Raised anion gap metabolic acidosis (RAGMA) is a commonly encountered acid–base disturbance in clinical practice. Aetiologies for RAGMA were previously represented by the popular mnemonic MUDPILES, which stands for Methanol, Uraemia, Diabetic ketoacidosis, Paraldehyde, Iron or Isoniazid, Lactic acidosis, Ethylene glycol, and Salicylate. This old mnemonic includes underrepresented and lately identified but also important causes of RAGMA. The new mnemonic GOLDMARK was first introduced by Mehta et al. [1] as an acronym for Glycols (ethylene and propylene glycol),
A 73-year-old man with inoperable adenocarcinoma of the right lung received concurrent chemoradiotherapy. The irradiated site developed
On day 40 of the hospital stay, the patient developed acidotic breathing, and blood gas analysis showed severe metabolic acidosis with raised anion gap (Table 1). There was no lactic acidosis, and his serum osmolal gap was normal. There was no exposure to salicylate, toxic alcohols, or glycols. Although both his creatinine and beta-hydroxybutyrate levels were moderately raised, these were not sufficient to account for the degree of metabolic acidosis. Urine anion gap (UAG) was grossly elevated which indicated increased excretion of unmeasured anions in urine. PGA was suspected at this point, in light of an unexplained RAGMA, positive UAG, and chronic APAP use since hospital admission with a total cumulative dose of 160 g.
Relevant laboratory studies on day of diagnosis
Parameter | Result | Reference interval |
---|---|---|
Sodium, plasma (mmol/L) | 142 | 137– 44 mmol/L |
Potassium, plasma (mmol/L) | 4.4 | 3.5–4.5 mmol/L |
Chloride, plasma (mmol/L) | 107 | 98–107 mmol/L |
Bicarbonate, plasma (mmol/L) | 5.8 (L) | 23–27 mmol/L |
Anion gap* (mmol/L) | 29 (H) | 8–12 mmol/L |
Albumin, plasma (g/L) | 25 (L) | 35–52 mmol/L |
Total bilirubin, plasma (μmol/L) | 5 | <19 μmol/L |
ALP, plasma (U/L) | 251 (H) | 43–105 U/L |
ALT, plasma (U/L) | 11 | <53 U/L |
Urea, plasma (mmol/L) | 4.9 | 3.1–7.8 mmol/L |
Creatinine, plasma (μmol/L) | 176 (H) | 65–109 μmol/L |
eGFR (CKD-EPI) (ml/min/1.73m2) | 32 | >90 ml/min/1.73m2 |
Lactate, plasma (mmol/L) | 2.4 (H) | <2.2 mmol/L |
Beta-hydroxybutyrate, plasma (mmol/L) | 2.92 (H) | ≤0.30 mmol/L |
Osmolality, serum (mOsm/kg) | 294 | 274–295 mOsm/kg |
Osmolal gap, plasma** (mOsm/kg) | 3 | <10 mOsm/kg |
Random glucose, plasma (mmol/L) | 8.3 | - |
Acetaminophen, serum (μmol/L) | 119 | Therapeutic range: 66–199 μmol/L |
pH | 7.17 (L) | 7.35–7.45 |
PaCO2 (kPa) | 1.73 | 4.66–6.00 kPa |
PaO2 (kPa) | 12.4 | 10–13.33 kPa |
Actual bicarbonate (mmol/L) | 4.7 (L) | 22–26 mmol/L |
Base excess (mmol/L) | −21.7 (L) | –2.0–+2.0 mmol/L |
Sodium, urine (mmol/L) | 93 | - |
Potassium, urine (mmol/L) | 26 | - |
Chloride, urine (mmol/L) | <20 | - |
Urine anion gap*** (mmol/L) | >99 (H) | <10 mmol/L |
Urine organic acids analysis by LC-MS/MS. | Significant hyper-excretion of pyroglutamic acid. |
Remarks: eGFR: estimated glomerular filtration rate; CKD-EPI: Chronic Kidney Disease Epidemiology Collaboration.
Plasma anion gap = (Plasma Na+ + Plasma K+) – (Plasma Cl− - Plasma HCO3−)
Osmolal gap = Measured osmolality – Calculated osmolality [2(Plasma Na+) + Plasma urea + Plasma glucose]
Urine anion gap = Urine Na+ + Urine K+ - Urine Cl−
The prescription of APAP was immediately discontinued. Intravenous
It has been widely recognised that in acute APAP overdose, saturation of sulfation, and glucuronidation systems together with glutathione depletion results in an accumulation of the toxic metabolite
Pathway of glutathione synthesis and mechanism of pyroglutamic acidosis in cysteine and glutathione depletion.
