnutrition
• Decreased oxidation: anaerobic conditions, PDH problems
Lactic Acidosis
• 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
Type A Type B
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
Ethanol Acetaldehyde
L-Lactate Pyruvate
NAD+ NADH + H+
Decreasing Rate of Metabolism in Specific Organs
Organ Strategy
Brain AnestheticsSedatives
Kidney Lower GFRLower Na pumping
Muscles Paralytic agents
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
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
Metabolic Acidosis Caused by Toxins
Alcohol AldehydeAlcohol dehydrogenase
Carboxylic AcidAldehyde dehydrogenase
Ethanol Acetaldehyde Acetic acid
Methanol Formaldehyde Formic acid
Ethylene glycol Glycoaldehyde Glycolic acidOxalic acid
Ethanol Methanol EthyleneGlycol
Isopropanol
CNSdepressant
+ + + +
Convulsion + + + +
Odor + - - Acetone
Blood gases Respiratoryacidosis,
ketoacidosis
Severemetabolicacidosis
Severemetabolicacidosis
Mild metabolicacidosis
AG + +++ +++ +
Osmo gap + + + +
Oxalatecrystaluria
- - ++hypocalcemia
-
Symptomsonset
30 minutes 12-48 hr 30 min-12 h Rapid
Lethal dose 5-8 g/kg 1-5 g/kg 1.5 g/Kg 3-4 g/kg
Lethal bloodlevel
350-500 80 200 400
Specialtreatment
HD ETOH, HD ETOH, HCO3,HD
HD, HCO3
Basis of Metabolic Acidosis
H+ + HCO3- H2O + CO2
Added acids
Loss ofNaHCO3
New A- No New A-(rise in plasma AG) (no rise in plasma AG)
(Exhaled)
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 HCO3-
• Acid 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 UrineNa 134 Na 10K 2.8 K 40CL 115 CL 100HCO3 10 Osmo 800H 62 Urea 300pH 7.20 pH 5.9
Acid IngestionAnion 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] HCO3content
Normal 15 24 360
ContractedECF
10 24 240
RestoredECF
15 16 240
Metabolic Acidosis Caused by ToxinsNormal Plasma Osmolal Gap
Toluene (Glue Sniffing)
Toluene Benzyl alcohol
Benzoate- + H+
Glycine
Hippurate-
+ H+
To urine along withNa, K, NH4
HCO3- +NH4+
Glutamine
H2O + CO2to exhaled air
Excessive Excretion of HCO3-
Inadequate Indirect Reabsorption of filtered HCO3-
HCO3- Na
H2CO3
H+ + HCO3-
CO2 + H2O
HCO3- Na+
H+
Na+
CA
CA
HCO3-
Indirect Reabsorption of HCO3-
Using 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 proximalreabsorption
Distaldelivery
Hco3Excretion
NH4excretion
Normal 4500 4000 500 0 30
ProximalRTA, onset
4500 3000 1500 >100 0
ProximalRTA,established
3600 3000 600 0 20
Indirect Reabsorption of HCO3-
Using 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
A ld os te ron e p rob lemTyp e IV
H yp erka lem ia
N H 3 p rob lem
< 5
H + sec re tionp rob lem
> 6
H yp oka lem ia
W h at is th e p lam a K ?
< 1 0 0 = R TA
O ccu lt overp rod u c tiono f ac id
> 2 5 0
W h at is th eu rin e osm ola l
g ap
N a+ K > C l
G I lossA ce tazo lam id e
A fte r h yp ocap n eaH C l,N H 4 C l,C aC l2
C l > N a+ K
M etab o lic A c id os isN orm a l A G
What is the urine pH?
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 Stronglypositive
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
TGAcetyl-
CoA
BrainATP
cells
Fatty acids
Low ECF-adrenergics
-
Low net insulin
+ + Ketoacids
Ethanol -
-
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
Glucose
2 Pyruvate
2 Lactate + 2 ATP +
CO2 + H2O + 36 ATP
Alanine
Oxaloacetate
2H+
KrebsPDH
LDH
Gluconeognesis
Transamination
Glycolysis
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 LuckAlcoholic 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 OverdosePlasma 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
