Paracetamol and Metabolic Acidosis

The product information documents for paracetamol are being updated to include warnings of high anion gap metabolic acidosis. Metabolic acidosis is a pathological process or condition that leads to a reduction in blood pH.

There are three major mechanisms that can produce metabolic acidosis:

• Increased acid generation
  • Lactic acidosis
  • Ketoacidosis
  • Ingestions or infusions (e.g. toxic alcohols, chronic paracetamol use)
• Loss of bicarbonate
  • Severe diarrhoea
  • Complication following urinary diversion surgery
  • Proximal (type 2) renal tubular acidosis (RTA)
• Reduced renal acid excretion
  • Renal failure
  • Distal (type 1) RTA and type 4 RTA

There are also two distinct types of metabolic acidosis: high anion gap metabolic acidosis (HAGMA) and normal anion gap metabolic acidosis (NAGMA). Calculation of the anion gap can be used to distinguish between the two.

Anion gap

For electrical charge to be neutral, the total number of positive charges (from cations) must equal the total number of negative charges (from anions). However, not all ions are easy to measure. Therefore, the anion gap equation uses only the dominant cations (i.e. sodium +/- potassium) and the dominant anions (i.e. chloride and bicarbonate). The rest of the ions in the blood can be considered “unmeasured”.

Anion gap = (Na⁺ + K⁺) – (Cl^– + HCO₃^–)

The anion gap is, therefore, the difference between measured cations and measured anions in the blood (which can be used to evaluate the presence of unmeasured anions).

The typical adult reference ranges for these measured ions is shown below:

• Sodium 135 to 145 mmol/L
• Potassium 3.5 to 5.2 mmol/L
• Chloride 95 to 110 mmol/L
• Bicarbonate 22 to 32 mmol/L.

The normal anion gap is often quoted as 8-16 mmol/L (or 4-13 mmol/L if potassium is excluded from the equation). This figure largely represents unmeasured anions like organic acids and negatively charged plasma proteins, such as albumin.

In both HAGMA and NAGMA there is a reduction in bicarbonate. This can be due to increased use of bicarbonate as a buffer, reduced bicarbonate production, or increased loss. However, as electrochemical neutrality must be maintained, there is always a corresponding increase in anions (either chloride or unmeasured anions). If it is the chloride level that increases, a normal anion gap would be seen. However, if it is unmeasured anions that increase, the anion gap increases.

Calculation of the anion gap can be useful to help identify the cause of metabolic acidosis and, therefore, the most appropriate treatment.

Paracetamol and HAGMA

Metabolic acidosis is associated with paracetamol overdose. However, metabolic acidosis can also occur during chronic therapy when therapeutic doses are used. This may also be referred to as pyroglutamic acidosis as it is related to a buildup of pyroglutamic acid.

Pyroglutamic acid (also known as 5-oxoproline) is an intermediate in glutathione metabolism. Glutathione is present in most cells, where it functions as an antioxidant. The γ-glutamyl cycle is responsible for the synthesis and degradation of glutathione, and can be summarised in the following steps:

• Glutathione utilisation
  • Glutathione donates its γ-glutamyl group to amino acids via the enzyme γ-glutamyl transpeptidase (GGT).
  • This forms γ-glutamyl amino acids and cysteinylglycine.
• Transport and conversion
  • γ-glutamyl amino acid is transported into the cell and converted to pyroglutamic acid by γ-glutamyl cyclotransferase.
• Recycling
  • Pyroglutamic acid is converted to glutamate by 5-oxoprolinase.
  • Glutamate then combines with cysteine (via γ-glutamylcysteine synthetase) to form γ-glutamylcysteine.
• Glutathione resynthesis
  • γ-glutamylcysteine combines with glycine (via glutathione synthetase) to regenerate glutathione.

5-oxoprolinase, the enzyme responsible for breaking down pyroglutamic acid, operates at low capacity. Therefore, pyroglutamic acid will accumulate when its rate of production is high.

There are many factors that can interrupt this cycle, including inherited enzyme defects and acquired deficiencies in cellular glutathione and cysteine. Prolonged use of paracetamol can cause depletion of both glutathione and cysteine which may disrupt this cycle.

Risk factors

There are many other factors that increase the risk of metabolic acidosis during prolonged paracetamol use, including:

• Malnutrition;
• Infection;
• Antibiotics;
• Renal failure; and
• Pregnancy.

These risk factors are common, and it has been suggested that the incidence of this condition may be under-reported.

Flucloxacillin, in particular, has been highlighted as the antibiotic more likely to contribute to this condition. This antibiotic can inhibit 5-oxoprolinase, thereby promoting the accumulation of pyroglutamic acid. Caution is advised when flucloxacillin and paracetamol are co-administered, especially when the maximum paracetamol dose is used and where other risk factors for HAGMA exist.

Ciprofloxacin is another antibiotic that may impair this pathway, along with the anticonvulsant vigabatrin.

Presentation

Pyroglutamic acidosis has a fatality rate of around 20%. Prompt recognition is essential as the condition is reversible if the causative agents are ceased.

Signs and symptoms may include:

• Reduced consciousness;
• Kussmaul breathing (rapid, deep breathing);
• Nausea and vomiting;
• High anion gap;
• Low bicarbonate levels (often < 10 mmol/L);
• Hypokalaemia; and
• Severe deterioration of kidney function.

Treatment

Treatment of paracetamol-induced HAGMA involves cessation of paracetamol and any other causative agent (i.e. any medication that can inhibit enzymes involved in the γ-glutamyl cycle).

Supportive measures, such as intravenous fluids and respiratory support, may be sufficient for the management of mild cases. A sodium bicarbonate infusion may be considered for patients with more severe disease (i.e. serum pH < 7.1).

As glutathione depletion is thought to be key in the pathogenesis of this condition, administration of N-acetylcysteine (NAC) may also be considered. A recently published systematic review found that NAC was associated with a lower fatality rate (11% with NAC vs 24% without). Case reports have also shown that haemodialysis may hasten the removal of pyroglutamic acid.

Reports in Australia

In the past ten years, the Therapeutic Goods Administration (TGA) has received 96 reports of metabolic acidosis in patients taking paracetamol. While many of these patients were taking multiple medications, paracetamol was the only suspected medicine involved in 32 of these reports.

Demographics of reports to the TGA:

• 7% related to children (< 17 years);
• 41% occurred in people aged 18-64;
• 26% in people > 64 years
• 57% related to females and 36% to males.

The patient age was unknown for 26% of the reports and gender was not specified in 6% of cases.

Summary

Pyroglutamic acid accumulation is a rare cause of metabolic acidosis and may occur in association with chronic therapeutic use of paracetamol. Risk factors are common in hospitalised patients, and it is thought to be an underdiagnosed condition. Awareness is essential as untreated cases can progress to severe acidosis.

Patients presenting with HAGMA in association with paracetamol are typically women with chronic illness and malnutrition. The co-administration of flucloxacillin is thought to be a significant contributing factor.

The possibility of paracetamol as a causative agent should be considered in patients with HAGMA who are taking long-term paracetamol, particularly if additional risk factors exist.