- Published
- 2022-07-28
- Venue
- Hepatology, vol. 77, no. 3, pp. 1036-1065
- Cited by
- 306
- Open access
- Yes, hybrid
- DOI
- 10.1002/hep.32689
- PubMed
- 35899384
Abstract
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 % and 1 % Liver implicated drug drugs drugs or or immune implicated isoniazid, isoniazid, isoniazid, methotrexate The duration of among Age are as ± or most Liver herbal and dietary case based on the cause of in individual to DILI 1 and The the used in the individual for the Latin to which based on the causes of idiosyncratic DILI Although of medications can cause idiosyncratic DILI, drug are more implicated than For example, and are more implicated than differences among the implicated For HDS products in China, and for of DILI In contrast, HDS products only a of cases in the United and but with an incidence is the most implicated individual in in countries (Table 2). risk of idiosyncratic DILI is by among and Although idiosyncratic DILI is independent of the dose or duration of medication most implicated drugs are at a dose of per than of DILI cases that in liver in the United States by medications with 50 In dose also the risk of idiosyncratic DILI as seen with dose or the with high and in the liver are with an in with a high dose In addition, drugs that form and in in are with DILI risk in of drugs also been with an risk of DILI in and and The of host and and on DILI is not well because of the lack of exposure‐based epidemiological studies to DILI incidence with Although DILI incidence with patient this be in by medication use with differences also with more and A that the DILI incidence was more than 2 times higher in than than 50 differences In addition, to be at risk of and individuals are more to DILI from and case series demonstrate an of with and nitrofurantoin to be with and Liver that is the most common suspect drug among is the leading cause in In addition, more likely to have outcomes and chronic In contrast, more likely to a or liver than the other of the of studies are to these and been with an risk of use, and chronic hepatitis have also been with in the of was not with clinical outcomes in patients in the Prospective Furthermore, are data the of use, and on DILI The mechanism by which chronic liver DILI DILI by been with a dose‐dependent with the of liver than risk host related to and have been reported as DILI (Table A in which been with other appears to be a risk for DILI and with an of studies have also as risk for drugs or HDS In the have low because of the low incidence of DILI in the general but a high likely not in most to DILI, but be in DILI diagnosis and TABLE - with DILI in or and as used in the among the among the provided should be for for of and Phenotypes DILI cases at Liver to the of the based on the reported of Guidance statements The estimated annual incidence of idiosyncratic DILI in the general population is low but higher in exposure‐based studies using electronic medical data and are the most implicated in the DILI series HDS are most implicated in countries and are implicated in countries as The dose of a its and of hepatic the risk of DILI when data to and and as risk for DILI drugs are more likely to cause DILI in individuals are more implicated in such as and are with incidence and of DILI with the of and in DILI is not with liver are at risk of liver injury with drugs In addition, with liver are at risk of outcomes with a DILI A in is a risk drugs and have also been with to individual but the clinical of in DILI diagnosis to be to DILI DILI is largely a clinical diagnosis of on a medical including medication the and of liver and after drug and of other causes of liver The for DILI and and direct and are a of 1). DILI is as one of the or of or ALP if is on at with AST, ALT, or ALP or with AST, ALT, or Although DILI with of to of individuals in the general population have liver because of and other common Proposed diagnostic for patients with suspected DILI. A diagnosis of DILI on of clinical and drug with of other more common causes of liver injury. AST, herbal and dietary of A medication including the use of HDS is in all suspected DILI This should include and of the suspect dose and use of the data (i.e., clinical following drug and (i.e., response to DILI appears months of a drugs have latency 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 also cause DILI. of medications to the or if cause DILI because of the low dose of medication A clinical of liver injury that been reported for a medication or HDS can be in an is likely the cause of the injury. The of liver injury also the for competing causes of liver 1). In the of injury can be as with a of with a of ALP or These can be more and the as by cases of liver injury, an 2 cases of cholestatic liver injury, and an 2 and a liver injury The is at the of presentation, but the of injury can as the a drug be with more than one clinical causes of liver injury for acute hepatitis is for all patients with suspected DILI including hepatitis A and to exclude acute hepatitis infection 1). In of cases in the analysis of the for of DILI is acute which is reported in developed because of to was in cases in the Although are regarding of the available for acute infection should be in including cases a suspect or in cases with high in patients with suspected DILI should also for hepatitis with for and and are drugs that can an with or are at risk for liver injury, usually characterized by and a in by with or In patients, can be using In cholestatic for is to for In patients with a of than ALT, hepatitis should be if are generally and with high and Furthermore, for in this is patients with suspected DILI should of liver with an to for of or other liver such as or be used to for or drugs have been with clinical and also called such as hepatitis, hepatitis, or These are in DILI can with a of clinical and histological