AASLD practice guidance on drug, herbal, and dietary supplement–induced liver injury

INTRODUCTION There are currently more than 1000 prescription medications available for use in the United States and more than 100,000 over‐the‐counter herbal and dietary supplements (HDS) available for purchase in retail stores and online. In addition, the average adult American receives more than six prescription medications per year.1,2 Many of these drugs and HDS products have been implicated as causes of DILI. Furthermore, DILI is a leading reason for regulatory actions regarding drugs in development as well as those in the marketplace.1 Confidently establishing a diagnosis of DILI is difficult because of the need to exclude more common competing causes of liver injury, the protean clinical manifestations from an individual agent, and the lack of a validated diagnostic biomarker.3–5 This guidance was developed with the support and oversight of the American Association for the Study of Liver Diseases Practice Guidelines Committee, who chose to commission a guidance, rather than a guideline, because of the paucity of randomized controlled trials on this topic. This document was developed by consensus of an expert panel and provides guidance statements based on formal review and analysis of the literature on the topics and questions related to the needs of patients with drug and supplement–induced liver injury. The aim of this practice guidance is to provide recommendations regarding the common clinical, laboratory, and histological features seen in patients with DILI based on observational and epidemiological data reported in case series or DILI registries. In addition, expert opinion–based recommendations for patient management, including risk stratification, are provided to assist patients and practitioners. DILI classification DILI can be mechanistically classified as being either direct (i.e., dose‐dependent, intrinsic, and predictable) or idiosyncratic (largely dose‐independent, idiosyncratic, and unpredictable) (Table 1). Direct hepatotoxins such as acetaminophen (APAP) (N‐acetyl‐para‐aminophenol) can cause liver injury in nearly all exposed individuals if a threshold dose or duration is exceeded. In contrast, idiosyncratic hepatotoxins are usually neither dose‐related nor duration‐related but rather occur at varying times during or after drug administration.6 Idiosyncratic DILI is uncommon, with most approved drugs occurring in only 1 in 1000 to 1 in a million exposed individuals. Although most patients do not have rash, eosinophilia, or other hypersensitivity features at presentation, aberrant host immunity is implicated in most instances of idiosyncratic DILI.3 TABLE 1 - Proposed classification of DILI Mechanistic classification Direct hepatotoxicity Idiosyncratic hepatotoxicity Indirect hepatotoxicity Incidence Common Rare Intermediate Dose relatedness Yes No No Predictable Yes No Partially Reproduced in animal models Yes No Not usually Latency Rapid (days) Variable (days to years) Delayed (months) Phenotypes of injury Serum AST, ALT, or ALP elevations, hepatic necrosis, acute fatty liver, nodular regeneration Mixed or cholestatic hepatitis, bland cholestasis, chronic hepatitis Immune‐mediated hepatitis, fatty liver, chronic hepatitis Examples Acetaminophen, niacin, intravenous methotrexate Amoxicillin‐clavulanate, cephalosporins, isoniazid, nitrofurantoin Immune checkpoint inhibitors, anti‐CD20 monoclonal Ab, protein kinase inhibitors Touted mechanism of injury Intrinsic hepatotoxicity that is dose‐dependent Idiosyncratic host metabolic or immune reaction Indirect effect on liver or host immunity Source: Adapted from Björnsson et al.5 A third mechanism of hepatotoxicity is called indirect DILI, which arises when the biological action of the drug affects the host immune system, leading to a secondary form of liver injury. Like idiosyncratic DILI, indirect hepatotoxins are generally independent of the dose of medication administered and have a latency of weeks