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