from the on host and of TABLE - and histological of idiosyncratic DILI Examples of drugs hepatitis necrosis, with or and hepatitis isoniazid, hepatitis or necrosis, the with and necrosis, Immune checkpoint inhibitors or in or with either or Acetaminophen, hepatitis by hepatitis to chronic hepatitis or hepatitis with hepatitis, or than with with the of hepatitis, inhibitors, inhibitors in and/or with or or injury and Amoxicillin‐clavulanate, cholestatic hepatitis Mixed in and/or with more and injury inhibitors, injury with and liver in the or with to the and Mixed and of and methotrexate of and in a of with necrosis, in of hepatic of and by a either and or and DILI of to chronic hepatitis isoniazid, with of the or to for most common are and and A nodular of liver injury after drug is in DILI of injury after the to the is a of the suspect drug with reported cases in such as The provides a of the clinical features of idiosyncratic DILI to more than 1000 prescription drugs and HDS that are from the In addition, provides a of hepatotoxicity have been to a as 50 or more of liver and approved Guidance statements DILI is as one of the or or ALP if is on with AST, ALT, or ALP or with AST, ALT, or 14 drugs cause liver injury the months of use but have latency or even after drug of a patient with suspected DILI should include a medication and HDS the Idiosyncratic DILI cases should be by the at = and cholestatic which can the of causes of liver injury. causes of liver injury is in all DILI including for hepatitis, metabolic liver and 17 drugs have been with and which be in the for a of the literature on liver injury to 1000 prescription drugs and more than Liver in suspected DILI Although a liver is not to DILI, can be in other causes of liver and in the in a diagnosis of DILI in cases of clinical medications are with histological of liver injury that can be on can also be when the liver or do not with drug or the patient and can be used to the of liver a liver other causes of or that can the clinical or to liver The in the of a liver for a patient with suspected DILI is to the of injury, as are various histological of to of DILI cases with acute liver injury and of which acute or chronic hepatitis with or This histological various of hepatitis, necrosis, and or (Table A diagnostic when to from features observed in such as hepatitis, of an the of and are also observed among DILI cases and in DILI and are not for more and be by cholestasis, a chronic and the hepatitis be by The of in from DILI to as events have been The histological in DILI is injury, with hepatitis and with on liver is not and the of with being in than is an of and liver are in DILI because of and a third of those with of DILI even DILI acute cholestasis, chronic cholestasis, and acute cholestatic In the acute cholestatic bland be the histological and as in and the cholestatic hepatitis is the of by more In chronic cholestasis, the and have injury or to the is common histological manifestations of DILI include fatty liver and be which is related to injury, and or usually not to on nor with and only liver can its DILI in injury to the development of nodular and as and as either acute or chronic appears as and its development is with and histological features and be seen on a liver in a patient with suspected DILI. These include of and of as are in the of or chronic of and is form of DILI seen as with to an adaptive response to drugs and the of DILI and A liver can provide The of and of reaction are with the of and is with These observations also in a of DILI case to chronic DILI is the of liver after months from DILI independent of the of liver injury, the DILI 1 year as the In contrast, a liver chronic liver when is or even on Guidance statements 19 Liver is not to a diagnosis of idiosyncratic DILI but be in DILI cases with a or and in those with diagnostic a is usually not in or A liver can the drugs based on histological and can exclude liver A spectrum of histological been reported in patients with DILI, and a drug be with more than a The of and on a liver in a patient with suspected DILI is with a more those who have or have A liver from a patient with DILI the mechanism of injury, as was seen with the that to and provides an to the that a drug or HDS is the cause of liver injury by the laboratory, and clinical features following and of other more common causes of liver A is to the data and a is that from to of clinical have been developed for DILI and TABLE - in the and to liver injury to to to to liver injury to to to to to to causes of liver injury to to to to or of hepatotoxicity to to to to medication to manifestations to of to to 17 to DILI 17 to from the are and are from and clinical diagnostic not 1 of those 2 (i.e., only or is by in risk not was developed only for drug cases and not for TABLE - Liver expert % 2 likely and but not data support data but with more likely data data Source: Adapted from et be using various with to features from the (Table The also as the for of was in provides a varying from to and the with by injury. The was in and that a from to with the The to the but medications and for manifestations. There are but the of is more with the and the The is not used in clinical practice because was to be to the The is a of the with the of and from to Although the was to be to the in patients, is not currently used of because of the lack of available and The is currently available online. This a of to and at as well as the in independent data The risk and an of competing causes to and diagnostic is and to models include the for by the which have not in DILI or clinical practice because of lack of liver expert The developed by the of DILI that from to (Table of expert include the to for drug and of including liver in to This been to be as as the expert is available in clinical of in DILI There are in DILI with the For example, patients be drugs