to months with varying clinical manifestations. Examples of indirect hepatotoxicity include the immune‐mediated hepatitis (IMH) observed with immune checkpoint inhibitors (ICIs) and reactivation of HBV infection following rituximab infusions.7,8 Guidance statements Clinicians should be familiar with the three main types of hepatotoxicity when evaluating patients with suspected DILI. Direct hepatotoxins such as APAP can cause liver injury in nearly all exposed individuals once a threshold dose or duration of use is exceeded. Idiosyncratic DILI is largely independent of the dose and duration of medication use and characterized by a low incidence and variable drug latency and clinical and histological features. Idiosyncratic DILI is believed to arise from an aberrant adaptive host immune response to the drug and/or its metabolite(s). Indirect hepatotoxins are generally independent of the dose administered and have a variable latency and manifestations that arise from the biological action of the drug on the liver and/ or host immune system. Epidemiology of idiosyncratic DILI Idiosyncratic DILI is uncommon, with an estimated annual incidence in the general population of 14 to 19 events per 100,000 inhabitants or 60,000 cases per year in the general US population.9,10 The estimated incidence of idiosyncratic DILI also varies based on the case definition as well as the methods used for case ascertainment. For example, the incidence appears to be higher in exposure‐based studies using electronic medical records (32.8 per 100,000 adult patients who received one of the top implicated drugs in the United States and 40 per 100,000 patients at a pediatric hospital).11,12 The incidence of idiosyncratic DILI is even higher in hospitalized patients, being reported as high as 1.4% among medical inpatients.13–16 Results of ongoing DILI registry studies demonstrate that the spectrum of suspect drugs and demographics of afflicted patients substantially differ among countries and regions.17–24 These observations likely reflect differences in case definitions as well as differences in medication use, health care systems, and sociocultural and medical attributes in the various populations (Table 2). TABLE 2 - Etiologies and outcomes with DILI in different countries Country United States/DILIN, n = 899 Spain, n = 843 Iceland, n = 96 Latin America, n = 311 China, n = 25, 927 India, n = 313/1288 Study design Prospective registry30 Prospective registry29 Prospective, population‐based9 Prospective registry18 Retrospective case series22 Prospective case series21,31 Publication year 2015 2021 2013 2019 2019 2010/2021 Age distribution, years 49 ± 17 54 (11–91) 55¥ (16–91) 50 (11–91) 43% (40–59 years) 39 (12–84)/43 (1–86) % Female 59 48 56 61 49 42/48.6 % Liver‐ and non‐liver‐related fatality Liver‐related: 3.0; non‐liver‐related: 3.2 Liver‐related: 2.1; non‐liver‐related: 1.7 Overall fatality: 1 Overall fatality: 4.9 Liver‐related: 0.28a; non‐liver‐related: 0.11a Overall fatality: 17.3/12.3 % Liver transplant 3.7 1.5 0 0 0.01 0 Top 3 implicated drug classes Antimicrobials, HDS, cardiovascular agents Anti‐infectives, CNS drugs, musculoskeletal drugs (including NSAID) Antibiotics, immuno‐suppressants, psychotropic drugs Antibiotics,b NSAIDs,b antitubercularb TCM or HDS, antitubercular, antineoplastic or immune modulators Antitubercular, HDS, antiepileptics Top 10 implicated agents HDS, amoxicillin/clavulanate, isoniazid, nitrofurantoin, trimethoprim‐sulfamethoxazole, minocycline, cefazolin, azithromycin, ciprofloxacin, levofloxacin Amoxicillin/clavulanate, antitubercular, HDS, ibuprofen, anabolic androgenic steroids, flutamide, isoniazid, atorvastatin, diclofenac, ticlopidine Amoxicillin/clavulanate, diclofenac, infliximab, nitrofurantoin, isotretinoin, atorvastatin, doxycycline, azathioprine Amoxicillin/clavulanate, nitrofurantoin, diclofenac, RIP + INH + PIZ, nimesulide, ibuprofen, cyproterone, carbamazepine, methyldopa, atorvastatin Natural medicine, rifampicin, TCM, isoniazid, pyrazinamide, He