Paracetamol is a non-opioid analgesic recommended as a first-line treatment for mild to moderate pain and fever.1 It is one of the most widely used over-the-counter medications worldwide. In Hong Kong, >600 registered pharmaceuticals contain paracetamol.2 Adverse drug reactions in healthy individuals are rare within the therapeutic dose range. According to the British National Formulary, the recommended daily dose of paracetamol is 4 g/day in divided doses for adults with body weight ≥50 kg.3 Special precautions are needed for individuals with a high risk of hepatotoxicity, including those with body weight <50 kg, chronic alcoholism, chronic dehydration, chronic malnutrition, hepatocellular insufficiency, and/or concomitant use of P450 liver enzyme inducers (eg, antituberculosis drugs, antiepileptic drugs, and herbs/dietary supplements such as St John’s wort).

Paracetamol is metabolised through various pathways in the liver. In healthy individuals taking normal therapeutic doses, >90% of paracetamol undergoes glucuronidation and sulphation, followed by renal excretion.4 Only 5% to 10% is oxidised by cytochrome P450 to the toxic metabolite N-acetyl-p-benzoquinone imine, which is subsequently neutralised by glutathione and undergoes renal excretion. However, in cases of paracetamol overdose or glutathione depletion, excessive production and accumulation of N-acetyl-p-benzoquinone imine in hepatocytes can result in acute liver injury. N-acetylcysteine, the primary antidote in such situations, acts by replenishing hepatic glutathione.5 Theoretically, paracetamol hepatotoxicity can occur after normal therapeutic dose use in patients with critically depleted glutathione levels.

There have been few reports of paracetamolinduced hepatotoxicity after normal therapeutic doses use.6 7 8 Most of these cases had at least one of the aforementioned risk factors. In 2022, the United Kingdom’s Healthcare Safety Investigation Branch published a report recommending a prescription alert for individuals with body weight <50 kg who are prescribed paracetamol.9 The Queensland Government’s Department of Health of Australia also revised its paracetamol use guidelines, recommending ≤3 g/day for adults with risk factors such as advanced age or low body weight.10 When risk factors are present and treatment continues beyond 48 hours, liver function test and international normalised ratio (INR) monitoring is recommended.10 The United States Food and Drug Administration states that it is safe to consume ≤4 g of paracetamol within 24 hours,11 whereas the Irish Health Products Regulatory Authority recommends ≤2 g of paracetamol for patients with mild to moderate hepatic insufficiency or chronic alcoholism.12

Isolated cases of paracetamol-induced hepatotoxicity causing death or acute hepatic failure after normal therapeutic doses use have been reported to the Hong Kong Poison Information Centre (HKPIC). However, no local reports have been published concerning the incidence of this rare adverse drug reaction in the Hong Kong population. This study aimed to describe the epidemiology and incidence of paracetamol-induced hepatotoxicity in the Hong Kong Chinese population.

This territory-wide retrospective observational study included adult patients with suspected paracetamol-induced hepatotoxicity after normal therapeutic doses use reported to the HKPIC from 1 January 2011 to 30 June 2022 (11.5 years in total).

The HKPIC was the only poison control centre in Hong Kong during the study period. This centre provides round-the-clock phone consultations regarding poisoning cases to local healthcare professionals and receives voluntary reports of poisoning from all public emergency departments.13 14 The HKPIC maintains an electronic database, the Poison Information and Clinical Management System (PICMS), that contains information about all consultations and reports received. Clinical data from consultations and reports are entered into the PICMS by staff trained in clinical toxicology.14 The data source for this study consisted of data retrieved from the PICMS. When PICMS data were incomplete, supplementary data were retrieved from the Hospital Authority’s electronic Patient Record system, which contains all medical records (ie, clinical data, laboratory results, and outcomes) of patients treated in public hospitals in Hong Kong.

All cases of paracetamol poisoning recorded in the PICMS during the study period were identified. Exclusion criteria were applied to ensure the inclusion of only adult patients with suspected paracetamol-induced hepatotoxicity after normal therapeutic doses use. These exclusion criteria were age <18 years, intentional self-harm with paracetamol, daily paracetamol consumption >4 g, unknown paracetamol dose, co-ingestion with other hepatotoxic drugs, or hepatotoxicity unrelated to paracetamol.

For the included cases, the following data were collected: demographic characteristics including age, sex, and ethnicity; duration of paracetamol use, daily paracetamol dose, and reasons for paracetamol use; risk factors including history of preexisting liver disease, chronic alcoholism, use of P450 liver enzyme-inducing medications, and malnutrition; poisoning data including peak serum paracetamol concentration, peak alanine transaminase (ALT) level, peak INR, and receipt of N-acetylcysteine; and clinical outcomes including death, acute liver failure, mildly deranged liver function, and minimal effect.

