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Pyroglutamic acidosis

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Pyroglutamic acidosis. Elevated pyroglutamic acid is an example of an endogenous acid. Seen in those who are already glutathione-depleted

About

Acidosis due to glutathione depletion

Aetiology

Pyroglutamic acid is produced from Gamma-glutamyl cysteine by the enzyme Gamma-glutamyl cyclotransferase
When glutathione levels are low, the activity of Gamma-glutamyl cyclotransferase is increased, resulting pyroglutamic acid accumulation.
Glutathione is acutely depleted by paracetamol and sepsis; it can also be chronically depleted in liver disease and malnutrition.

Diagram

Table of causes

Category	Causes	Mechanism
Genetic Disorders	Glutathione synthetase deficiency 5-Oxoprolinase deficiency	Inherited enzyme deficiencies disrupt the gamma-glutamyl cycle, leading to accumulation of 5-oxoproline.
Medication-Induced	Prolonged use of acetaminophen (paracetamol) High-dose antibiotics (e.g., flucloxacillin, netilmicin)	Acetaminophen depletes glutathione, leading to increased production of pyroglutamic acid. Some antibiotics can alter glutathione metabolism, leading to accumulation of 5-oxoproline.
Critical Illness	Sepsis Chronic kidney disease Malnutrition	Increased oxidative stress and compromised detoxification pathways result in 5-oxoproline accumulation.
Dietary Factors	Low dietary intake of glycine or cysteine High dietary intake of glutamic acid	Imbalance in amino acids necessary for glutathione synthesis can lead to accumulation of pyroglutamic acid.
Metabolic Conditions	Diabetes mellitus Alcoholism	Metabolic stressors increase the demand for glutathione, leading to its depletion and subsequent pyroglutamic acidosis.

Risk factors

Paracetamol ingestion, Severe sepsis
Renal failure, Female gender
Chronic alcoholism or Chronic liver failure of any cause
Weird diet, or malnutrition in general
Dysfunction of 5-oxoprolinase
Flucloxacillin, Vigabatrin
Netilmicin (but apparently not any other aminoglycosides)
Inherited enzyme deficiency (known only from case reports)
Gender-specific difference in enzyme activity (women seem more prone to this acidosis)
Diminished 5-oxoproline clearance

Clinical

Acidotic Kussmaul's respiration
May have sepsis
Paracetamol ingestion

Investigations

Confirms the diagnosis.

Test	Causes	Mechanism
Blood Gas Analysis	ABG to check for high anion gap metabolic acidosis.	Confirms the presence of metabolic acidosis, a key feature of pyroglutamic acidosis.
U&E and Anion Gap	Check U&E to calculate the anion gap.	Diagnosis supported by elevated anion gap metabolic acidosis due to an accumulation of pyroglutamic acid.
Urine Organic Acids	Check urine organic acid analysis using gas chromatography-mass spectrometry (GC-MS).	Confirms the diagnosis by directly measuring the elevated pyroglutamic acid levels.
Plasma 5-Oxoproline Levels	Elevated plasma levels of 5-oxoproline are diagnostic of pyroglutamic acidosis.
Toxicology Screening	Conduct a toxicology screen to identify acetaminophen overdose or other substances.	Check for medication-induced pyroglutamic acidosis.
Assessment of Liver Function	Perform liver function tests (LFTs) to assess the liver function.	Liver dysfunction can contribute to impaired metabolism and detoxification.

Management

Management Step	Details	Rationale
Discontinuation of Causative Agents	Stop acetaminophen/other drugs contributing to glutathione depletion.	Removing the source of glutathione depletion halts the overproduction of pyroglutamic acid.
Glutathione Repletion	Administer N-acetylcysteine (NAC) IV/PO.	NAC replenishes glutathione stores and reduces pyroglutamic acid levels.
Correction of Metabolic Acidosis	Consider sodium bicarbonate infusion if severe acidosis is present.	Helps buffer the excess acid, preventing complications from severe acidosis.
Supportive Care	Ensure adequate hydration with IV fluids. Monitor U&E regularly.	Hydration helps clearance of pyroglutamic acid.
Treatment of Underlying Conditions	Treat illnesses (e.g., infection, sepsis) that may have triggered the condition.	Reduce metabolic stress that contributes to pyroglutamic acidosis.
Monitoring and Follow-Up	Regularly monitor blood pH, anion gap, and 5-oxoproline levels until stabilized.	Ensures that the treatment is effective and the patient is recovering.

References

PLEASE NOTE LEGAL ADVICE: The contents are under continuing development and improvements and may contain errors of omission or fact. Feedback vital and always welcome at drokane at gmail.com. This is not to be used for the assessment, diagnosis or management of patients. It should not be regarded as medical advice. It is only for educational purposes. Please adhere to your local protocols. If you are unwell please seek healthcare advice from your doctor. This does not replace senior or specialist advice. If you do not accept this then please do not use the website. If you need medical advice, please consult a doctor or other appropriate medical professional. If you are a medical professional and you need advice then speak to your senior or colleagues.

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