Shou Wu, methimazole, propylthiouracil, atorvastatin, methotrexate Antitubercular, phenytoin, dapsone, olanzapine, carbamazepine, cotrimoxazole, NSAIDs, atorvastatin, leflunomide, ayurvedic Note: The duration of follow‐up varied among studies. Age distributions are presented as ¥median (range), mean ± SD, or most prevalent age group (%).Abbreviations: CNS, central nervous system; DILIN, Drug‐Induced Liver Injury Network; HDS, herbal and dietary supplement; INH, isoniazid; NSAID, nonsteroidal anti‐inflammatory drug; PIZ, pyrazinamide; RIP, rifampin; TCM, traditional Chinese medicine.aThe case fatality rates (liver‐related vs. non‐liver‐related) were computed based on the cause of death in individual fatal cases: liver‐related (72 deaths due to DILI + 1 cirrhosis/DILI case) and non‐liver‐related (20 DILI‐contributing death +9 nonrelated death). The table follows the classification/terminology used in the individual manuscripts, except for the Latin America study,b to which categories were assigned based on the listed drugs. Leading causes of idiosyncratic DILI worldwide Although hundreds of medications can cause idiosyncratic DILI, several drug classes are more frequently implicated than others. For example, antimicrobials, central nervous system agents, immunomodulatory agents, and antineoplastic agents are more frequently implicated than antihypertensives.17–24 Also, striking geographic differences exist among the specific implicated drugs. For instance, HDS products surpass pharmaceuticals in China, Korea, and Singapore, accounting for 27%–62% of their DILI cases.22,25,26 In contrast, HDS products represent only a minority of cases in Japan, the United States, and Spain but with an increasing incidence over time.23,27–31 Amoxicillin‐clavulanate is the most frequently implicated individual agent in many western countries, whereas anti‐tuberculosis (TB) agents dominate in Asian countries (Table 2). Risk determinants An individual's risk of developing idiosyncratic DILI is determined by complex interactions among host, drug, and environmental factors.32 Drug properties: Although idiosyncratic DILI typically is independent of the total dose or duration of medication administered, most implicated drugs are given at a daily dose of > 50–100 mg per day.33 More than 80% of DILI cases that resulted in liver transplantation in the United States were caused by medications with daily doses exceeding 50 mg.34 In some instances, dose escalation may also increase the risk of developing idiosyncratic DILI as seen with azathioprine, whereas dose reduction or increasing the dosing interval may improve tolerability.35–37Drugs with high lipophilicity and extensive metabolism in the liver (> 50%) are associated with an increased hepatotoxic potential, especially in combination with a high daily dose (> 100 mg daily).38,39 In addition, drugs that form reactive metabolites, exert mitochondrial toxicity, and inhibit bile acid transporters in in vitro test systems are associated with increased DILI risk in humans.32 Concomitant administration of multiple hepatotoxic drugs has also been associated with an increased risk of DILI in several studies.40–43Host age, sex, and race and ethnicity: The impact of host age, sex, and race and ethnicity on DILI susceptibility is not well established because of the lack of large exposure‐based epidemiological studies to compare DILI incidence with drug‐treated controls. Although standardized DILI incidence increases with patient age, this may be explained, in part, by greater medication use with increasing age.9 Noticeable differences also exist between sexes, with women experiencing more frequent and severe hepatotoxicity.44,45 A French population‐based study showed that the standardized DILI incidence was more than 2 times higher in women than men older than 50 years, although no sex differences were noted under age 50.9,10 In addition, older subjects appear to be at increased risk of isoniazid and amoxicillin‐clavulanate