‘MUD PILES’: FINDING THE CAUSE OF ANION GAP METABOLIC ACIDOSIS
The possible causes of metabolic acidosis with an elevated anion gap (as in our patient) can be summarized in the mnemonic MUD PILES (methanol, uremia, diabetes, paraldehyde, isoniazid, lactate, ethylene glycol, and salicylates), which has been used for many years. Parts of it are no longer useful, but rather than discard it, we propose to update it (Table 3).
Methanol and ethylene glycol
We will address toxic ingestion of methanol and ethylene glycol (the “M” and “E” of MUD PILES) at the same time.
In cases of suspected ingestion of toxic substances such as these, it is useful to examine the osmol gap, ie, the difference between the calculated and the measured serum osmolality. Serum osmolality (in mOsm/kg) is calculated as the sodium concentration in mmol/L times 2, plus the glucose concentration in mg/dL divided by 18, plus the blood urea nitrogen concentration in mg/dL divided by 2.8 (Table 4). If the measured osmolality is higher than this calculated value, the difference may be due to solutes in the blood that should not be there such as ethylene glycol, diethylene glycol, methanol, and their many metabolic products.
In our patient, ingestion of both methanol and ethylene glycol should be considered, since she lives alone and has been suspected of alcohol and opioid abuse. Her calculated osmol gap is 278 mOsm/kg. Her measured osmolality is 318 mOsm/kg (Table 1). The osmol gap is 40 mOsm/kg (normal is ≤ 10).4,5 Therefore, her osmol gap is elevated.
Identifying the specific substance the patient ingested that caused metabolic acidosis with anion gap may be difficult. Poisonings with these agents do not always increase the osmol gap.6 A high index of suspicion is essential. It is helpful to have the family search for any sources of ethylene glycol and methanol at home and initiate treatment early if an ingestion is suspected, using fomepizole (an alcohol dehydrogenase inhibitor) or parenteral ethanol and hemodialysis.7 Liquid chromatography identifies these two toxins, but results are not available emergently.
Diethylene glycol ingestion should also be considered.8 Since it is diagnosed and treated like ethylene glycol intoxication, it can be placed with the “E” of (di)ethylene glycol in the mnemonic.
Renal failure can lead to metabolic acidosis.9 Our patient has no history of kidney disease, but her blood urea nitrogen and creatinine concentrations are above normal, and her estimated glomerular filtration rate by the Modification of Diet in Renal Disease formula is 48 mL/min/1.73 m2—low, but not uremic.
Rhabdomyolysis (suspected by elevated creatine kinase values) should be considered in any patient with mental status changes, suspected toxic ingestion, and metabolic acidosis (see the “I” in MUD PILES below). Compartment syndromes with muscle necrosis may present in a subtle fashion. Therefore, renal failure from rhabdomyolysis may complicate this patient’s course later, and should be kept in mind.
The patient has no history of diabetes and has a normal blood glucose level. Blood testing did not reveal ketones. She is not taking metformin (alleged to cause lactic acidosis) or a sodium-glucose cotransporter 2 inhibitor (which have been associated with ketoacidosis).10
There is another, less common cause of ketoacidosis: alcohol.11 Although alcoholism is common, alcoholic ketoacidosis is uncommon, even in heavy drinkers. Ethyl alcohol causing metabolic acidosis is similar to metabolic acidosis with (di)ethylene glycol and methanol, and if suspected it should be treated empirically (first with thiamine, then dextrose and saline, and correcting other electrolyte disturbances such as hypokalemia and hypomagnesemia) before specific identification is made. Ketones (predominantly beta-hydroxybutyrate) may persist up to 2 weeks after alcohol ingestion has stopped.11 Ketosis in the setting of alcoholic ketoacidosis is frequently accompanied by other markers of alcohol target organ injury: elevated bilirubin, aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase levels. The term “ketohepatitis” has been suggested as an alternative to alcoholic ketosis.11
This patient did not have an elevated blood ethanol level, and her liver markers were otherwise normal.
THE NEW MUD PILES
2. Which of the following is (are) true? Regarding the remaining letters of the MUD PILES mnemonic:
- The “P” (paraldehyde) has been replaced by pyroglutamic acid (5-oxoproline) and propylene glycol.
