Paracetamol-induced hepatotoxicity after normal therapeutic doses: Risk factors in HK population

Paracetamol at normal therapeutic doses may induce hepatotoxicity in high-risk individuals, data from the Hong Kong Poison Information Centre (HKPIC) have shown. Identification of risk factors for significant clinical outcomes based on the HKPIC data has enabled experts to provide practical recommendations relevant to the Hong Kong Chinese population.

In a territory-wide retrospective observational study, researchers analyzed data from 76 patients (median age, 74 years; male, n=23) with suspected paracetamol-induced hepatotoxicity after taking normal therapeutic doses to investigate the incidence and epidemiology of this adverse drug reaction in the Hong Kong Chinese population. The 76 patients were identified among 3,873 cases of paracetamol poisoning reported to HKPIC from January 2011 to June 2022. [Hong Kong Med J 2024;30:355-361]

Among the 76 patients, 14 had significant clinical outcomes, including death (n=5) and acute hepatic failure (n=9), while 62 developed mildly deranged liver function or showed minimal effect. “The incidence of significant clinical outcomes was 1.2 cases per year,” the researchers reported.

Five risk factors for significant clinical outcomes were identified, namely:

·      Age >80 years (odds ratio [OR], 7.2; 95 percent confidence interval [CI], 2.0–26.2; p=0.0028);

·      Body weight <50 kg (OR, 3.8; 95 percent CI, 1.0–12.1; p=0.049);

·      Duration of paracetamol use >2 days (OR, 16.9; 95 percent CI, 2.1–136.9; p=0.008);

·      Daily paracetamol dose >3 g (OR, 7.2; 95 percent CI, 2.0–26.2; p=0.0028); and

·      Malnutrition (OR, 4.07; 95 percent CI, 1.2–13.8; p=0.02).

Among the 14 patients with significant clinical outcomes, 71.4 percent were >80 years of age, 42.9 percent had body weight <50 kg, 92.9 percent used paracetamol for >2 days, 71.4 percent took a daily paracetamol dose of >3 g, and 64.3 percent had malnutrition.

“The median duration of paracetamol use [in patients with significant clinical outcomes] was 5–7 days, indicating that life-threatening paracetamol-induced hepatotoxicity can develop and rapidly progress within a few days in susceptible individuals receiving [normal therapeutic doses of ≤4 g/day],” the researchers pointed out.

Impaired hepatic paracetamol metabolism may account for the significant clinical outcomes experienced by susceptible individuals after taking normal therapeutic doses. According to the researchers, the supratherapeutic serum paracetamol concentrations detected in patients who died (median, 410 µmol/L) and patients who experienced acute hepatic failure (median, 195 µmol/L) (normal range, <130 µmol/L) provided evidence of impaired hepatic paracetamol metabolism, which led to gradual accumulation of paracetamol within the body.

“The subsequent pathophysiology of hepatotoxicity is considered to be identical to that of paracetamol overdose. Therefore, use of the antidote N-acetylcysteine is recommended in all identifiable cases of paracetamol-induced hepatotoxicity after taking normal therapeutic doses,” the researchers noted.

“For susceptible patients, a reduced maximum paracetamol dose of ≤3 g/day is recommended. Paracetamol dosage, especially if consumed at 4 g/day for >48 hours, should be reviewed, with liver function and international normalized ratio monitoring in place for susceptible patients,” they advised.

“Considering the widespread use of paracetamol in Hong Kong, the incidence of paracetamol-induced hepatotoxicity is low. Current dosage recommendations [maximum 4 g/day in divided doses] are considered safe for the vast majority of the general population,” they added.