Idiosyncratic drug-induced liver injury (DILI) due to xenobiotics (drugs, herbals and dietary supplements) remains an uncommon cause of liver disease showing a wide range of phenotypes and disease severity, acute hepatitis imitating viral hepatitis to autoimmune hepatitis, steatosis, fibrosis or rare chronic vascular syndromes. Disease severity varies from asymptomatic liver test abnormalities to acute liver failure. DILI has been traditionally classified as having predictable or intrinsic (dose-related) or unpredictable (not dose-related) mechanisms. Few prospective studies aim in assessing the real prevalence and incidence of hepatotoxicity in the general population. 

DILI registries can serve as useful networks for the study of liver toxicity, aspired at improving the understanding of causes, phenotypes, natural history, and standardized definitions of hepatotoxicity. Although most of the registries do not involve population-based studies, they may furnish important data related to the prevalence of DILI, and also may facilitate comparing features from different countries. 

With the support of the Spanish Registry of Hepatotoxicity, a Latin American Registry (LATINDILI) was created in 2011, which has recruited more than 350 DILI patients and have explained the following-

Risk factors for DILI

Older age may be a contributing factor determining the susceptibility to DILI, secondary to particular drugs, and contributing to the phenotype of DILI. 

Ethnicity too should be considered a risk factor for liver toxicity. 

Although not proven, schistosomiasis should be considered as a potential risk factor for DILI in HIV patients.

Challenging phenotypes in clinical practice

Hepatotoxicity should be suspected when a specific diagnosis other than DILI has not been fully established.

No consensus exists on prescribing duration and schedule of immunosuppressive drugs while facing drug-induced AIH.

No treatment has been shown to benefit ductal damage and drug-induced ductopenia.

Diagnosis

CIOMS/RUCAM training is essential to improve the epidemiological studies, case discussion in clinical practice, pharmacovigilance organisms or regulatory agencies.

 Role of liver biopsy

Generally, a DILI diagnosis does not require a liver biopsy, but it can exclude other causes.

Other patterns like AIH induced by drugs, steatohepatitis associated with MTX and SOS linked to intake of oncologic drugs can also be reckoned on liver histology.

In patients with prolonged cholestasis, liver biopsy best diagnose bile duct damage and vanishing bile duct syndrome induced by drugs.

A liver biopsy may also be useful in patients suspected to have chronic hepatitis induced by drugs medicaments linked to an absence of serological markers

Suspected drug-induced granulomatous hepatitis requires liver histology evaluation to approach this diagnosis or to rule out other causes of liver granulomata.

The emerging role of novel biomarkers

Combination of the diagnostic scales and biomarkers will benefit the most significant future diagnosis.

Developing PCR-based miRNA panels will be a promising approach.

Differential diagnosis 

Hepatitis E should be the first line of differential diagnosis when finding clinical hepatocellular and mixed phenotypes.

Antibodies anti HCV may be initially negative, and acute hepatitis C should be ruled out by HCV RNA determination

Dengue and yellow fever can be considered as the differential diagnosis of DILI in endemic regions, mainly when severe or fulminant liver diseases have been the main phenotype at presentation.

Yellow fever often has a more severe liver disease than dengue; thus serologic analysis of IgM has a high diagnostic value, while PCR is used only in doubtful cases.

Acute schistosomiasis shows clinical hypersensitivity that can sometimes mimic mixed DILI. It may induce granulomatous hepatitis confirmed by liver biopsy.

Hepatitis B, with or without delta virus, should be considered high endemic areas for both viruses and can be ruled out by using serological and virological determinations.

 Treatment of DILI

A detailed investigation should be done of potential drugs causing DILI, which should be initially removed.

N-acetylcysteine therapy should be initiated for treating ALF induced by other drugs than paracetamol.

Cholestyramine can be utilized for leflunomide toxicity.

 L-carnitine can be administered in children with severe liver injury associated with valproate therapy.

UDCA course in prolonged cholestasis induced by drugs might be beneficial in some cases by improving both pruritus and biochemical parameters.

Prognosis

While the DILI prognosis is usually benign, a small percentage of cases may progress to acute liver failure. 

Prolonged forms of DILI, both hepatocellular and cholestatic that do not resolve within the first year from starting symptoms possess a high probability to evolve to chronic liver disease.

 Monitoring strategies in patients with suspected DILI

Close monitoring should be carried out while prescribing the anti-TB scheme.

Drugs using immunoalergic mechanisms of liver damage does not require close monitoring (e.g. phenytoin, carbamazepine).

SOURCE- Bessone F, Hernandez N, Tagle M et al. Drug-induced liver injury: A management position paper from the Latin American Association for Study of the liver, Annals of Hepatology,2021; 24. https://doi.org/10.1016/j.aohep.2021.100321.