- There are two isomers of lactate (dextro and levo), and consequently two clinical varieties of lactic acidosis.
- Isoniazid is no longer associated with metabolic acidosis with elevated anion gap.
- Salicylates can paradoxically be associated both with elevated and low anion gaps.
Isoniazid is still associated with metabolic acidosis with elevated anion gap, and so the third answer choice is false; the rest are true.
Paraldehyde, isoniazid, lactate
The “P,” “I,” and “L” (d-lactate) of the revamped MUD PILES acronym are less common than the others. They should be considered when the more typical causes of metabolic acidosis are not present, as in this patient.
UPDATING THE ‘P’ IN MUD PILES
Paraldehyde is rarely prescribed anymore. A PubMed search on December 21, 2015 applying the terms paraldehyde and metabolic acidosis yielded 17 results. Those specific to anion gap metabolic acidosis were from 1957 to 1986 (n = 9).12–20
Therefore, we can eliminate paraldehyde from the MUD PILES mnemonic and replace it with pyroglutamic acid and propylene glycol.
5-Oxoproline or pyroglutamic acid, a metabolite of acetaminophen
Acetaminophen depletes glutathione stores in acute overdoses, in patients with inborn errors of metabolism, and after chronic ingestion of excessive, frequent doses. Depletion of glutathione increases metabolic products, including pyroglutamic acid, which dissociates into hydrogen ions (leading to metabolic acidosis and an anion gap), and 5-oxoproline, (which can be detected in the urine).21,22
Risk factors for metabolic acidosis with acetaminophen ingestion include malnutrition, chronic alcoholism, liver disease, and female sex. In fact, most cases have been reported in females, and altered mental status has been common.
Metabolic acidosis with pyroglutamic acid can occur without elevated acetaminophen levels. Serum and urine levels of pyroglutamic acid may assist with diagnosis. Since identification of urine pyroglutamic acid usually requires outside laboratory assistance, a clinical diagnosis is often made initially and corroborated later by laboratory results. When the anion gap metabolic acidosis is multifactorial, as it was suspected to be in a case reported by Tan et al,23 the osmol gap may be elevated as a consequence of additional toxic ingestions, as it was in the reported patient.
No controlled studies of treatment have been done. n-Acetylcysteine may be of benefit. Occasional patients have been dialyzed for removal of excess pyroglutamic acid.
Propylene glycol, a component of parenteral lorazepam
Lorazepam is a hydrophobic drug, so when it is given parenterally, it must be mixed with a suitable solvent. A typical formulation adds propylene glycol. In patients receiving high doses of lorazepam as relaxation therapy for acute respiratory distress syndrome in the intensive care unit, or as treatment of alcohol withdrawal, the propylene glycol component can precipitate anion gap metabolic acidosis.24,25
Although nearly one-half of the administered propylene glycol is excreted by the kidneys, the remaining substrate is metabolized by alcohol dehydrogenase into d,l-lactaldehyde, then converted into d- or l-lactate. l-Lactate can be metabolized, but d-lactate cannot and leads to anion gap metabolic acidosis. This is another toxic metabolic acidosis associated with an elevated osmol gap. An increasing osmol gap in the intensive care unit can serve as a surrogate marker of excessive propylene glycol administration.23
Although it is uncommon, there are reports of isoniazid-induced anion gap metabolic acidosis,26 either due to overdoses, or less commonly, with normal dosing. Isoniazid should therefore remain in the mnemonic MUD PILES and may be suspected when metabolic acidosis is accompanied by seizures unresponsive to usual therapy. The seizures respond to pyridoxine.
The “I” should also be augmented by newer causes of metabolic acidosis associated with “ingestions.” Ecstasy, or 3,4-methylenedioxymethamphetamine, can cause metabolic acidosis and seizures. Ecstasy has been associated with rhabdomyolysis and uremia, also leading to anion gap metabolic acidosis.27 A newer class of abused substances, synthetic cathinones (“bath salts”), are associated with metabolic acidosis, compartment syndrome, and renal failure.28
Lactic acidosis and metabolic acidosis can result from hypoperfusion (type A) or other causes (type B). Not all lactic acidosis is contingent on l-lactate, which humans can metabolize. Metabolic acidosis may be a consequence of d-lactate (mammals have no d-lactate dehydrogenase). d-Lactic acidosis as a result of short bowel syndrome has been known for more than a generation.29 However, d-lactic acidosis occurs in another new setting. The new “P” in MUD PILES, propylene glycol, can generate substantial amounts of d-lactate.29
d-lactic metabolic acidosis is always accompanied by neurologic manifestations (slurred speech, confusion, somnolence, ataxia, abusive behavior, and others).30 With short bowel syndrome, the neurologic manifestations occur after eating and clear later.30
Although our patient’s anion gap is more than 20 mmol/L, her blood level of lactate is not elevated, and she had no history to suggest short-bowel syndrome.
