5-Oxoproline (pyroglutamic) acidosis associated with chronic acetaminophen use

Metabolic acidosis is a common acid-base disturbance in hospitalized patients. Distinguishing anion gap from non–anion gap metabolic acidosis is a very helpful exercise and enables the clinician to narrow the etiology of the particular acidosis. The use of the anion gap was popularized in an article by Emmett and Narins (1). Over the past few years, the list of conditions that can cause an anion gap metabolic acidosis has expanded. Mehta et al recently developed a “new mnemonic for the 21st century” to add three forms of anion gap metabolic acidosis not included in several popular mnemonics and to delete several obsolete causes (2). The new mnemonic is GOLD MARK, an acronym for glycols (ethylene and propylene), oxoproline (5-oxoproline also called pyroglutamic acid), L-lactate, D-lactate, methanol, aspirin, renal failure, and ketoacidosis. The new additions are D-lactic acidosis, typically seen in patients with short gut syndromes; the accumulation of propylene glycol, a common diluent for intravenous medications; and 5-oxoproline, an increasingly recognized disorder most commonly associated with chronic acetaminophen ingestion. We report a case of 5-oxoproline acidosis in a woman with a history of chronic acetaminophen use.

CASE PRESENTATION

A 39-year-old white woman had a past history of bipolar psychiatric disease, several suicide attempts, recurrent methicillin-resistant Staphylococcus aureus infections, and a chronic and ill-defined pain disorder treated with acetaminophen/hydrocodone. Three days prior to admission, she developed nausea and vomiting and reduced her food intake. After ingesting an unknown amount of acetaminophen/hydrocodone, she fell asleep for a few hours. Her significant other had difficulty arousing her and called emergency medical services. In the emergency department, she was obtunded and required emergent endotracheal intubation and mechanical ventilation. An anion gap metabolic acidosis (and respiratory acidosis) was noted. She was transferred to Baylor University Medical Center for a higher level of care. Admission and subsequent laboratory studies are shown in Tables 1, 2, and 3.

Table 1.

Laboratory values

Hospital day	pH	pCO2 (mm Hg)	HCO3 (mEq/L)	Sodium (mEq/L)	Chloride (mEq/L)	BUN (mg/dL)	Creatinine (mg/dL)	Anion gap (mEq/L)	Albumin (g/dL)
Admission	7.09	28	10	140	108	59	3.6	22	3.5
Admission pm	7.27	26	11	140	113	47	2.6	16	−
Day 2	7.47	27	20	142	111	24	1.3	11	3.3
Day 3	7.44	33	22	144	113	16	1.0	9	3.3
Day 4	−	−	23	143	109	23	0.8	9	3.3

pCO₂ indicates partial pressure of carbon dioxide; HCO₃, bicarbonate; BUN, blood urea nitrogen.

Table 2.

Other laboratory studies

Test	Result
Salicylate level	Negative
Lactate level (mmol/L)	0.4
Osmolal gap	10
Ethanol alcohol level	Negative
Acetaminophen level (mcg/mL)	<3
Serum ketones (dilution)	1:8
Urine creatinine (mg/100 mL)	36
Urine anion gap (mmol/L)	49.5

Table 3.

Urine organic anions

Urine OA anion	mmole OA/ mole Cr	mmole OA/L	Upper reference range (mmole/mole Cr)
5-Oxoproline	8555	27	70
Acetoacetate	3386	11	7
3-Hydroxybutyrate	6176	20	17
2-Hydroxybutyrate	145	1	0
Lactate	195	0.5	101

OA indicates organic acid; Cr, creatinine.

Following admission to the intensive care unit, she was given aggressive intravenous fluids containing sodium chloride, sodium bicarbonate, and dextrose. Her laboratory studies and clinical status returned to her baseline.

The principal organic acid anion identified in her urine was 5-oxoproline (see Table 3). This was most likely due to chronic ingestion of acetaminophen and poor nutrition. She also developed a component of “starvation” ketoacidosis and acidosis associated with acute kidney injury. Her anion gap fell quickly with aggressive volume expansion and glucose administration. Renal function also improved.

A spot urine electrolyte analysis (on admission) showed the urine anion gap to be very positive at about 49 mEq/L. This is consistent with increased levels of “unmeasured,” probably organic, anions in the urine (3). Excretion of urine 5-oxoproline, acetoacetate, 3-hydroxybutyrate, lactate, and 2-hydroxyacids were all increased and together accounted for about 60 mEq/L.

The patient was extubated on hospital day 3 and continued to improve after adjustment of her psychiatric medications. She was discharged home with instructions to avoid acetaminophen and to receive appropriate psychiatric follow-up.

DISCUSSION

The accumulation of millimolar quantities of 5-oxoproline was first identified in infants with certain inherited enzyme defects affecting the γ-glutamyl cycle (glutathione synthetase deficiency and 5-oxyprolinase deficiency) (Figure 1). These inherited abnormalities are extremely rare. More recently, 5-oxoproline accumulation has been identified as an acquired disorder in several clinical settings.

Figure 1.

Gamma-glutamyl cycle.

Most adult patients with acquired 5-oxoproline acidosis have a history of chronic acetaminophen use (4, 5). Chronic acetaminophen ingestion has been associated with reduced plasma glutathione levels (6) and elevation of 5-oxoproline levels in serum and urine. However, the exact mechanistic explanation has not yet been defined. Previous publications suggest that acquired 5-oxoproline acidosis occurs more frequently in women than in men, possibly due to gender differences in the enzyme activities of the γ-glutamyl cycle (7). Women may also be more likely to develop this disorder because they may be more likely to chronically ingest acetaminophen for various pain conditions.

Patients who develop 5-oxoproline acidosis associated with chronic acetaminophen use usually present with therapeutic or low acetaminophen levels. This disorder is to be distinguished from acute metabolic acidosis developing in patients with acetaminophen poisoning and hepatic necrosis. If those individuals develop a metabolic acidosis, it is almost always a lactic acid and is related to mitochondrial damage.

Patients who develop severe anion gap metabolic acidosis from an accumulation of 5-oxoproline related to chronic acetaminophen ingestion generally have other conditions that seem to predispose to this problem. They include malnourishment, pregnancy, vegetarian diet, sepsis, chronic renal insufficiency, and/or hepatic dysfunction, especially liver disease that results from chronic alcohol use (5). Several antibiotics (netilmicin and flucloxacillin) and the antiseizure drug vigabatrin have also been implicated.

This form of metabolic acidosis often promptly responds to extracellular fluid expansion with dextrose containing saline. Acetyl cysteine (Mucomyst) has also been proposed for treatment of this metabolic acidosis because it rapidly replenishes glutathione levels.

In conclusion, metabolic acidosis due to 5-oxoproline is an increasingly recognized disorder and must be included in the differential diagnosis of patients with otherwise unexplained high anion gap metabolic acidosis. Suspicion should be increased when acidosis occurs in women who have chronically ingested acetaminophen. Urine testing for organic acids is available at Baylor University Medical Center's Institute of Metabolic Disease.