hepatotoxicity, whereas younger individuals are more prone to develop DILI from anticonvulsants and minocycline.45,46 Finally, case series demonstrate an overrepresentation of women with diclofenac, macrolide, flucloxacillin, halothane, ibuprofen, interferon beta‐1a, and nitrofurantoin hepatotoxicity. Similarly, men appear to be overrepresented with azathioprine, anabolic steroid, and amoxicillin‐clavulanate hepatotoxicity.45–47The Drug‐Induced Liver Injury Network (DILIN) has demonstrated that trimethoprim‐sulfamethoxazole is the most common suspect drug among African Americans, whereas amoxicillin‐clavulanate is the leading cause in White populations. In addition, African Americans were more likely to have adverse outcomes and develop chronic DILI.48,49 In contrast, Asian Americans were more likely to experience a liver‐related death or undergo liver transplant than the other racial groups.48,49 Because of the limited number of ethnic minorities included, additional studies are needed to confirm these data.Medical comorbidities and environmental factors: Obesity has been associated with an increased risk of tamoxifen‐induced steatosis/steatohepatitis.50 Being overweight, having diabetes, alcohol use, and chronic viral hepatitis have also been associated with progressive fibrosis in methotrexate‐treated patients.51,52 However, the amount of alcohol consumed was not associated with clinical outcomes in consecutive patients enrolled in the DILIN Prospective registry.53 Furthermore, there are limited data exploring the impact of diet, tobacco use, and coffee consumption on DILI susceptibility. The mechanism by which chronic liver disease (e.g., NAFLD, viral hepatitis) impacts DILI susceptibility remains unclear.54 However, DILI caused by anti‐TB therapy has been associated with abnormal baseline serum aminotransferases, showing a stronger dose‐dependent association with the severity of liver enzyme elevation than older age.55 Host genetic risk factors: Various host genetic factors related to drug‐metabolizing enzymes and transporters have been reported as increasing DILI susceptibility56 (Table 3). A missense variant (rs2476601) in PTPN22, which has been associated with other autoimmune disorders, appears to be a risk factor for all‐cause DILI across multiple racial and ethnic groups with an OR of 1.4.57,58 Several genetic studies have also identified distinct human leukocyte antigen (HLA) alleles as risk factors for specific drugs or HDS products. In general, the identified HLA alleles have low positive predictive value, because of the low incidence of DILI in the general population, but a high negative predictive value. Therefore, pretreatment HLA testing will likely not prove useful in most circumstances to prevent DILI, but HLA testing may be helpful in DILI diagnosis and causality assessment.59,60 TABLE 3 - Genetic polymorphisms associated with DILI susceptibility Drug HLA group Genetic variants OR MAF in controlsa Multiple drugs58,61 Non‐HLA PTPN22 (rs2476601) 1.4 0.08 rs72631567 (Chromosome 2) 2.0 0.03 Mixed/cholestatic HLA‐I A*33:01/rs114577328g 5.0 0.01 A*33:01/B*14:02/C*08:02. 5.6 0.009 Hepatocellular Non‐HLA rs28521457 (chromosome 4/LRBA) 2.1 0.04 Amoxicillin‐clavulanate62,63 HLA‐I A*02:01 (rs2523822) 2.3 0.28/0.28b A*30:02 6.7 (HC) 0.029 B*18:01 2.9 (HC) 0.096 HLA‐II DRB1*15:01/DQB1*06:02 (rs3135388) 2.8 0.14/0.05b rs9274407 3.1 0.15/0.081b rs9267992 3.1 0.14/0.063b Non‐HLA PTPN22 (rs2476601) 1.6 0.08 Flucloxacillin64,65 HLA‐I B*57:01 36.6 0.04 B*57:03 79.2 0.0003 Minocycline66 HLA‐I HLA‐B*35:02 29.6 0.006 Trimethoprim‐sulfamethoxazole67 HLA‐I A*34:02 (EUR) 47.5 0.001 B*14:01 (EUR) 9.2 0.009 B*27:02 (EUR) 13.5 0.002 HLA‐B*35:01 (AA) 2.8d 0.087 Isoniazid‐containing antitubercular treatments61,68 Non‐HLA rs72631567 (Chromosome 2) 5.8 0.03 rs117491755 (ASTN2: EUR) 4.4 0.037 NAT2*6/*6, *6/*7, or *7/*7 (ultraslow) (EUR/IND) 2.0/1.8 0.10/0.19 HLA‐I C*12:02 (EUR) 6.4 0.006 B*52:01 (EUR) 6.4 0.007 B*52:01‐C*12:02 (EUR/IND) 6.7/1.8 0.01/0.07 HLA‐II