Analysis of Liver Injury Risk Factors in a Multiethnic Population Treated With Antituberculosis Drugs

Tuberculosis (TB) is the world's second leading cause of death from a single infectious agent in 2022, after COVID-19. In 2022, TB disease was estimated to affect 10.6 million people, of whom 1.3 million died because of it, despite the WHO's adoption of the End TB Strategy. The standardised therapy involves a treatment regimen of isoniazid (INH), rifampin (RIF), ethambutol (EMB), and pyrazinamide (PZA) for 2 months, then INH and RMP for at least an additional 4-7 months [3]. Even though 85% of TB cases are successfully treated, significant morbidity from treatment-related adverse events, such as hepatotoxicity, skin reactions, and gastrointestinal and neurological disorders, reduces the efficacy of therapy. In 11% of patients receiving INH, RMP, and PZA in combination, hepatotoxicity is the most frequent adverse effect that results in drug discontinuation. One of the most prevalent subtypes of idiosyncratic hepatotoxicity is caused by anti-TB drugs. There are many factors contributing to the development of liver injury that are related both to the drug and to the patient's characteristics. As to drug-related factors, acetylhydrazine, which is generated by NAT2, is widely considered a crucial INH metabolite that contributes to drug-induced liver injury (DILI). Given the importance of acetylation in INH metabolism, several studies have investigated NAT2 loss of function polymorphisms as possible risk factors for anti-TB DILI. In addition, advanced age, female gender, poor nutritional status, HBV or HCV infection, HIV infection, chronic liver disease, and alcoholism are environmental, physiological, and pathological factors contributing to anti-TB DILI incidence. Geographic and ethnic characteristics also play a role in the occurrence of DILI. This event is also ascribed to the polymorphisms observed at the level of genes encoding for metabolic enzymes. Of note, most studies available in the literature have been conducted in Asiatic geographical areas, where TB is considered of great concern due to its high incidence. Moreover, it is well known that the Chinese population is commonly composed of NAT2 rapid acetylators, showing a lower susceptibility to the development of anti-TB DILI. There is still considerable controversy and uncertainty regarding the potential role that the acetylator status of individuals (rapid or slow) may play in INH-induced hepatotoxicity, given the fact that the results of previous studies have shown such considerable variability.

Due to the impossibility of treating liver injury, the only recovery strategy is drug discontinuation in tuberculosis patients; its prevention is essential to avoiding this condition. To prevent the progression of the disease, increase the efficiency of treatment, and reduce mortality, screening patients for risk factors may be extremely useful. Consequently, the current study's aim is to determine the association between anti-TB DILI incidence and potential environmental, physiologic, and pathologic factors. Since 2020, a cohort of patients has been followed in the Department of Infectious Diseases of Luigi Sacco Hospital in Milan, Italy. Moreover, despite the multi-ethnic characterisation of the cohort enrolled in this study, the high prevalence of Caucasian patients (who also present a greater frequency of slow acetylators) may be provide a complementary perspective to previously published studies, mostly focusing on Asian populations. Based on this cohort, we performed a nested case-control study to understand the role of several drug- and host-related factors in DILI.