D-Pyroglutamic Acid: A Cause of High Anion Gap Acidosis and Its Clinical Implications

D-Pyroglutamic acid is a compound that is part of the gamma-glutamyl cycle. It can cause high anion gap acidosis and is most commonly diagnosed in the pediatric population with inherited autosomal recessive enzyme deficiencies. It has also been studied for its efficacy in treating memory deficits in aged subjects.

Pyroglutamic acidosis as a cause for high anion gap metabolic acidosis

D-Pyroglutamic acid (PGA) in the absence of acetaminophen use has been rarely reported as a cause for high anion gap metabolic acidosis. We investigated the prevalence and risk factors for elevated PGA concentrations among hospitalized patients with high anion gap metabolic acidosis: We prospectively enrolled patients with high anion gap metabolic acidosis hospitalized in the department of medicine. For each patient we collected the main diagnosis, concurrent medications and laboratory parameters. Spot urine samples were tested for D-Pyroglutamic acid concentration. Levels ≥63 µmol/mmol creatinine were considered elevated. Overall, forty patients were prospectively followed. Mean age was 66.9 (17.9) years. Four (6.3%) patients had a high urine PGA level and demonstrated also lower blood pH (7.2 vs 7.3, p = 0.05) and lower serum lactate concentration (17.5 mg/dl vs 23.0 mg/dl, p = 0.04).The most common causes are the accumulation of lactate, ketones, urea and ingestion of toxins. However, in cases where no other explanation is found, less common etiologies such as accumulation of D-Pyroglutamic acid (PGA) should be suspected. The latter has been mostly reported in the presence of chronic acetaminophen use. Given no explanation for the high anion gap metabolic acidosis (HAGMA), vigabatrin induced pyrogluatmic acidosis was suspected. Urine sample demonstrated extremely elevated D-Pyroglutamic acid levels of 15,000 µmol/mmol creatinine (normal values ≤ 63 µmol/mmol creatinine). [1]

Accordingly, vigabatrin was discontinued and N-acetylcysteine (NAC) in a dose similar to acetaminophen overdose treatment protocol was initiated. Due to slow improvement in the acidosis and the presence of D-Pyroglutamic acid, two courses of hemodialysis were conducted. The patient regained consciousness and urine assay showed improving anion gap and urine PGA levels. D-Pyroglutamic acid, also known as 5-oxoproline, is an intermediate metabolite in glutathione cycle. It is synthesized by γ-glutamyl cyclotransferase and catabolized by 5-oxoprolinase. The former is induced by glutathione depleted states which enhances D-Pyroglutamic acid production. Depletion is most commonly encountered secondary to acetaminophen consumption, as well as in severe sepsis, chronic alcoholism, chronic liver failure and malnutrition. Other recognized risk factors are old age, pregnancy and female gender. On the other hand, accumulation can be secondary to inherited deficiency or the inhibition of 5-oxoprolinase. Vigabatrin use has been previously reported to be associated with elevated PGA concentration.

The treatment of 5-oxoprolinemia is mainly based on the etiology, PGA concentration and clinical picture. Our patient treated with vigabatrin had significant higher values as compared to the 4 patients in high D-Pyroglutamic acid group. This difference is probably attributed to the additive effect of the offensive drug on the accumulation of PGA and hence such agents should be discontinued. Based on the clinical picture and laboratory values NAC treatment should be considered. Noteworthy is the high rates of anaphylactoid reactions reported to be as high as 48%. Our cohort consisted of patients with mild to moderate acidosis reflected by their mean pH and bicarbonate values, and hence our findings might underestimate the real prevalence of elevated D-Pyroglutamic acid concentrations among acidotic patients. Furthermore, since only spot urine samples were collected, we could not account for the intra-individual variability of D-Pyroglutamic acid concentration. The latter is particularly emphasized given the known variation among healthy individuals; nevertheless, this variability is reported to be mostly within normal range.

Pyroglutamic Acidemia: A Case Report and Review of Literature

Pyroglutamic acidemia is a condition in which the body is unable to produce glutathione. Glutathione is generated in the small intestines, kidney, and liver by the gamma-glutamyl cycle. The gamma-glutamyl cycle is responsible for maximizing the absorption of amino acids and plays an important role in chemical detoxification. Most cases of pyroglutamic acidemia are reported in the pediatric population and are due to hereditary deficiencies in key enzymes involved in this cycle. Since 1989, when the first case of acquired pyroglutamic metabolic acidosis was reported, numerous additional cases have been described. These cases have shown that although rarely diagnosed (if not rare in occurrence), D-Pyroglutamic acid accumulation does occur in the adult population without a hereditary enzyme deficiency, typically presenting with a high anion gap metabolic acidosis along with mental status changes.[2]

Pyroglutamic acidemia (oxoprolinemia) is an underrecognized cause of high anion gap acidosis resulting from derangement in the gamma-glutamyl cycle. Pyroglutamic acidemia is most commonly diagnosed in the pediatric population in patients with inherited autosomal recessive enzyme deficiencies. However, acquired pyroglutamic acidemia can present in the adult population. Patients often present with confusion, nausea, and vomiting as well as an elevated anion gap metabolic acidosis. This article describes a case of acquired pyroglutamic acidemia and emphasizes the need to consider this entity. It is thought that the accumulation of D-Pyroglutamic acid occurs as a result of depletion of glutathione stores, which removes the negative feedback and essentially “backs up” the cycle, leading to elevated levels of 5-oxoproline.  One potential cause for this condition becoming more prevalent and at the same time contributing to its under-recognition is the abundant and widely accepted use of acetaminophen. There is a need to acknowledge and consistently incorporate D-Pyroglutamic acid into the differential, not only in pediatric patients but also in the adult population.

References

[1]Raibman Spector S, Mayan H, Loebstein R, Markovits N, Priel E, Massalha E, Shafir Y, Gueta I. Pyroglutamic acidosis as a cause for high anion gap metabolic acidosis: a prospective study. Sci Rep. 2019 Mar 5;9(1):3554. doi: 10.1038/s41598-019-39257-4. Erratum in: Sci Rep. 2020 Aug 4;10(1):13397. doi: 10.1038/s41598-020-70345-y. PMID: 30837497; PMCID: PMC6400893.

[2]Venkataraman SS, Regone R, Ammar HM, Govindu RR. Pyroglutamic Acidemia: An Underrecognized and Underdiagnosed Cause of High Anion Gap Metabolic Acidosis - A Case Report and Review of Literature. Cureus. 2019 Jul 24;11(7):e5229. doi: 10.7759/cureus.5229. PMID: 31565630; PMCID: PMC6758980.

You may like