LIVER DISORDERS, SERIES #17

Drug-Induced Liver Injury (DILI): A Practical Review

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Drug-induced liver injury (DILI) is a common cause of acute liver injury and is the most common cause of acute liver failure in the United States1. DILI can be caused by a wide variety of compounds, including antibiotics, anticonvulsants, antidepressants, and herbal supplements. The risk of DILI is increased in patients with underlying liver disease, alcohol use, and certain genetic polymorphisms.

The diagnosis of DILI is based on a history of drug exposure, liver enzymes, and, less commonly, liver biopsy. Clinical and histologic presentation can mimic other causes of liver injury, which can make diagnosis challenging. The treatment of DILI, however, is supportive and includes stopping the offending drug and treating any complications. The prognosis of DILI is variable, but most cases are mild and resolve with discontinuation of the offending drug. Accurate diagnosis is paramount to prevent further unnecessary testing, therapies, complications, and lengthy hospital stays. 

Background

Drug-induced liver injury (DILI) is a common cause of acute liver injury and is the most common cause of acute liver failure in the United States.1 It is estimated that DILI occurs in 1-6% of hospitalized patients and liver injury may occur 10-15% of patients taking new medications. A study by Chalasani et al. conducted in a large academic medical center in the US found that DILI accounted for 13% of cases of acute liver injury in hospitalized patients between 1994 and 2006.18 Additionally, DILI remains the leading reason for the post-market withdrawal of medications by the Federal Drug Administration (FDA) in the United States.2,16 Compounds commonly implicated in DILI include antimicrobials, antidepressants, anticonvulsants, analgesics, and herbal and dietary supplements. In Western countries, acetaminophen remains the leading cause of DILI.3

The incidence of DILI ranges between 2.4 in 100,000 to 19 in 100,000 persons per year globally24,7 according to population studies in the UK, France, and Sweden. A recent study by Björnsson et al. encompassing the population of Iceland utilizing a national healthcare database revealed an incidence of non-acetaminophen DILI of 19 in 100,000 per year8 in that population. The true incidence of DILI, however, is difficult to accurately determine. Liver injury is a significant consideration during drug development given the vast number of medications metabolized in the liver. Adverse effects of medications, including DILI, often can be discovered in clinical trials prior to regulatory approval and drug marketing. These clinical trials, however, are generally comprised of a limited number of subjects. Given the low incidence of DILI, the majority of cases are only discovered after regulatory approval and increased use of a medication in the general population. In a prospective survey to physicians in France performed over a 3-year period, the incidence of symptomatic DILI was found to be 14 in 100,000 patients per year.7 Notably, this number was 16 times greater than adverse hepatic events reported to the French regulatory authority.7 Similarly, in the United States, the post-market Adverse Events Reporting System established by the FDA is voluntary, may be incomplete, and may skew attribution of causality, ultimately underestimating true incidence of DILI25 in the general population.  

Pathophysiology

The pathophysiology of DILI is complex and not fully understood. However, it is thought to involve a combination of genetic, environmental, and drug-related factors. Liver injury related to drugs or herbal and dietary supplements can generally be subdivided into two types of DILI—intrinsic or idiosyncratic. 

Intrinsic DILI is defined as a direct, dose-dependent, and predictable hepatotoxicity. These compounds are generally thought to cause predictable liver injury in patients regardless of risk factors in a mainly dose-dependent fashion. Injury commonly arises from the drug itself or an active metabolite. This results in a series of events resulting in cell death. Mechanisms include production of free radicals, reactive oxygen species, interfering with native cellular components and cellular functions.36 This can subsequently lead to entities such as acute hepatitis or sinusoidal obstruction syndrome. Many intrinsically hepatotoxic compounds are identified in pharmaceutical trials or removed by regulatory agencies after post-market reporting.37 Some compounds, however, normally limited to therapeutic doses, are known to cause intrinsic hepatotoxicity in higher doses. The most common and well-studied example is acetaminophen (APAP), which is the leading cause of drug-induced liver failure in the US. In supratherapeutic doses, the accumulation of the hepatotoxic APAP metabolite N-acetyl-p-benzoquinone imine (NAPQI) causes direct oxidative cellular injury.3 Other compounds implicated with intrinsic liver injury in high doses include niacin and iron sulfate as well as those naturally occurring in some mushrooms such as Amanita phalloides

Idiosyncratic DILI, however, is unpredictable and liver injury may not be dose dependent. The difficulty in identifying idiosyncratic DILI arises from its variable presentation and unpredictability. The incidence of idiosyncratic reactions to medications is low and, as a result, often escapes identification in preclinical and clinical pharmaceutical trials.36,38 Idiosyncratic DILI is thought to affect a predisposed population based on risk factors that are not well understood. 

