MUDPILES is a long-standing acronym that is used to quickly recall the likely causes of high anion gap metabolic acidosis but it usually stops right there. How do the components cause acidosis? Why is it important to know the how?
Understanding vs Memorizing
As our patients increasingly present with more complex comorbidities the straight pathway to correction of pathologies is becoming more twisted. The body is one big continuous chemical reaction, one pathology bleeds into the next and it is becoming increasingly difficult to apply the strict recommendations of clinical guidelines to very complex patients. If we understand the mechanics of these pathologies rather than just know what they are, we are better able to respond to unique patient presentations.
Organic Acids
Plasma is 92% water. In plasma an organic acid will dissolve, releasing its hydrogen ion (H+) and becoming an anion. The increase in hydrogen ions increases acidity (lower pH). The increase in anions increases the calculated anion gap because they are not accounted for in the anion gap equation. This is the basis for the occurrence of high anion gap metabolic acidosis.
As you will see, many of the causes of high anion gap metabolic acidosis are secondary to the production of varying organic acids. These acids accumulate due to impaired clearance or are introduced into the body in overwhelming quantities.
Organic acids all share the common molecular structure:
Anion Gap
Understanding how the anion gap is calculated and its interpretation with regards to plasma’s electrical neutrality is necessary for understanding how these organic acids will lead to an increase in the anion gap.
Calculated anion gap looks at the difference between predominant cations and anions to provide a normal value of 4-12mEq/ml. Any anions not included in the equation will increase the anion gap as it accumulates.
The unit Anion Gap has everything you need to truly understand this concept.
MUDPILES
The components of MUDPILES are:
How does methanol cause acidosis?
Methanol is an alcohol used commercially in the production of fuel, windshield washer fluid and as a solvent in inks and dyes. It is poisonous when consumed or when its vapors are inhaled in high concentrations.
When methanol enters the body it is oxidized into formic acid. Formic acid is an organic acid that will dissolve in plasma to form the anionic formate ion by releasing acidic hydrogen ions. Thus increasing both acidity and the anion gap leading to high anion gap metabolic acidosis.
How does uremia cause acidosis?
When protein is metabolized it produces ammonia, which is a toxic by-product. The liver converts ammonia to urea which is then cleared by the kidneys. When kidney function is impaired urea accumulates in plasma resulting in uremia.
Urea is neither acidic nor basic. In reality is has no real effect on the bloods pH. It is really just a measurable surrogate marker for organic compounds that are also cleared by the kidneys. If urea is not being cleared, these organic compounds are also not being cleared. These other organic compounds are acidic. They include sulfates and phosphates.
In plasma, organic acids will release their hydrogen ions, increasing acidity causing metabolic acidosis. While the accumulation of the accompanying anion will increase the calculated anion gap.
Subscribe for Access to Exclusive Content
How does DKA cause acidosis?
DKA refers to diabetic ketoacidosis. In the absence of sufficient insulin to convert glucose into energy the liver will convert fat to energy instead. A byproduct of this conversion is ketones.
Ketogenesis is a normal biological process. Under normal conditions ketones are readily cleared by the kidneys. However ketogenesis is intended to be temporary compensation for short periods of insufficient insulin and/or glucose. When the body remains in ketogenesis for too long, this can lead to toxic accumulation that the kidneys are not able to handle.
Ketones are organic acids. Therefore in plasma they will dissociate into acidic hydrogen ions and organic anions. As both accumulate, acidity and the anion gap will also increase.
How does propylene glycol cause acidosis?
Propylene glycol is a synthesized clear liquid used across many industries including pharmaceutical and food industries because of its ability to absorb and maintain moisture in medicines and foods. It is also used as an alternative to ethylene glycol in antifreeze. Propylene glycol is also the main compound in artificial smoke used at concerts and shows.
Propylene glycol can cause toxicity when it is encountered in high concentrations. This can occur as an occupational hazard or from prolonged exposure to artificial smoke in enclosed spaces. In medicine, propylene glycol toxicity can occur when large doses of intravenous benzodiazepines like lorazepam and IV phenytoin are given over a prolonged period of time or as a continuous infusion.