DQA1*03:01(IND) 2.6 0.06 Terbinafine69 HLA‐I A*33:01/rs114577328g 40.5 0.01–0.03 A*33:01/B*14:02/C*08:02 49.2 0.009 Valproate70 Non‐HLA Mitochondrial DNA polymerase γ (POLG) 23.6e p.Q1236H ≤ 0.086 p.E1143G ≤ 0.04 Allopurinol71 HLA‐I HLA‐A*34:02 (AA) 8.0/4.5f 0.033/0.057c HLA‐B*53:01 (AA) 4.1/2.5f 0.120/0.184c HLA‐B*58:01 (AA) 5.6/13.3f 0.046/0.020c Green tea72 HLA‐I B*35:01 6.8 0.06 C*04:01 3.7 0.12 Polygonum multiflorum 73 HLA‐I B*35:01 30.4 0.027 Abbreviations: AA, African American; ASNT2, astrotactin 2; EUR, European descendants; HC, hepatocellular injury; HLA, human leukocyte antigen; IND, Indian; LRBA, LPS‐responsive vesicle trafficking, beach and anchor containing gene; MAF, minor allele frequency (presented as fractions).aControls used in the analyses vary among the studies. Because allele frequencies significantly vary among racial groups, the provided allele frequencies should be interpreted cautiously.bNorthwestern European/Spanish controls.cThe Charles Bronfman Institute for Personalized Medicine BioMe, National Center for Biotechnology Information database of Genotypes and Phenotypes (phs000925.v1.p1)/non‐allopurinol DILI cases at Drug‐Induced Liver Injury Network.dUnadjusted OR due to the limited size of the cohort.eCombined odds.fComputed based on the reported data.gA proxy marker of HLA‐A*33:01. Guidance statements 6 The estimated annual incidence of idiosyncratic DILI in the general population is low (14–19/100,000) but higher in exposure‐based studies using electronic medical record data (33–40/100,000). 7 Antimicrobials, central nervous system agents, and anti‐inflammatory agents are the most commonly implicated agents in the DILI series worldwide. However, HDS are most commonly implicated in some Asian countries and are increasingly implicated in Western countries as well. 8 The daily dose of a medication, its lipophilicity, and extent of hepatic metabolism influence the risk of causing DILI when comparing medications. 9 Insufficient data exist to confirm subject age, sex, and race and ethnicity as reliable risk factors for DILI susceptibility. However, some drugs are more likely to cause DILI in older individuals (e.g., amoxicillin‐clavulanate, isoniazid), whereas others are more commonly implicated in children (valproate, minocycline). 10 Medical comorbidities such as obesity and diabetes are associated with increased incidence and severity of DILI with specific drugs. However, the role of alcohol, tobacco, and diet in DILI susceptibility is not established. 11 Patients with pre‐existing liver disease are at increased risk of developing liver injury with selected drugs (e.g., methotrexate, anti‐TB therapy). In addition, subjects with pre‐existing liver disease are at increased risk of poor outcomes with a DILI episode. 12 A polymorphism in PTPN22 is a genetic risk factor across multiple drugs and major ethnic groups. Various HLA alleles have also been associated with increased susceptibility to individual drugs, but the clinical utility of HLA testing in DILI diagnosis has yet to be determined. Diagnostic approach to DILI DILI is largely a clinical diagnosis of exclusion, relying on a detailed medical history including medication exposure, the pattern and course of liver biochemistry tests before and after drug discontinuation, and exclusion of other causes of liver disease. The initial laboratory testing for DILI includes serum aminotransferases (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase [ALP]) and total and direct bilirubin levels, whereas serum albumin and international normalized ratio (INR) levels are a marker of severity (Figure 1). Clinically significant DILI is commonly defined as any one of the following: (1) serum AST or ALT > 5× upper limit of normal (ULN) or ALP > 2× ULN (or pretreatment baseline if baseline is abnormal) on two separate occasions at least 24 h apart; (2) total serum bilirubin > 2.5 mg/dl along with elevated serum AST, ALT, or ALP level; or (3) INR > 1.5 with elevated serum AST, ALT, or ALP.30,74 