Inherited forms of PGA are rare and mostly due to glutathione synthetase deficiency, which can manifest as severe metabolic acidosis, haemolytic anaemia, and progressive encephalopathy. Acquired PGA, usually associated with chronic APAP intake, is more common and was first described in 1989 [3]. Additional risk factors for PGA include female sex, malnourishment, concomitant sepsis, hepatic and renal impairment [4, 5]. These risk factors are prevalent and often co-existent in hospitalised patients. Therefore, PGA is likely to be an underrecognised and underdiagnosed condition. Concurrent use of the antibiotics flucloxacillin and netilmicin [6], and the anticonvulsant vigabatrin [7] have also been implicated in PGA. These drugs inhibit the enzyme 5-oxoprolinase, preventing the breakdown of pyroglutamic acid into
Urine pyroglutamic acid to creatinine (Cr) ratio in our patient was estimated to be 1716 μmol/mmol Cr as measured by liquid chromatography–mass spectrometry (LC-MS/MS). This high level of urine pyroglutamic acid was at comparable levels as reported PGA cases in the literature, ranging from 700 to 11000 μmol/mmol creatinine [8–10]. Because measurement of pyroglutamic acid is only available in specialised metabolic laboratories, it can be difficult to confirm the diagnosis of PGA. On the other hand, UAG is a readily available test which may provide a clue as to the diagnosis. As in our patient, a positive UAG indicates increased excretion of unmeasured anions in urine, including pyroglutamic acid. Though such a finding is non-specific, it would nevertheless be useful if interpreted in a proper clinical context. In addition, it must be noted that a therapeutic level of APAP does not rule out the diagnosis of PGA as the pathogenesis is different from acute overdose.
Apart from chronic APAP ingestion, additional risk factors are often present in patients with PGA. Our patient had chronic infection, prolonged hospitalisation, and malnutrition, which likely led to a depletion of glutathione and cysteine stores. His renal impairment likely also reduced the clearance of pyroglutamic acid and contributed to its accumulation. The patient was also on chronic voriconazole, which has also been reported to cause glutathione depletion and have potential hepatotoxicity based on an animal study [11]. Recently, a 7-year-old patient with leukaemia who was given chronic APAP, antibiotics, and antifungals including voriconazole was reported to have developed PGA [12]. These findings suggest that voriconazole might be a contributing culprit. We would like to advise cautious use of APAP in susceptible individuals, particularly patients with multiple of the aforementioned risk factors. Prolonged use of APAP should be avoided, the dosages should be kept to a minimum, and alternative analgesics should be used where appropriate.
Treatment for PGA should be initiated based on clinical grounds and must not be delayed until laboratory confirmation. APAP and other offending agents should be withheld, and alternative prescriptions should be employed where appropriate. NAC is widely used as an antidote for acute APAP poisoning and is the standard treatment for hereditary glutathione synthetase deficiency. Its mechanism of action is regeneration of glutathione and cysteine stores [13]. Although there has been limited experience with its use in acquired PGA and the optimal dosage is not uncertain, it appears to be safe and effective according to published case reports [4, 5, 9, 10]. We adopted the treatment protocol as in acute APAP poisoning and demonstrated rapid reversal of acidosis with no noticeable adverse effects after NAC administration in our patient.
This case illustrates acute severe RAGMA due to PGA in a patient on therapeutic doses of APAP. Although PGA is a recognised entity in literature, this represents the first reported local case of PGA in Hong Kong. Extra caution should be exercised when administering repetitive doses of APAP in hospitalised patients at risk of glutathione depletion. Prolonged use of high therapeutic APAP doses, such as 4 g/day in our case, should be avoided. PGA should be considered when patients develop unexplained RAGMA. Elevation of UAG reflect urinary excretion of unmeasured organic acids and may be an informative adjunct to the diagnosis of PGA in an appropriate clinical context. Diagnosis of PGA should be confirmed by measuring organic acids in the serum or urine. However, testing may not be readily available, and results are often delayed. High clinical suspicion in at-risk patients is the key to a timely diagnosis and effective treatment by withholding the offending agents and giving NAC empirically.