Transcript Metabolic Acidosis

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
• 2ATP2 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