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A 40-year-old man comes to the emergency department unresponsive. Vital signs show a blood pressure of 90/60 mmHg, a heart rate of 125/min, and a respiratory rate of 24/min. The patient’s pupils are fixed and dilated and a fruity breath odor is present. Physical examination reveals the liver edge is palpable 5 cm below the rib border. Laboratory data is consistent with metabolic acidosis with a high anion gap and normal glucose levels. Which of the following is the most likely diagnosis?
Content Reviewers:Rishi Desai, MD, MPH
With metabolic acidosis, “acidosis” refers to a process that lowers blood pH below 7.35, and “metabolic” refers to the fact that it’s a problem caused by a decrease in the bicarbonate HCO3− concentration in the blood.
Normally, blood pH depends on the balance or ratio between the concentration of bases, mainly bicarbonate HCO3−, which increases the pH, and acids, mainly carbon dioxide CO2, which decrease the pH.
The blood pH needs to be constantly between 7.35 and 7.45, and in addition the blood needs to remain electrically neutral, which means that the total cations, or positively charged particles, equals the total anions, or negatively charged particles.
Now, not all of the ions are easy or convenient to measure, so typically the dominant cation, sodium Na+, which is typically around 137 mEq/L and the two dominant anions, chloride Cl−, which is about 104 mEq/L, and bicarbonate HCO3−, which is around 24 mEq/L, are measured.
The rest are unmeasured. So just counting up these three ions, there’s usually a difference, or “gap” between the sodium Na+ concentration and the sum of bicarbonate HCO3− and chloride Cl− concentrations in the plasma, which is 137 minus 128 (104 plus 24) or 9 mEq/L.
This is known as the anion gap, and normally it ranges between 3 and 11 mEq/L. The anion gap largely represents unmeasured anions like organic acids and negatively charged plasma proteins, like albumin.
So, basically, metabolic acidosis arises either from the buildup of acid in our blood, which could be because it’s produced or ingested in increased amounts, or because the body can’t get rid of it, or from excessive bicarbonate HCO3− loss from the kidneys or gastrointestinal tract.
The main problem with all of this is that they lead to a primary decrease in the concentration of bicarbonate HCO3− in the blood.
In this case, the bicarbonate HCO3− ion concentration decreases by binding of bicarbonate HCO3− ions and protons H+, which results in the formation of H2CO3 carbonic acid, which subsequently breaks down into carbon dioxide CO2 and water H2O.
These protons can come from organic acids which have accumulated in the blood, but they can also come from increased production in our body.
Fats are then converted to ketoacids, such as acetoacetic acid and β-hydroxybutyric acid.
Another way acids can build up in our blood is due to an inability of the kidneys to throw them away, although they are produced in normal amounts.
This can happen in cases of chronic renal failure, in which organic acids such as uric acid or sulfur- containing amino acids can accumulate because they aren’t excreted normally.
In other cases, organic acids don’t come from inside our bodies at all, but, instead, they are accidentally ingested.
These include oxalic acid which can build up after an accidental ingestion of ethylene glycol, which is a common antifreeze, formic acid, which is a metabolite of methanol, a highly toxic alcohol, or hippuric acid, which comes from toluene, which is found in paint and glue.
All of these organic acids have protons, and at a physiologic pH, these organic acids dissociate into protons H+ and corresponding organic acid anions.
The protons H+ attach to bicarbonate HCO3− ions floating around, decreasing its plasma concentration and shifting the pH towards the acidic range.
The key is that the plasma maintains its electroneutrality, because for each new negatively charged organic acid anions, there’s one less bicarbonate HCO3− ion, and because the organic acid anions are not part of the anion gap equation, the anion gap will be high.
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