Although DILI may present with lower levels of laboratory abnormalities, up to 20% of individuals in the general population have increased liver because of NAFLD, alcohol, and other common Proposed diagnostic for patients with suspected DILI. A diagnosis of DILI on of clinical history and drug along with exclusion of other more common causes of liver injury. Abbreviations: alkaline ALT alanine AST, HDS, herbal and dietary supplement; international normalized total upper limit of history A detailed medication including the use of HDS is in all suspected DILI This should include and of the suspect dose any and use of the medication, data (i.e., clinical course following drug and (i.e., response to DILI appears 6 months of a medication, although drugs have latency (e.g., nitrofurantoin, In contrast, hypersensitivity can have latency of only Although DILI is to to an agent, is to that to an intravenous agent, such as monoclonal may also cause DILI. However, of medications to the or if cause DILI because of the low dose of medication laboratory A clinical pattern of liver injury that has been reported for a medication or HDS can be helpful in an agent is likely the cause of the injury. The pattern of liver injury also the for competing causes of liver disease (Figure 1). In general, the pattern of injury can be as with a of with a of ALP or These can be more and the defined as serum by serum An > cases of hepatocellular liver injury, whereas an 2 cases of cholestatic liver injury, and an between 2 and a liver injury The is at the of presentation, but the pattern of injury can as the a given drug may be associated with more than one clinical causes of liver injury for acute viral hepatitis is for all patients with suspected DILI including hepatitis A and to exclude acute hepatitis infection (Figure 1). In of cases in the initial analysis of the DILIN positive for of DILI is acute which is increasingly reported in developed because of to 3 was in cases in the DILIN Although there are regarding of the available testing for acute infection should be in selected instances, including cases a suspect agent or in cases with high aminotransferase in older patients with suspected DILI should also undergo for autoimmune hepatitis with testing for (e.g., and and serum levels, although there are some drugs that can an Patients with or are at risk for liver injury, usually characterized by and a increase in serum aminotransferase by with normal or bilirubin In younger patients, disease can be using In cholestatic testing for is to for In patients with a of AST greater than ALT, hepatitis should be especially if aminotransferase are (e.g., AST generally and associated with high and Furthermore, testing for serum levels in this is patients with suspected DILI should undergo some of liver typically with an to for of or other liver such as or may be used to for or drugs have been associated with specific clinical and also called such as hepatitis, hepatitis, bile or These are in However, DILI can present with a of clinical and histological from the drug, on host factors and of TABLE - and histological of idiosyncratic DILI Examples of associated drugs Hepatocellular hepatitis necrosis, with or and hepatitis dapsone, isoniazid, hepatitis or necrosis, the with and necrosis, Immune checkpoint inhibitors (e.g., or in 3 or with either or Acetaminophen, halothane, hepatitis by significant phenytoin, carbamazepine, hepatitis to chronic viral hepatitis or autoimmune hepatitis with hepatitis, or HDS, methotrexate, More than along with with the of hepatitis, diclofenac, minocycline, inhibitors, inhibitors in and/or bile with or no or injury and bile Amoxicillin‐clavulanate, flucloxacillin, cholestatic hepatitis Mixed in and/or bile with more and injury inhibitors, injury with and fibrosis liver in the acid or with to the methotrexate, NSAIDs, (e.g., and Mixed and of and large methotrexate of and in a of methotrexate, with necrosis, in of hepatic of containing and by may a will either an