When propylene glycol is absorbed by the body, it is converted by the liver to lactic acid. Under normal conditions, lactic acid can be cleared by the body. Lactic acid will dissolve to release its hydrogen ion and anionic lactate ion. When present in large quantities this will increase acidity and the calculated anion gap respectively causing high anion gap metabolic acidosis.
How does Isoniazid cause acidosis?
Isoniazid is an antibiotic used to treat tuberculosis. Toxicity has been reported with both therapeutic and toxic doses. Acute isoniazid toxicity presents primarily as seizures. It is those seizures that leads to an accumulation of lactic acid and progression to severe lactic acidosis.
The recurrent and intense muscle contractions that occur during a seizure results in anaerobic metabolism, a byproduct of which is lactic acid. Isoniazid toxicity is associated with recurrent seizures overwhelming the body’s normal mechanisms for clearing lactate leading to accumulation.
Again lactic acid will dissolve in plasma to release its hydrogen ions and anionic lactate ion. In large concentrations, this will cause metabolic acidosis and an increase in the anion gap.
How does Iron cause acidosis?
Iron is available over the counter and cause toxicity when excess amounts are ingested especially by curious kids. The 2023 annual report from the National Poison Data System lists iron among fatal pharmaceutical exposures for that year.
Iron can cause acidosis in multiple ways. On a cellular level accumulation will disrupt ATP (the energy source of cells) forcing the cells to use anaerobic metabolism. This will increase lactic acid.
Consuming large amount of iron will also have very corrosive effects on the gastrointestinal tract with symptoms ranging from nausea and vomiting to gastrointestinal bleeds and hypovolemic shock. All of these will decrease perfusion and increase lactic acid.
Just as we’ve seen, the accumulation of lactic acid will lead to an accumulation of acidic hydrogen ion and anion lactate, increasing acidity (metabolic acidosis) and the calculated anion gap.
How does lactic acid cause acidosis?
So far we have seen via iron, isoniazid and propylene glycol that any process that will increase the body’s accumulation of lactic acid or decrease its clearance will lead to acidosis and an increase in the anion gap.
The L in MUDPILES reserves a spot for any condition or drug that has the potential to increase lactic acid and cause metabolic acidosis. Lactic acid accumulation can occur:
- any time the body is deprived of oxygen for a prolonged period of time
- when organs or systems that would normally facilitate its clearance are impaired
- as an adverse effect from the routine use of medications
- many other causes including intentional and unintentional poisoning
How does ethylene glycol cause acidosis?
Ethylene glycol is the main component in antifreeze. Like propylene glycol it is used commercially in manufacturing and cosmetics industries because of its ability to absorb and maintain moisture. It is considered a hazardous substance.
Once absorbed ethylene glycol is metabolized by the liver into glycolaldehyde. Glycolaldehyde is then metabolized into multiple organic acids including glyoxylic acid and formic acid.
We see again that these organic acids will increase the concentration of hydrogen ions which increases acidity (metabolic acidosis) and increases the concentration of organic anions which increases the anion gap.
How do salicylates cause acidosis?
In medicine salicylates refer to aspirin. Aspirin is used in treatment of pain, inflammation and to reduce the risk of strokes and heart attacks. Methyl salicylate as the plant wintergreen, is used in traditional medicine to reduce pain and inflammation. Salicylates remain among the top exposures according to the 2023 Annual Report of the National Poison Data System.
Accumulation of salicylates can interrupt normal cellular pathways in multiple ways leading to the build up of lactic acid which contributes to acidosis. Salicylates themselves are weak acids. In plasma they will exist as hydrogen ions and anions leading to metabolic acidosis and an increased anion gap.
The common thread among the elements of MUDPILES is the accumulation of organic acids leading to acidosis.
I hope this unit has helped to expand your knowledge of MUDPILES beyond simple memorization. If you have found this unit helpful, I would love to hear from you! Leave a comment or question below.
Subscribe
Subscribe to get the latest study unit in your inbox.
The information on this website is intended to be used solely for educational and informational purposes. While the content may be about specific medical and health care issues, it is not a substitute for or replacement of personalized medical advice and is not intended to be used as the sole basis for making individualized medical or health-related decisions.