Drug-Induced Hepatotoxicity

Etiology

There are patient risk factors associated with the development of DILI, which include female sex, older age, and increased body mass index (BMI).[8][9] More than 1000 medications and herbal compounds are known to cause hepatotoxicity and can be found on a searchable database maintained by the National Institute of Diabetes and Digestive, and Kidney Diseases (NIDDK) called LiverTox.[10][4] Intrinsic DILI is most commonly caused by acetaminophen, while it is less often seen in aspirin, tetracycline, and vitamin A [3].

Idiosyncratic DILI cases are caused by:

• Antibiotics (45.4%): amoxicillin-clavulanate (most common), sulfamethoxazole-trimethoprim, ciprofloxacin, isoniazid (INH)
• Nonsteroidal anti-inflammatory drugs (NSAIDs)
• Herbal and dietary supplements (HDS) (16.1%): green tea extract, anabolic steroids, multi-ingredient nutritional supplements
• Cardiovascular drugs (10%): statins, amiodarone
• Central nervous system (CNS) agents: valproate, phenytoin
• Antineoplastic drugs: tyrosine kinase inhibitors, tumor necrosis factor inhibitors, alpha inhibitors, methotrexate [2][9]

Epidemiology

The true incidence of DILI is difficult to determine as it is often underreported, and several different diagnostic criteria are used.[3] In the United States (US) and worldwide, DILI annual incidence in the general population is under 15 to 20 per 100,000.[2][7][11] In the US, it is the most common cause of acute liver failure episodes (13%-16%), yet it is important to note that it is still a much less common etiology of acute liver injury overall.[1][9] The incidence of idiosyncratic DILI is higher in women (59%) when compared to men, which may be due to hormonal interactions with immunomodulating drugs or differing pharmacokinetics. Patients more than 50 years old are more likely to develop DILI, possibly due to increased prescription drug use.[3]

Pathophysiology

The pathogenesis of DILI can be divided into 2 mechanisms: intrinsic and idiosyncratic. The intrinsic mechanism is both predictable and reproducible from drugs that are known to cause liver injury in a dose-dependent manner with a short latency period.[7][12][13][14] For example, in acetaminophen toxicity, the drug's metabolite leads to the production of reactive metabolites that excessively accumulate, causing apoptosis and necrosis of the hepatocytes.[1][4][8][15][16] The idiosyncratic mechanism of DILI is characterized by a more unpredictable course and is not reproducible. It occurs in susceptible patients, usually independent of the drug dose, with a variable latency period generally beginning 7 to 14 days after first ingestion.[7][13][12] Although the exact mechanism is unknown, it is thought to be due to a combination of host, drug, and environmental factors. The host factors are patient age, gender, genetic polymorphisms, immune status, and metabolism. Drug factors include the dose, duration, weight, and degree of lipophilicity. Environmental factors consist of concomitant alcohol use, diet, tobacco, and toxins.[3][13][14] Idiosyncratic DILI mechanisms can be divided into immune-mediated (allergic) liver injury from hypersensitivity or non-immune-mediated metabolic (non-allergic) mechanisms from mitochondrial injury.[12]

Histopathology

Although liver biopsy is not required for diagnosis, drug-induced hepatotoxicity can be classified based on histologic findings. The histological appearance can also assist in identifying an etiology, excluding other diagnoses, and thus drive management. It is also a tool that can assist in prognostication.[13][17][14][9][6] 

• Acute hepatocellular injury: severe inflammation with necrosis and apoptosis seen in isoniazid (INH), aspirin, and phenytoin
• Chronic hepatocellular injury: findings as above with fibrosis resembling other chronic liver disease seen in amoxicillin-clavulanate, valproic acid, amiodarone
• Acute cholestasis: bile plugging with hepatocellular cholestasis, commonly seen in anabolic steroid use
• Chronic cholestasis: bile stasis, portal inflammation, bile jury, bile plugs, and duct paucity seen in amoxicillin-clavulanate
• Steatosis: microvesicular often related to mitochondrial injury seen in tetracycline and valproic acid
• Zonal necrosis: usually in intrinsic DILI and associated with poor outcomes, seen in acetaminophen toxicity
• Granulomas: associated with milder injury and can result from many drugs or even talc exposure through the bloodstream

History and Physical

Clinical presentations in drug-induced hepatotoxicity are varied and, most times, can be asymptomatic.[4][5][6] DILI manifests most commonly as jaundice, then weakness, abdominal pain, dark stools or urine, nausea, and pruritis (usually seen in cholestatic liver injury). DILI can present as acute or chronic liver failure, which makes it very difficult to distinguish from other liver conditions.[18] In immune-mediated hepatotoxicity, patients may present with fever, rash, eosinophilia, and even Stevens-Johnson syndrome.[3] The patient’s history will reveal signs or symptoms that develop within 3 to 6 months of exposure to the offending agent; thus, a thorough medication history is of paramount importance. On physical exam, there may be jaundice, the presence of right upper quadrant tenderness, and sometimes hepatomegaly when liver injury leads to chronic liver disease.[6]