Risk Factors

Several risk factors for DILI have been proposed in the medical literature, however there is no clear evidence to suggest that they represent major risk factors for the development of all-cause DILI independent of a specific compound.40

Certain risk factors, however, may predispose an individual to injury with specific medications. Children are thought to be at higher risk of developing DILI with certain medications such as anticonvulsant and antimicrobial medications whereas older adults are more likely to develop liver injury with amoxicillin-clavulanate, nitrofurantoin, and isoniazid.39,40 Females may have an increased risk with minocycline, methyldopa, diclofenac, nitrofurantoin, and nevirapine. Risk for DILI in pregnancy may be increased with methyldopa, hydralazine, and antiretrovirals.42

Risk FactorMedications
Age
 ChildrenAnticonvulsants Antimicrobials
 Older AdultsNitrofurantoin Amoxicillin-clavulanate Isoniazid
Female SexMinocycline Methyldopa Diclofenac Nitrofurantoin Nevirapine
PregnancyTetracycline Methyldopa Hydralazine Antiretrovirals
Diabetes MellitusMethotrexate Antituberculosis medications
Alcohol ConsumptionAcetaminophen (chronic alcohol use) Methotrexate Isoniazid Anabolic steroids
Drug-drug InteractionsAntituberculosis medications Anticonvulsants
Table 1.
Risk Factor Associated with DILI
Related to Particular Compounds

Other chronic comorbidities have been seen associated with higher risk of liver injury in combination with specific agents. In particular, diabetes mellitus may be related to a higher risk of DILI with methotrexate and antituberculosis medications as seen in a publication by the US DILI Network (DILIN).9

Environmental risk factors such as chronic alcohol use may be an additional risk factor for DILI, particularly with methotrexate and isoniazid41. Chronic alcohol use also increases the risk of liver injury from acetaminophen overdose. Interestingly, acute coingestion of alcohol with an acetaminophen overdose has been seen to confer a lower risk of DILI due to suspected substrate competition for metabolism of both compounds.43 

Drug-drug interactions, particularly with antituberculosis medications and anticonvulsants, may potentially increase the risk for DILI.41

R ratio =ALT ÷ ALT ULN _________________ Alk Phos ÷ Alk Phos ULN
Table 2. Calculation of R Ratio47
ALT: alanine aminotransferase, ULN: upper limit of normal of resulting laboratory, Alk Phos: alkaline phosphatase

Gender may also be associated with different outcomes following acute liver injury. Notably, acute liver injury in females was more likely to progress to acute liver failure as seen in several DILI registries.4,18,29

Other risk factors have been proposed which may increase the risk of DILI, such as other underlying liver disease, smoking, obesity, and malnutrition, however there is no clear evidence to suggest that these are major independent risk factors.41

Another risk factor proposed in the medical literature is race, however there remains no convincing evidence to suggest this as an independent risk factor due to confounding socioeconomic variables. Data from the US DILIN cohort saw that DILI in African-Americans was noted to occur in a younger age group and was associated more frequently with chronic symptoms when compared to Caucasians despite no significant difference in patterns of injury and recovery time. African Americans in that cohort, when compared to Caucasians, were seen to be twice as likely to develop severe liver injury leading to worse outcomes.19 Reasons for these outcomes are unclear, but may be related to unaccounted-for disparities in access to healthcare and reporting of adverse effects as well as other socioeconomic biases.51

Clinical presentation

The clinical presentation of DILI is variable and depends on the severity of the injury. Patients with mild DILI may have no symptoms or only mild symptoms, such as fatigue, nausea, and vomiting. With increasing severity of DILI, patients may exhibit jaundice, abdominal pain, and ascites. In very severe cases, DILI can present with coagulopathy and encephalopathy (signifying acute liver failure) and can subsequently lead to death.8

Clinically, DILI can be subcategorized based on the pattern of injury to the liver—hepatocellular, cholestatic, or mixed hepatocellular and cholestatic injury.44 Hepatocellular injury can be identified by a disproportionate increase in serum aminotransferases when compared to alkaline phosphatase. Cholestatic injury is identified by a disproportionate increase in alkaline phosphatase when compared to aminotransferases. In both cases, serum bilirubin may be elevated and synthetic function of the liver may be affected. These patterns can typically be differentiated by the calculation of the R ratio (Table 2) which compares the values of ALT and alkaline phosphatase. Typically, certain medications have been found to be more commonly associated with a specific pattern of hepatic injury (Table 3). 