The diagnosis of paracetamol-induced hepatotoxicity was established on the basis of compatible clinical and biochemical features, excluding other causes of deranged liver function (eg, acute viral hepatitis, autoimmune causes, and other drug- or herb-induced hepatitis). All cases were reviewed by at least one clinical toxicologist working in the HKPIC. Clinical outcomes were defined as follows: ‘death’ was defined as poisoning-related death, as judged by a clinical toxicologist, within 30 days after hospitalisation; ‘acute hepatic failure’ was defined as severe acute liver injury with an ALT level >1000 IU/L, associated with encephalopathy and impaired synthetic function within 26 weeks15; ‘mildly deranged liver function’ was defined as a peak ALT level >2 times the upper limit of normal, without encephalopathy or impaired synthetic function; and ‘minimal effect’ was defined as a peak ALT level <2 times the upper limit of normal, along with normal mental status. ‘Significant clinical outcome’ cases were those with a clinical outcome of death or acute hepatic failure. Malnutrition was defined as documented insufficient energy intake for >1 week.16

Data were analysed using SPSS software (Windows version 29.0; IBM Corp, Armonk [NY], United States). Continuous data were expressed as medians (interquartile ranges); the Mann-Whitney U test was used to compare the death and acute hepatic failure groups with the minimal effect group. Categorical variables were expressed as frequencies and percentages; they were compared using the Chi squared test or Fisher’s exact test, as appropriate. All statistical tests were two-sided, and P values <0.05 were considered statistically significant. Due to the small sample size and low incidence of significant clinical outcomes, multivariable logistic regression was not performed.

Within the study period, 3873 cases of paracetamol poisoning were identified. Reasons for exclusion were intentional paracetamol poisoning, age <18 years, other causes of deranged liver function, daily paracetamol dose >4 g, and unknown paracetamol dose (Fig). In total, 76 patients were included in the analysis; these patients were grouped according to clinical outcomes. During the study period, five patients died, nine patients developed acute hepatic failure, one patient developed mildly deranged liver function without coagulopathy or altered mental status, and 61 patients showed minimal effect; no patients underwent liver transplantation. The incidence of significant clinical outcomes (including death and acute hepatic failure) was 1.2 cases per year. Baseline demographic and clinical characteristics are summarised in Table 1.

Most patients were women (69.7%). The median age was 74 years and the median body weight was 54.2 kg. All patients were of Chinese ethnicity. Compared with the minimal effect group, patients in the death group were older (median age: 83 vs 72 years; P=0.003), had a longer duration of paracetamol use [median duration: 7 vs 1 day(s); P=0.001], and had a higher daily paracetamol dose (median dose: 4 vs 2 g; P=0.004). Their body weights tended to be lower, but this difference was not statistically significant (median: 50 vs 56.4 kg; P=0.11). Moreover, a higher percentage of patients in the death group suffered from malnutrition (80% vs 31.1%; P=0.04), and their peak serum paracetamol concentrations were higher (median peak concentration: 410 vs 0 μmol/L; P<0.001), exceeding the normal range of <130 μmol/L despite the use of normal therapeutic doses (Table 1).

Patients with significant clinical outcomes were evaluated by combining the death and acute hepatic failure groups. Five risk factors for significant clinical outcomes were identified, namely, age >80 years (odds ratio [OR]=7.2, 95% confidence interval [CI]=2.0-26.2), body weight <50 kg (OR=3.8, 95% CI=1.0-12.1), duration of paracetamol use >2 days (OR=16.9, 95% CI=2.1-136.9), daily paracetamol dose >3 g (OR=7.2, 95% CI=2.0-26.2), and malnutrition (OR=4.07, 95% CI=1.2-13.8). A summary of the risk factors is provided in Table 2.

The maximum recommended daily dose of paracetamol for healthy adults is 4 g/day in divided doses.17 As one of the most widely used analgesics worldwide for decades, this dosage recommendation is considered safe and generally has not been questioned by most healthcare professionals. Physicians have been taught to use the convenient dosing of 1-g paracetamol four times daily as a first-line analgesic in adults. Historically, paracetamol-induced hepatotoxicity was solely regarded as a consequence of overdose. Paracetamol-induced hepatotoxicity after normal therapeutic doses use was considered a therapeutic misadventure of doubtful existence.7 However, case reports of this adverse drug reaction were published.6 7 8 The situation becoming clear after a single-blind randomised controlled trial by Watkins et al18 revealed elevated ALT levels in 40% of healthy individuals who had received 4 g/day of paracetamol for 2 weeks. Subsequent studies confirmed this observation and showed that continuous use of paracetamol by individuals with high ALT levels did not result in hepatotoxicity.19 20 Their ALT levels returned to baseline after continuous paracetamol use, suggesting hepatic adaptation.21 Nevertheless, the mechanisms underlying hepatic adaptation are not fully understood, and paracetamol-induced hepatotoxicity after normal therapeutic doses use may represent a rare adverse drug reaction due to failed hepatic adaptation. In a prospective study in Spain,22 the incidence of this adverse drug reaction was estimated to be 10 per million paracetamol users-year (95% CI=4.3-19.4). Prior to the present study, there has been little information on how often paracetamol-induced hepatotoxicity occurs in the Hong Kong Chinese population.

