Published: 4 December 2025

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Paracetamol can cause high anion gap metabolic acidosis (HAGMA) 

Published: 4 December 2025
Prescriber Update 46(4): 63–64
December 2025

The paracetamol data sheets were recently updated with information about the risk of HAGMA associated with paracetamol use. We are including this article to provide more information about this condition.

What is HAGMA? 

Metabolic acidosis is an acid-base disturbance characterised by a low blood pH with low bicarbonate.¹ It can be life-threatening, particularly in patients with comorbidities such as chronic kidney disease or advanced liver disease.¹

Various measures are used to try and identify the cause of the metabolic acidosis, with the anion gap being the most popular.² The anion gap is a mathematical equation based on the balance of specific cations (sodium, and sometimes potassium) and anions (chloride, bicarbonate) measured in the blood.³ A high anion gap indicates the presence of unmeasured anions in the blood.¹

High anion gap metabolic acidosis (HAGMA) is a type of metabolic acidosis associated with acid accumulation and characterised by a high anion gap.¹ Causes include lactic acidosis, ketoacidosis, renal failure and poisoning.¹

Pyroglutamate (5-oxoproline) is metabolite that can contribute to a high anion gap and is another cause of HAGMA.¹ The metabolism of paracetamol can cause pyroglutamate to accumulate (pyroglutamic acidosis), particularly when glutathione levels are low.^4,5  

Paracetamol-induced HAGMA 

Cases of paracetamol-induced HAGMA, due to pyroglutamic acidosis, have been reported in patients with severe illness (renal impairment, sepsis), malnutrition or alcoholism, and who are taking paracetamol long term at therapeutic doses. The risk is higher if the patient is also taking flucloxacillin.^5–7

Measuring urinary 5-oxoproline may be a useful way to identify pyroglutamic acidosis as the underlying cause of HAGMA in patients with multiple risk factors.^6,7

If HAGMA due to pyroglutamic acidosis is suspected, promptly discontinue paracetamol and closely monitor the patient.^6,7 Follow local clinical guidelines for treatment.

New Zealand case reports

As of 30 September 2025, there were four case reports of metabolic acidosis associated with paracetamol (report IDs: 053710, 127319, 146042, NZ-Medsafe-163566). Flucloxacillin was a co-suspect medicine in three of the four reports. Reported terms included acidosis, anion gap abnormal, metabolic acidosis and/or pyroglutamic acidosis.

References

1. Kharsa A, Vashist R, Rout P, et al. 2025. Anion gap and non-anion gap metabolic acidosis (updated 6 August 2025). In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. URL: www.ncbi.nlm.nih.gov/books/NBK448090/ (accessed 2 Octocber 2025).
2. Forni LG, McKinnon W, Hilton PH. 2006. Unmeasured anions in metabolic acidosis: unravelling the mystery. Critical Care 10(4): 220. DOI: 10.1186/cc4954 (accessed 7 November 2025).
3. Pandey DG and Sharma S. 2023. Biochemistry, anion gap. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. URL: www.ncbi.nlm.nih.gov/books/NBK539757/ (accessed 12 November 2025).
4. Crisp T, Sizeland P, Du Toit S, et al. 2021. Pyroglutamic acidosis: an under-recognised cause of high anion gap metabolic acidosis. New Zealand Medical Journal 134 (1546): 117–21. URL: nzmj.org.nz/media/pages/journal/vol-134-no-1546/pyroglutamic-acidosis-an-under-recognised-cause-of-high-anion-gap-metabolic-acidosis/c74b54851f-1696476732/pyroglutamic-acidosis-an-under-recognised-cause-of-high-anion-gap-metabolic-acidosis.pdf (accessed 29 October 2025).
5. Scafetta T, Kovacs O, Milani GP, et al. 2024. Drug-related pyroglutamic acidosis: Systematic literature review. Journal of Clinical Medicine 13(19): 5781. DOI: 10.3390/jcm13195781 (accessed 1 October 2025).
6. Stewart GW. 2024. Pyroglutamate acidosis 2023. A review of 100 Cases. Clinical Medicine 24: 100030. DOI: 10.1016/j.clinme.2024.100030 (accessed 29 September 2025).
7. Ipca Pharma (NZ) Pty Limited. 2025. Pacimol New Zealand Data Sheet October 2025. URL: www.medsafe.govt.nz/profs/Datasheet/p/pacimoltab.pdf (accessed 12 November 2025).