Pattern of Liver InjuryCompounds Associated with DILI
Hepatocellular   R ratio ≥5Fluoroquinolones Isoniazid Macrolides Nitrofurantoin Minocycline Phenytoin Lamotrigine Valproate NSAIDs Diclofenac  INF-beta INF-alphaAnti-TNF agents Immune-checkpoint inhibitors (ipilimumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, durvalumab) Allopurinol Azathioprine Amiodarone Inhaled anesthetics Sulfasalazine
Cholestatic   R ratio ≤2Amoxicillin-clavulanate Androgen-containing steroids Trimethoprim/Sulfamethoxazole AzathioprineFluoroquinolones Phenytoin Sulfasalazine
Mixed   R ratio = 2 to 5Allopurinol  Immune-checkpoint inhibitors (early) FluoroquinolonesPhenytoin Sulfasalazine
Table 3. Pattern of Liver Injury Associated with Common Culprits of DILI
*Note: some compounds can produce multiple patterns of injury or can initially cause one pattern and later cause another pattern. These compounds are listed several times in this table

A poorly understood mechanism of injury, however, is immune-mediated DILI. This pattern of injury, thought to be related to an immune-mediated attack of the liver as a result of a specific metabolite, can often be associated with symptoms of hypersensitivity such as fever, rash, joint pains, lymphadenopathy, and eosinophilia.45 This symptomatic presentation may also resemble infectious mononucleosis. This pattern of injury has been associated with amoxicillin-clavulanate, diclofenac, phenytoin, and allopurinol.46

Another specific pattern includes drug-induced autoimmune hepatitis (DI-AIH). This presents with features of autoimmune hepatitis (AIH) such as elevated gamma-globulins, antibodies against smooth muscle, and/or antinuclear antibodies.46 Interestingly, this entity is responsive to treatment with corticosteroids and, as such, it is important to differentiate this entity from other injury patterns of DILI, where steroids may be less efficacious. Particularly, minocycline use in children can be seen to have a delayed pattern of injury resembling AIH. 

Globally, the most common medications implicated in DILI are antibiotics, with the most common culprit in Western countries being amoxicillin-clavulanate (Table 4).8,19,48 More recently, however, with the increased use of herbal/dietary supplements (HDS), incidence of liver injury attributed to these agents has also been increasing.59,60 The most common cause of injury among HDS are bodybuilding supplements.60 Clinically, this can present with prolonged jaundice in otherwise healthy young men. Liver injury related to non-bodybuilding supplements is more commonly seen in females, usually presents with a hepatocellular pattern of injury and is associated with worse outcomes and higher rates of transplantation.60 

Diagnosis 

Despite its low incidence, DILI should always be included in a differential diagnosis of liver injury. Diagnosis of DILI poses significant difficulty to the clinician given the variability of objective markers of liver injury and the difficulty to assign causality to a certain medication. One of the earliest definitions of DILI, specifically that with an hepatocellular pattern of injury, was developed by Dr. Hyman Zimmerman based on observations published in 1968 and again in 1999, suggesting that elevation of aspartate transaminase (AST) or alanine transaminase (ALT) more than three times the upper limit of normal (ULN) along with an elevation of total bilirubin more than two times the ULN in the absence of cholestasis (elevation of alkaline phosphatase < 2x the ULN) is a predictor of severe liver injury and poor outcomes (with a mortality of 10-50%, in pre-transplant days).26,27 Later dubbed Hy’s law, these parameters, in the absence of other etiologies of liver injury, signaled the potential for a drug to cause liver injury and have comprised part of the recommendations by the FDA for pharmaceutical trials. 

Spanish Registry (n = 843)48DILIN (n = 899)19Icelandic Study (n = 96)8
Amoxicillin-clavulanate (22%)Amoxicillin-clavulanate (10%)Amoxicillin-clavulanate (22%)
Anti-tuberculosis (4.5%)Isoniazid (5.3%)Diclofenac (6.3%)
Ibuprofen (3%)Nitrofurantoin (4.7%)Nitrofurantoin (4%)
Flutamide (2.6%)Sulfam-trimeth (3.4%)Azathioprine (4%)
Atorvastatin (1.9%)Minocycline (3.1%)Infliximab (4%)
Diclofenac (1.8%)Cefazolin (2.2%)Isotretinoin (3%)
Ticopidine (1.4%)Azithromycin (2%)Atorvastatin (2%)
Azathioprine (1.3%)Ciprofloxacin (1.8%)Doxycyline (2%)
Fluvastatin (1.3%)Levofloxacin (1.4%)Imatinib (1%)
Simvastatin (1.3%)Diclofenac (1.3%)Isoniazid (1%)
HDS (3.4%)HDS (16.1%)HDS (16%)
Table 4. The Most Common Implicated Agents Causing DILI in Three Prospective Studies on DILI
Abbreviations: DILI, drug-induced liver injury; HDS, herbal and dietary supplements; Sulfam-trimeth, sulfamethoxazole-trimethoprim
Reproduced from: Björnsson ES. Clinical management of patients with drug-induced liver injury (DILI). UEG Journal. 2021 Sep;9(7):781-6.

