Clinical presentations in drug-induced hepatotoxicity are varied and, most times, can be asymptomatic.[5][4][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-Johnsons 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 is history is of paramount importance. On physical exam, there may be jaundice, presence of right upper quadrant tenderness, and sometimes hepatomegaly when liver injury leads to chronic liver disease.[6]

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.[17][6][3] 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) in comparison 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][7][17][6] 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][21][14][15][22] 

Several clinical prediction scores have also been developed to develop an objective diagnostic tool for DILI. Among them is the Roussel Uclaf Causality Assessment (RUCAM), which 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 subsequently, the likelihood of DILI can be determined.[12][2]

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 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]

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, 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, pancreatobiliary malignancy

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]

Generally, patients have a favorable prognosis after discontinuation of the offending drug, as 90% recover. Mortality risk can be predicted through “Hy’s law,” which include criteria 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.[14][3][9] Individuals more than 65 years old 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.[14][3][9] In general, about 10% of patients progress to requiring liver transplantation. Following liver transplantation, survival is 66%.[4][3]

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

Prevention of DILI can begin with patient education on their medications, which include over the counter drugs, prescription medications, and HDS. If patients should experience signs and symptoms of liver toxicity or ALF, further evaluation is required.

More than 1000 medications and herbal compounds can cause drug-induced hepatotoxicity.[10][4] Patients can present with symptoms that manifest similarly to other hepatobiliary disorders. Thus, it is important to perform a thorough drug history when drug-induced hepatotoxicity is suspected.[17][6][3] Once DILI is suspected as the likely etiology of hepatotoxicity, remove the offending agent, and monitor for signs of ALF as transplantation evaluation is necessary.[3][4][7] A multidisciplinary approach with clinicians, pharmacists, and nursing is required for diagnosis and to report suspected drugs to regulatory organizations to assess its potential removal from the market.[9] A web-based resource can aid healthcare providers in this. It contains a database of offending compounds with a description of its liver toxicity, and there is also a case submission registry that allows users to report DILI cases directly; this can then be forwarded to the U.S. Food and Drug Administration's Event Reporting System.[10] [Level 2]