Evaluation

Diagnosis begins with a compatible history, known drugs, and excluding underlying liver disease. Subsequently, a high index of suspicion is required, as there are no specific tests available to diagnose DILI.[3][6][17] Testing should include alanine aminotransaminase (ALT), aspartate transferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), total bilirubin, albumin, prothrombin time (PT), and international normalized ratio (INR). Other laboratory tests that could assist in diagnosis are complete blood count (CBC), electrolytes, viral serologies, and autoantibodies.[14][19] The pattern of liver test abnormalities can distinguish between the types of liver injury. In hepatocellular injury, there is a marked elevation of transaminases (typically 3 times the upper limit) in comparison to the ALP level. In cholestatic injury or cholestasis, ALP is typically 3 times the upper limit of normal (ULN) compared to transaminases. There also exists a mixed pattern of injury where both the aminotransferases and ALP are 3 times the ULN.[1][3][12] In ALF, coagulopathy may be observed, indicating impaired liver function.[1]  Imaging studies such as abdominal ultrasound or MRI can be helpful in cholestatic injury to exclude other biliary tract pathology.[20][9] Again, liver biopsy is not necessary for diagnosis but can be useful in exclusion, especially if other causes of liver disease are suspected.[3][6][7][17]Emerging data exists on potential biomarkers to aid in the diagnosis or predict the progression of DILI. It has been shown that micro-RNAs are found in increased quantity in DILI, suggesting its release from damaged cells. Though this is not specific, it can be used to assess liver injury.[7][9][14][15][21][22] 

Several clinical prediction scores have also been developed to develop an objective diagnostic tool for DILI. The Roussel Uclaf Causality Assessment (RUCAM) includes risk factors, course of liver enzymes, suspected offending agents, and alternative causes into the scoring system. Using the calculated “R” score, the type of liver injury can be classified, and the likelihood of DILI can be determined.[6][12]

Treatment / Management

The principal treatment for drug-induced hepatotoxicity is the removal of the offending agent.[3][7] N-acetyl-cysteine (NAC) is the treatment for intrinsic DILI secondary to acetaminophen toxicity, as this promotes the regeneration of glutathione, leading to the detoxification of the toxic metabolite.[1] The other specific therapy that is available is L-carnitine for valproic acid overdose.[3] Glucocorticoid therapy is usually used when the histological appearance of DILI resembles that of autoimmune hepatitis. For this reason, it has a limited role and usually does not change the course of recovery.[6] Symptomatic therapies such as bile acid sequestrants for cholestatic DILI or antihistamines for pruritis can be used with some efficacy.[6][3][7] Hospital admission is required for patients with signs or symptoms of DILI progression or ALF.[7] If ALF is suspected, early liver transplant consideration is essential because there is high mortality with ALF.[3] An important additional aspect of management is reporting cases of DILI to regulatory bodies to evaluate if the suspected drug needs to be withdrawn from the market.[9]

Differential Diagnosis

DILI is clinically challenging to diagnose as it can mimic any acute or chronic hepatobiliary condition.[14][12]

• Liver diseases: viral hepatitis (A, B, C, E), cytomegalovirus (CMV), Epstein-Barr virus, ischemic hepatitis, autoimmune hepatitis, Hemochromatosis, Wilson disease, non-alcoholic fatty liver disease (NAFLD), alcoholic hepatitis, Gilbert syndrome
• Biliary disease: cholangitis, choledocholithiasis, primary biliary cirrhosis, primary sclerosing cholangitis
• Malignancy: hepatocellular cancer, lymphoma, pancreaticobiliary malignancy

Pertinent Studies and Ongoing Trials

The Drug-Induced Liver Injury Network (DILIN) was developed to advance research in DILI through a prospective clinical trial of patients. It created the DILIN Causality Scoring System to understand better the etiology, pathogenesis, risk factors, and outcomes of drug-induced hepatotoxicity.[2][23]

Prognosis

Generally, patients have a favorable prognosis after discontinuing the offending drug, as 90% recover. Mortality risk can be predicted through “Hy’s law,” which includes the following criteria that are associated with a poorer prognosis: ALT/AST more than 3 times ULN, total bilirubin up to 2 times ULN in the absence of obstruction, and no other explanation of the mentioned laboratory values.[3][9][14] Individuals 65 years and older had a higher incidence of Hy’s law; however, mortality does not differ.[2] Hepatocellular injury is more likely than cholestatic injury to have a 10% to 50% higher risk of mortality or to require a liver transplant.[3][9][14] In general, about 10% of patients progress to requiring liver transplantation. Following liver transplantation, survival is 66%.[3][4]

Complications

There is a 17% risk of progression to chronic liver disease, mostly seen in patients with prolonged cholestatic injury such as vanishing duct syndrome.[2][3] Acute liver failure results more often from hepatocellular injury than cholestatic.[3][14]