In an effort to further delineate causality based on objective measurements, the Roussel Uclaf Causality Assessment Method (RUCAM) system was developed in 1993 as an assessment score reflecting the likelihood that liver injury can be attributed to a specific compound.30 This system was validated on findings of a consensus meeting of experts (including Drs. Benhamou, Bircher, Dana, Maddrey, Neuberger, Orlani, Tygstrup and Zimmerman) and uses a combination of serologic, clinical, and radiologic features of liver injury assigned to a point system. This study found that scores usually agreed among the experts, with only 16% of scores being more than 1 point divergent.30,47

History

DILI should be considered amongst a wider differential diagnosis of more common causes of liver injury, as it largely remains a diagnosis of exclusion. Obtaining an accurate and thorough history is paramount to making a diagnosis of DILI. This should particularly involve a comprehensive review of medications with respect to the timing of their initial dosing, onset and chronicity of symptoms, and liver chemistry abnormalities. Additionally, care should be taken to inquire about the use of herbal and dietary supplements as these are increasingly more common causes of DILI.13 

Figure 1. A diagnostic workflow for assessing cases of suspected DILI 49. Reproduced from Kullak-Ublick GA, Andrade RJ, Merz M, End P, Benesic A, Gerbes AL, Aithal GP. Drug-induced liver injury: recent advances in diagnosis and risk assessment. Gut. 2017 Jun 1;66(6):1154-64: Figure 3. Used with permission from BMJ Publishing Group Ltd.

A particularly useful tool for clinicians developed by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) along with the National Library of Medicine is LiverTox (https://www.ncbi.nlm.nih.gov/books/NBK547852). This is a publicly available and easily accessible online textbook which maintains continuously up-to-date information on the likelihood and pattern of hepatotoxicity of over 1200 compounds.50 The aim of the LiverTox resource is to consolidate information that is not readily available and is dispersed throughout multiple publications in multiple disciplines throughout the world. This repository is constantly updated as new medications are introduced and their hepatotoxic side effects are brought to light through more frequent use. 

Laboratory Investigations

After a thorough history is obtained, liver chemistry abnormalities should be analyzed for their pattern of injury. This can be objectively accomplished by calculating an R ratio (Table 2). This in turn will help differentiate between hepatocellular injury, cholestatic injury, or a mixed injury. The pattern of injury can then guide further workup. 

For a hepatocellular pattern of injury (R ratio ≥5), causes of acute hepatitis should be further investigated. Preliminary testing should include serologies for acute viral hepatitis (including HCV RNA), serologies for autoimmune hepatitis, as well as imaging studies of the liver such as ultrasonography. If first-line testing is unrevealing, a hepatocellular pattern of injury should be further explored with ceruloplasmin and serologies for less common etiologies of viral hepatitis such as CMV, EBV (quickly assessed with monospot testing), and COVID, and possibly liver biopsy. 

For a cholestatic pattern of injury (R ratio ≤2), primary testing should involve imaging studies, such as abdominal ultrasound. If unrevealing, further testing by cholangiography, serologies for primary biliary cholangiopathy (PBC), and liver biopsy can be considered. 

A mixed pattern of liver injury (R ratio 2-5) should primarily involve workup for acute viral hepatitis (as detailed above), serologies for autoimmune hepatitis, as well as imaging studies of the liver with ultrasonography. If this is unrevealing, further testing for ceruloplasmin levels, serologies for less common causes of viral hepatitis, and liver biopsy can also be considered. 

If thorough testing and history can reasonably exclude a non-DILI etiology of liver injury, a literature review utilizing the LiverTox database should be performed to reexamine the likelihood of liver injury by reported medications and/or dietary or herbal supplements. 

Ultimately the final diagnosis of DILI is based on clinical judgment and clinical suspicion. Consultation with an expert should be sought if there remains a doubt about the diagnosis or if specialized assistance is needed for further workup such as with endoscopic cholangiography. 

