Acetaminophen , the missing anion gap in the patient with metabolic acidosis

Acetaminophen intake is well-known but an often missed cause of high anion gap (AG) metabolic acidosis, and physicians must understand the metabolic pathway which increases the AG. Multiple mnemonics for common causes of metabolic acidosis have been developed and are widely taught in medical schools. Some of them, such as MUDPILES and KUSMALE, may not lead to an adequate workup and miss the diagnosis for the acidosis. More recently developed memory tools, such as GOLDMARK, provide a complete differential diagnosis for high AG metabolic acidosis. Pyroglutamic acid accumulates after alterations of the gammaglutamyl cycle mediated by acetaminophen and glutathione deficiency in some patients. The lower capacity of 5-oxiprolinase to metabolize pyroglutamic acid into glutamate results in the gradual accumulation of oxoproline/pyroglutamic acid. Treatment is mainly supportive with the major aim of restoring glutathione levels, optimizing nutrition, and using N-acetylcysteine as needed. Different modalities of renal replacement therapy have also been used in these patients.

Managing metabolic acidosis is a frequent problem for internists, hospitalists, family physicians, intensivists, nephrologists, and even pediatricians.Due to the frequency of this metabolic disorder, many physicians have created their own step-wise approaches which have been validated by most medical organizations, including the American Society of Nephrology, which encourages this systematic approach (e.g., Boston approach, Copenhagen approach, Stewart Method). 1 Evaluating a metabolic acidosis disorder must always include calculation of the unmeasured anions present in serum, including proteins, phosphate, sulfate, and organic anions.
Anion Gap (AG) = Na + -(Cl -+ HCO 3 -) This requires the assumption of a normal extracellular fluid volume (ECFV) and albumin levels.Otherwise, the AG must be corrected for the deviation of plasma albumin from the normal value of 4.0 gm/dL [a 1gm/dl reduction in albumin reduces the AG ~2.5-3 mEq/L].An increased AG suggests the presence of an acid other than hydrochloric acid or its equivalent.
We were taught that after calculating and finding an abnormal AG, which ranges from 8-14, depending on the laboratory calibration and volume status, the next step should be correlating the increment of the gap with the decrement in bicarbonate and considering possible causes of the wide AG.Several mnemonics have been developed to create a differential diagnosis.One of the most widely used is MUDPILES (also discussed by "Dr.House" during the second season of this TV show).However, some disorders in MUDPILES (methanol, uremia, diabetes ketoacidosis, phenformin, isoniazid, lactic acid, ethylene glycol, salicylates) occur infrequently.Others mnemonics, like KUSMALE (ketosis, uremia, salicylates, methanol, aldehydes, lactate, ethylene glycol), have become outdated with examples like aldehyde which refers to paraldehyde, an old sedative used in delirium tremens patients.
A newer mnemonic, GOLDMARK (Table 1), includes more common clinically important causes of AG metabolic acidosis 2 ; this mnemonic includes an AG metabolic acidosis caused by 5-oxoproline/pyroglutamic acid and the potential contribution of acetaminophen. 3,4This drug is sold over-over-the-counter worldwide for prices which range from few cents for single tabs to less than $10 dollars for a 250 pill bottle and can cause pyroglutamic/oxoproline acidosis (The "O" in GOLDMARK). 3,4oprolinuria, as a cause of elevated AG metabolic acidosis, can present as an inherited disorder (Table 2), 5,6 resulting from mutations in enzymes in the gamma glutamyl cycle. 4However, the most common presentation is an acquired disorder in malnourished patients given acetaminophen which unmasks the presence of glutathione deficiency (Figure 1). 7,8Other drugs, such as vigabatrin (gamma-vinyl-GABA), an anticonvulsant used more frequently in pediatrics, dietary glycine deficiency from conditions, such as pregnancy, diabetes, malnutrition, and the use of antibiotics have also been reported as causes of glutathione deficiency. 7e mechanism for increased accumulation of anions and therefore high AG acidosis results from alterations in the gamma glutamyl pathway. 8This pathway normally brings extracellular amino acids into the cytoplasm of the cell.Although glutathione is formed inside of the cell, it exerts feedback inhibition of the rate limiting enzyme: gamma-glutamyl cysteine synthetase (GGCS).If a patient is deficient in glutathione from, for example, malnutrition, and then ingests acetaminophen, which requires glutathione as part of its metabolism, the patient loses the inhibitory effect on GGCS.This inhibition increases the levels of gamma glutamylcysteine which moves through a shunt pathway to form endogenous pyroglutamic acid.Oxoprolinuria leads to the loss of bicarbonate as part of the buffer system, accompanied by the salt of the acid in this case sodium pyroglutamate.
With the accumulation of pyroglutamic acid in the setting of a low capacity 5-oxiprolinase to metabolize pyroglutamic acid into glutamate, there will be an "overwhelmed" enzyme unable to maintain a balance  between production and conversion, thus gradually building-up levels of oxoproline/pyroglutamic acid (Figure 2). 9th kidney disease (either acute or chronic) the clearance of oxoproline will decrease and thus worsen this process. 10Serum levels of acetaminophen can be measured in blood, but they might not be elevated or even detectable in these patients.Some specialized laboratories can measure 5-oxoproline in urine and/ or plasma by gas chromatography and mass selection.Most reported cases of pyroglutamic aciduria are caused by repeated therapeutic acetaminophen doses, usually in the setting of sepsis, pregnancy, or failure to thrive; typical clinical presentations are described in Table 3.
Stopping the offending agent and maintaining adequate diuresis with good hydration are the first steps in management.Expert opinion suggests the use of N-acetylcysteine to regenerate glutathione in addition to the use of bicarbonate if the pH is less than 7. Different modalities of renal replacement therapy using standard dialysis criteria, such as CVVH, CVVHD, CVVHDF, and IHD have been. 11The best way to help our patients' quick recovery requires a proper differential diagnosis for a high AG acidosis (GOLDMARK) and early intervention.

Table 3 . Case reports and clinical findings
Reviewer: Vaqar Ahmed MD Conflicts of interest: none