Drug‐induced liver injury (DILI) is a rare event, and is associated with significant morbidity and mortality. It is emerging as the prominent cause of acute liver failure in the developed countries. It is one of the most challenging diagnoses encountered by gastroenterologists. DILI is also regarded as the most frequently occurring adverse event leading to withdrawal of drugs from the marketplace, drug attrition, and failure of included drugs to obtain Food and Drug Administration approval.

Various risk factors responsible for DILI are listed below;

Age

Advancing age of the patient is highly important in increasing the susceptibility of DILI. A population‐based study showed increasing incidence of DILI with age; as it showed that incidence of DILI was 5 times higher for patients over 70 years in contrast to those between 15 and 29 years. Increasing age acts as a risk factor for liver injury from medications including isoniazid, amoxicillin/clavulanate, and nitrofurantoin. Cholestatic DILI is more common in the elderly in contrast to hepatocellular injury in younger individuals. Therefore, age may offer a susceptibility to DILI in a drug‐specific manner. 

Gender

Certain epidemiological studies have found female predilection to be a risk factor for DILI from some drugs. These drugs include minocycline and nitrofurantoin, in which DILI is typified by autoimmune features. Women with acute liver injury have higher possibility of progressing to acute liver failure.

Race

Race and ethnicity are risk factors affecting DILI frequency, liver injury patterns, and outcomes. A study suggested that African‐Americans with DILI were younger with higher rates of chronic DILI and the most common agents in this population were trimethoprim/sulfamethoxazole, methyldopa and phenytoin, in contrast to amoxicillin/clavulanate in Caucasians. Additionally, African‐Americans were twice as likely to develop severe liver injury, causing death or liver transplantation, despite absence of disparity in attaining health care, however, the reasons responsible are unclear. A peculiar study revealed that African‐Americans had higher risk of severe cutaneous reactions to allopurinol due to higher frequency of HLA‐B*5801.

Pregnancy

There is a dearth of data reported on DILI during pregnancy and is confined to therapeutic agents used to treat gestational hypertension and hyperthyroidism. The most common drugs are methyldopa, hydralazine, propylthiouracil, and antimicrobial agents like tetracycline. However, differentiation of DILI during pregnancy from other more common etiologies of abnormal liver tests including viral hepatitis, gallstone disease, or pregnancy‐related complications such as intrahepatic cholestasis of pregnancy is warranted.

Alcohol

The pathophysiology of acetaminophen‐associated liver injury along with alcohol use is complex and is regulated by the manner in which alcohol is consumed. Acute alcohol co‐ingestion with acetaminophen could be protective, due to their internal competition for use of CYP2E1 substrate, which in turn, reduces the byproduct N‐acetyl‐p‐benzoquinone‐imine. On the contrary, chronic alcohol acts as a CYP2E1 inducer and increases acetaminophen hepatotoxicity. 

Chronic Liver Disease and Comorbid Conditions

Patients with pre‐existing liver disease have shown higher rates of severe DILI and 3‐times higher risk of mortality in contrast to those without prior liver disease. Evidences suggest that nonalcoholic fatty liver disease (NAFLD) is a potential risk factor for increasing the risk of DILI. 

Genetics

Single nucleotide polymorphisms in numerous genes and HLA regions have the potenial to increase the risk for DILI. HLA‐B*5701 genotype has been recognized as a major determinant of flucloxacillin DILI. Moreover, HLA genotypes HLA DRB1*15:01 and DQB1*0602 are known to play a remarkable role in amoxicillin‐clavulanate DILI susceptibility. A study demonstrated that HLA‐B*35:02 increased the risk of minocycline DILI, with a 16% carrier frequency in DILI cases as compared to 0.6% in the controls. 

Dose-related factor

Some studies have shown that drugs with daily oral dosing of ≥50 mg is responsible for 70%‐80% of DILI cases in various population‐based studies.

Drug Metabolism

Medications administered orally with more than 50% hepatic metabolism had shown remarkable higher frequency of ALT >3‐times upper limit of normal, liver failure, and fatal DILI. In addition, drugs with biliary excretion exhibited higher frequency of jaundice.

Lipophilicity

Oral medication with high lipophilicity measured as LogP impacts drug pharmacokinetics and toxicity. A drug’s hepatotoxic potential has been conceptualized as the “rule of two,” identified by high lipophilicity (LogP > 3) and daily dosing (>100 mg), which are associated with an increased risk of DILI.

Source: Sandhu N, Navarro V. Drug-Induced Liver Injury in GI Practice. Hepatol Commun. 2020;4(5):631-645. Published 2020 Mar 13.