Liver Biopsy

The diagnosis of DILI typically does not require a liver biopsy. Biopsy findings may be supportive of DILI but are rarely diagnostic. Nearly every type of histologic abnormality can be mimicked by certain drugs, although each individual drug is typically associated with a histologic pattern characteristic to that drug. Review of every drug’s histologic pattern is beyond the scope of this article. Histologic evaluation may be useful, however, to exclude an alternate etiology of liver injury, particularly if there is no initial resolution of liver injury (i.e., persistently abnormal liver chemistries) following withdrawal of a suspect agent (dechallenge). 

Acute liver failure

Clinical symptoms should be closely evaluated during presentations with acute liver injury. Particular care should be taken to monitor for progression to ALF based on diagnostic indicators, namely an INR >1.5 and signs of hepatic encephalopathy (altered mental status/asterixis). A timely diagnosis of ALF should prompt immediate referral to a liver transplant center in order to begin evaluation for liver transplantation, particularly in the setting of DILI, due to the high associate mortality rate. 

Treatment

Once the diagnosis of DILI has been established, the mainstay of treatment is the removal of the offending compound/medication. Dechallenging results in a complete resolution of liver injury without the need for additional treatment in a vast majority (>90%) of cases.52,53 Furthermore, a successful dechallenge suggests the potential causality of a medication to liver injury and care should be taken to avoid re-exposure. Although care for DILI is mainly supportive, there are certain directed therapies which have shown to improve outcomes in liver injury by specific agents. 

Although treatment of liver injury related to acetaminophen with N-acetylcysteine (NAC) has been well-established, evidence has suggested that treatment of non-acetaminophen liver injury with NAC should be considered in patients presenting with ALF related to idiosyncratic DILI. A randomized trial by the US ALF study group revealed a two-fold increase in transplant-free survival in patients who received NAC vs a placebo infusion.54

Treatment of DILI related to terbinafine and leflunomide with a bile-acid binder has been shown to facilitate clearance of these compounds.52,55 Valproic acid hepatotoxicity can be treated with carnitine, which regulates fatty acid uptake and mitochondrial beta-oxidation.52,56 In patients undergoing myeloablative hemopoietic stem cell transplant (HSCT), ursodiol has shown good results as prophylaxis against sinusoidal obstruction syndrome (SOS, formerly veno-occlusive disease). Similarly, defibrotide can be considered not only as a treatment for severe SOS but also as prophylaxis for those at high risk.57

The use of corticosteroids in idiosyncratic DILI remains controversial, and corticosteroids are mainly reserved for use in the setting of drug-induced AIH, severe hepatitis related to immunotherapy, or in hypersensitivity. In patients with severe liver injury, lower survival was seen in patients treated with corticosteroids.58 Close monitoring is essential during treatment with corticosteroids. In the absence of a response to treatment, corticosteroid treatment should be discontinued in order to prevent steroid-related adverse effects, and an alternate diagnosis should be considered.51 In the event of response to corticosteroid treatment, steroids should be withdrawn in a gradual manner. This should be paired with close follow up and monitoring of liver chemistries for the reappearance of liver injury in order to detect an AIH component, which would require ongoing treatment.  

Conclusion

Drug-induced liver injury (DILI) is a serious condition that can lead to severe liver injury, acute liver failure, and even death. Although the incidence of DILI is relatively low, it is important for clinicians to be aware of DILI and its general workup in order to recognize and manage this condition early. Diagnosis is mostly clinical, with the assistance of resources such as LiverTox. The approach to suspected DILI involves recognizing general signs and symptoms, careful history taking, excluding alternative causes of liver injury, assessing severity, identifying and discontinuing the offending drug. It is similarly important to monitor for ALF in order to provide a timely referral to a liver transplant center. 

The most common cause of DILI in the US remains acetaminophen and the use of NAC is well-established in its treatment, but NAC should be considered in use for idiosyncratic DILI given data on improved outcomes in non-acetaminophen related DILI. In most cases, removal of the offending medication results in resolution.

The best way to prevent DILI, however, is to avoid agents that are known to cause liver injury, particularly in those individuals who are susceptible. Providers should be aware of the increased use of herbal and dietary supplements and the increasing incidence of liver injury related to their use. 

Aftermarket reporting of DILI remains extremely important in providing ongoing data regarding the hepatotoxicity of medications. Providers should strongly consider reporting hepatotoxic effects of medications to regulatory agencies. In the US, reports to the FDA Adverse Events Reporting System (FAERS) database can be submitted by anyone, including healthcare professionals, patients, and consumers. 

In some cases, it may be necessary to rechallenge a patient with the suspected drug if it is the only effective treatment for a particular condition, however this should only be done after careful consultation with a hepatologist. 

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