Salicylate overdose can cause a mixed acid-base disorder: metabolic acidosis with elevated anion gap and respiratory alkalosis.
Although our patient does not have respiratory alkalosis, an aspirin overdose must be considered. A salicylate level was ordered; it was negative.
Despite the typical association of salicylates with an elevated anion gap, they may also cause a negative anion gap.31 Chloride-sensing ion-specific electrodes contain a membrane permeable to chloride. Salicylates can increase the chloride permeability of these membranes, generating pseudohyperchloremia, and consequently, a negative anion gap.
WHAT ELSE MUST BE CONSIDERED?
3. In view of her anion gap metabolic acidosis, elevated osmol gap, and absence of diabetes, renal failure, or lactate excess, what are the remaining diagnoses to consider in this patient? (Choose all that are potential sources of metabolic acidosis and an increased anion gap.)
- Methanol, ethylene, or diethylene glycol
- Excessive, chronic acetaminophen ingestion
- Salicylate toxicity
- Alcoholic ketoacidosis
All of the above can potentially contribute to metabolic acidosis.
A search of the patient’s home did not reveal a source of methanol or either ethylene or diethylene glycol. Similarly, no aspirin was found, and the patient’s salicylate levels were not elevated. The patient’s laboratory work did not reveal increased ketones.
Since none of the common causes of metabolic acidosis were discovered, and since the patient had been taking acetaminophen, the diagnosis of excessive chronic acetaminophen ingestion was suspected pending laboratory verification. Identification of 5-oxoproline in the urine may take a week or more since the sample is usually sent to special laboratories. Acetaminophen levels in this patient were significantly elevated, as were urinary oxyproline levels, which returned later.
The patient was diagnosed with pyroglutamic acid metabolic acidosis. She was treated supportively and with n-acetylcysteine intravenously, although there have been no controlled studies of the efficacy of this drug. Seventy-two hours after admission, she had improved. Her acid-base status returned to normal.
GOLD MARK: ANOTHER WAY TO REMEMBER
Another mnemonic device for remembering the causes of metabolic acidosis with elevated anion gap is “GOLD MARK”: glycols (ethylene and propylene), oxoproline (instead of pyroglutamic acid from acetaminophen), l-lactate, d-lactate, methanol, aspirin, renal failure, and ketoacidosis).32
ACID-BASE DISORDERS IN DIFFERENT DISEASES
Diverse diseases cause distinctive acid-base abnormalities. Matching the appropriate acid-base abnormality with its associated disease may lead to more timely diagnosis and treatment:
Type 2 diabetes mellitus, for example, can lead to lactic acidosis, ketoacidosis, or type 4 renal tubular acidosis.33
Heart failure, although not typically framed in the context of acid-base physiology, can lead to elevated lactate, which is associated with a worse prognosis.34
Acquired immunodeficiency syndrome. Abacavir can cause normal anion gap metabolic acidosis.35,36
Cancer37,38 can be associated with proximal tubular renal tubular acidosis and lactic acidosis.
An expanding array of toxic ingestions
Metabolic acidosis may be the most prominent and potentially lethal clinical acid-base disturbance. When metabolic acidosis occurs in certain disease states—lactic acidosis with hypoperfusion or methanol ingestion with metabolic acidosis, for example—there is increased morbidity and mortality.
As reflected in the revisions to MUD PILES and in the newer GOLD MARK acronym, the osmol gap has become more valuable in differential diagnosis of metabolic acidosis with an elevated anion gap consequent to an expanding array of toxic ingestions (methanol, propylene glycol, pyroglutamic acid-oxoproline, ethylene glycol, and diethylene glycol), which may accompany pyroglutamic acid-oxoproline.