Metabolic Sources of Acid Flashcards
Equation for anion gap
[Na+] - { [HCO3-] + [Cl-]
Normal value for anion gap
8-16 mEq/L
MUDPILES sources for acidosis
M - methanol
U - uremia (chronic kidney failure)
D - diabetic ketoacidosis
P - propylene glycol, paraldehyde
I - infection, iron, isoniazid, inborn errors of metabolism
L - lactic acidosis
E - ethylene glycol
S - salicylates
GOLDMARK sources of acidosis
G - glycols (ethylene, propylene)
O - oxoproline (acetaminophen toxicity)
L - L- lactic acidosis
D - D- Lactate
M - methanol
A - aspirin
R - renal failure
K - ketoacidosis
Most common form of acidosis seen in hospitalized patients
Lactic acidosis
What concentration is considered lactic acidosis
Anything above 4 mmol/L
Major source of lactic acid in the body
formation from pyruvate by the action of lactate dehydrogenase (the lactic acid produced in this fashion is the L stereoisomer
All cells can do this, but red blood cells are major source
What is the purpose of forming lactic acid
In cells carrying out anaerobic metabolism, the production of lactate from pyruvate serves to recycle NADH back to NAD+, thereby preventing these cells from exhausting supplies of NAD+ and inhibiting glycolysis.
Is lactic acid formed in aerobic cells?
No. In cells undergoing aerobic metabolism, little lactic acid is formed because pyruvate formed during glycolysis is consumed by the pyruvate dehydrogenase reaction and cytoplasmic NADH is transported into mitochondria through various transporters and once inside mitochondria, NADH is converted back to NAD+ by donating its electrons to the electron transport chain
What is type A lactic acidosis caused by
Type A lactic acidosis is caused by impaired tissue oxygenation (hypoxia). Major causes of type A lactic acidosis include various types of circulatory shock (whole body circulatory failure) induced by hypovolemia, cardiac failure, or sepsis.
How does lack of oxygen cause acidosis
The lack of oxygen takes away the ultimate electron acceptor from the electron chain, inibiting cytochrome oxidase
This causes a back-up of NADH and pyruvate, causing an enventual shift to the formation of lactic acid
Lower ATP production pushes for more glycolysis, making more of a backup
What causes Type B lactic acidosis
Elevated levels of lactic acid are caused by mechanisms other than impaired tissue oxygenation. These mechanisms can include congenital or acquired defects in mitochondrial function.
Congenital causes of type B lactic acidosis
Maternal inheritance - mutations in mitochondrial DNA can affect either components of the electron transport chain, the F1/F0-ATPase, or components of the mitochondrial protein synthetic machinery, and so affecting the synthesis of all proteins encoded by mitochondrial DNA. Example is MELAS
Mendelian inheritance - mutations in nuclearly encoded components of the electron transport chain or the F1/F0 ATPase. Example is Leigh’s syndrome
Acquired causes of type b lactic acidosis
Linezolid - can impact mitochondrial functioning
Several HIV drugs can impact mitochondrial DNA polymerase gamma
Chronic alcoholism becuase accumulation of NADH
Biguanide (metformin, phenformin) therapy for type II diabetes
Mechanism of salicylate toxicity
Salicylate can cause a respiratory alkalosis due to direct effects on stimulating the respiratory center.
This respiratory effect is early in salicylate poisoning and is associated with an early decrease in CO2levels.
Metabolic acidosis then follows, with an increase in organic acids including lactic acid and in some cases, ketoacids.
Mechanism of propylene glycol acidosis
Propylene glycol can be metabolized into either L- or D-lactic acid depending upon which pathway predominates
Mechanism of D-lactic acidosis
D-lactic acidosis arises from the production of D lactic acid by intestinal bacteria and is most commonly observed in patients with short bowel syndrome.
Can also be caused by ingestion of too much propylene glycol and in diabetic keotacidosis
Causes of ketoacidosis
prolonged fasting
diabetes
alcoholism
Acids that accumulate in ketoacidosis
acetoacetate and β-hydroxybutyrate
Mechanism of fasting ketosis
During a fast, insulin is low and glucagon is now the predominant hormone regulating carbohydrate and fat metabolism. Ketoacids from from fat.
Adipose triacyglycerols eventually form B-hydroxybutrate and acetone
What is the driving force in diabetic ketoacidosis
Nn elevated glucagon to insulin ratio (an absolute insulin deficiency in type I diabetes, ketoacidosis is a less common feature of type II diabete)
What contributes to the severity of diabetic ketoacidosis
- Increased production of ketoacids
- Dehydration
- Impaired kidney excretion of ketoacids
Mechanism of alcoholic ketoacidosis
Driven by chronic alcohol consumption and associated malnutrition
Malnutrition shifts the glucagon/insulin ratio towards glucagon thereby favoring lipolysis and ketone body production.
Meanwhile metabolism of ingested alcohol shifts the NAD+/NADH ratio of cells toward NADH while at the same time increasing acetyl-CoA levels
Usually more serious than lactic acidosis caused by alcohol
Mechanism of methanol acidosis
Methanol is converted to formaldehyde by alcohol (slow)
Also converted to formic acid by aldehyde dehydrogenase (fast)
Formic acid is thn converted to formyl-tetrahydrofolate by formyl-THF synthase, and then to CO2 and water by formyl-THF dehydrogenase (very slow)
Formic acid is the cause of the acidosis, and persists because of its slow breakdown
Why does formic acid cause toxicity
Formic acid alone is toxic to the optic nerve, but it also inhibits cytochrome oxidase, disrupting mitochondrial function leading to elevated levels of lactic acid, adding further to the acidosis.
Mechanism of ethylene glycol toxicity
Ethylene glycol can be metabolized to a number of different acids.
The acid that contributes most to the metabolic acidosis is glycolic acid.
The other acids that accumulate contribute to additional toxicities:
formic acid, retina
oxalic acid, nephrotoxicity
ethanol, methanol, propylene glycol, and ethylene glycol are initially metabolized by _______.
alcohol dehydrogenase.
How can methanol, propylene glycol, and ethylene glycol intoxication can be delayed
administration of ethanol or another inhibitor of alcohol dehydrogenase, like fomepizole
How is acetominophen metabolised by the body
acetaminophen is subject to phase 2 metabolism and is conjugated with glutathione prior to being eliminated from the body
How does chronic acetaminophen cause acidosis
With chronic adminstration of acetaminophen, glutathione levels are depleted in order to metabolise it.
Drop in glutathione levels removed negative feedback and more gamma-glutamylcysteine is formed. This will normally be coupled with glycine to form glutathione
In settings of malnutrition, glycine is low, so gama-glutamylcysteine is broken down into cysteine and oxoproline
Oxoproline is converted to glutamate very slowly, and it is an acid so its backup causes acidosis