Our study confirmed the existence of this rare adverse drug reaction, with an incidence of 1.2 cases of significant clinical outcomes per year in the Hong Kong population (approximately 7 million people). Because the vast majority of the local population is served by public hospitals included in our poisoning surveillance protocol, we believed that this figure accurately reflects the rare occurrence of this adverse drug reaction. Concerning patient characteristics predictive of significant clinical outcomes, we found that age >80 years, body weight <50 kg, duration of paracetamol use >2 days, daily paracetamol dose >3 g, and malnutrition were associated with a higher risk of paracetamol-induced hepatotoxicity leading to death or acute hepatic failure. The median daily dose was 4 g of paracetamol, consistent with the convenient maximum therapeutic dosing (eg, 1 g four times daily) for adults. Additionally, the median duration of paracetamol use was 5 to 7 days, indicating that life-threatening paracetamol-induced hepatotoxicity can develop and rapidly progress within a few days in susceptible individuals receiving convenient paracetamol dosing. The supratherapeutic serum paracetamol concentrations detected in these cases provide evidence of impaired hepatic paracetamol metabolism, leading to gradual accumulation of paracetamol within the body. The subsequent pathophysiology of hepatotoxicity is considered identical to that of paracetamol overdose. Therefore, the use of the antidote Nacetylcysteine is recommended in all identifiable cases of paracetamol-induced hepatotoxicity after normal therapeutic doses use.

One argument against the existence of this adverse drug reaction has been the accuracy of documentation concerning paracetamol dosage.7 Because the clinical presentation of paracetamol-induced hepatotoxicity is indistinguishable from that of paracetamol overdose, it has been suggested that the hepatotoxicity cases actually represent undeclared or undiagnosed instances of paracetamol overdose, which are more common in clinical practice. The present findings exclude this possibility. All five patients who died had exhibited normal liver function upon or prior to hospital admission; they were prescribed therapeutic doses of paracetamol for various indications during their inpatient stay. The possibility of intentional or accidental paracetamol overdose was excluded in each case.

The association between older age and paracetamol-induced hepatotoxicity has been addressed in previous studies. In 2021, a prospective study by Louvet et al23 showed that older age was an important risk factor associated with acute liver injury after therapeutic doses of paracetamol. Paracetamol pharmacokinetics in older adults reportedly differ from those in younger adults. Although absorption from the gastrointestinal tract is not significantly reduced, paracetamol clearance is 46.8% lower in frail older individuals than in healthy older individuals.24 In another observational study,25 the effects of ageing and frailty on serum paracetamol and ALT levels were assessed in hospitalised patients after continuous exposure to therapeutic doses for 5 days. The results showed that serum paracetamol concentrations were higher in older frail patients.25

This study had some limitations. First, its retrospective nature required reliance on the accuracy and completeness of medical records. Incomplete information in medical records, particularly missing data concerning the daily dose and duration of paracetamol exposure, could substantially affected the results. Second, because all consultations were voluntarily reported, underreporting may contribute to reporting bias. Third, the sample size was relatively small, hindering analysis of confounders via logistic regression. Finally, the effects of some potential risk factors (eg, chronic alcoholism and concomitant use of P450 inducer) could not be quantified due to their low reported incidence and the small sample size.

Paracetamol-induced hepatotoxicity can occur at normal therapeutic doses in the Hong Kong Chinese population. Our study identified risk factors associated with significant clinical outcomes. Considering the widespread use of paracetamol in Hong Kong, the incidence of paracetamol-induced hepatotoxicity is low; current dosage recommendations are considered safe for the vast majority of the general population. Nevertheless, a maximum daily dose of ≤3 g is recommended for susceptible patients. Paracetamol dosage, especially if consumed at 4 g/day for >48 hours, should be reviewed; liver function and INR monitoring should be considered in susceptible patients.10

Concept or design: All authors. Acquisition of data: WH Tsang. Analysis or interpretation of data: WH Tsang, CK Chan. Drafting of the manuscript: WH Tsang. Critical revision of the manuscript for important intellectual content: WH Tsang, CK Chan.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

All authors have disclosed no conflicts of interest.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

This research was approved by the Kowloon Central / Kowloon East Cluster Research Ethics Committee of Hospital Authority, Hong Kong (Ref No.: KC/KE-23-0041/ER-4). The requirement for informed patient consent was waived by the Committee due to the retrospective nature of the research and the use of anonymised data in the research.

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