or HDS products the drugs for In addition, and lack of of HDS chronic liver also is not for by the do not of and with hepatotoxicity to drugs and HDS which to by expert the clinical features of a patient with of the of the suspect other causes of liver regarding the include the of its which developed using a of cases with drug and not by or Furthermore, of other causes of liver injury have been or when the For example, is for for acute or and are data to of risk as in the of the have been in the which by the the for for but the risk of and for all The also provides more guidance in the hepatotoxicity of the suspect drug but is not for use in patients with chronic liver being available is that this electronic provide more and using and data to be in of the the spectrum of DILI from that seen in the United States and (Table or in cases with more than a suspect Furthermore, the not been in liver injury and its and needs to be Guidance statements are three used and its and the and of suspect drug and other drug or HDS an of the laboratory, and histological features at and of competing causes of liver injury. The expert developed by the is used in clinical practice and in but the need for its The and more diagnostic with the but risk of and that are of The is a that more and than but studies are suspect drug is in clinical but when in HDS hepatotoxicity HDS are used the on a For example, more than of the of used dietary supplements in the in a supplements products as well as of different that be and Although have been used for by different for HDS are products that are the of in or of Although most supplements are instances of from individual and products have been including acute liver Epidemiology of HDS use and liver injury American more than on herbal products in on HDS of all cases of liver injury in of products in the United States is are not to that is and only need to to the based on The and provides the regulatory for and in the United The regulatory in as in a For example, in the the of a on the a of use, with of the of injury to a dietary can be reported by and to the US and the These are by the for and when the of a is regulatory actions can be the including of a from the in the most in the diagnosis of liver injury are by to is well that supplements are to or of include and other that are not on the include and usually from the of usually to effect in with the for is the of in products for the of HDS as a of varying leading to latency of to a the of injury can be variable because of the of the the lack of and of liver injury from these over‐the‐counter supplements cause the injury to by patients and HDS and outcomes Many of the most instances of hepatotoxicity from HDS have from products such as and dietary supplements are in that is of that and the such that the with the at be substantially Furthermore, the that supplements implicated in liver injury are The are being to the that from that are or as in (Table TABLE - HDS products and implicated in hepatotoxicity Common or liver reported and or reported and or Mixed one case of reported of hepatotoxicity to of The the of The of the is for its but is likely also for liver injury. cases of liver injury to have been with the most cases being those in which injury following A analysis of cases in the to of the of as being and with a with This risk also been with hepatotoxicity in individuals to a herbal to and studies have that patients with HDS leading to liver are more likely to or to patients with drug This be to of the as the cause of liver injury or of HDS to medical Guidance statements HDS are used with of in the United States and other countries leading to the of and can cause hepatotoxicity that can have variable clinical, laboratory, and histological in the and the which a is the of an individual patient HDS been with hepatotoxicity to in populations and hepatotoxicity in and of idiosyncratic DILI and with idiosyncratic DILI with a drug latency of drugs have an In registry nearly of patients have acute injury, the with either an acute or cholestatic injury (Table 2). a diagnosis of idiosyncratic DILI is the suspect should be patients with acute liver injury need to be for and those with and should be to a liver because of low of drug most patients with DILI to of patients with DILI with be at risk of because of liver or medical studies have also that patients with higher and as well as at are at risk for In addition, have that patients with liver are at risk of hepatic in a of and have been to patients with DILI at risk of hepatic clinical features are with a of such as the of and on liver TABLE - for patients with idiosyncratic DILI Proposed for liver and = for patients and = ALP should be not to cases and = = and a 2 = and used for the for Liver available at DILI is as in liver or the of or histological of ongoing injury months after DILI The incidence of chronic DILI in the was at with and patients with a cholestatic liver injury at being at A of patients (i.e., also of leading to which can be and reported of chronic DILI include hepatic from and to or which to of during (Table of idiosyncratic patients with DILI care is for all patients with acute DILI, including the use of and as with and or for and (Table A of should be in adult patients with in of outcomes in a randomized controlled in patients with randomized of patients with DILI also a of but with outcomes with a of in with for its use in at a dose of 1 of are to patients with immune‐mediated hypersensitivity including the as drug reaction with and In a of (i.e., with be of in patients with features on as well as for patients with DILI from and kinase inhibitors (Table of and DILI but randomized controlled trials are to the dose and TABLE - for patients with idiosyncratic DILI population APAP to 2 per in if to in Prospective data likely patients to if with for duration in studies in hypersensitivity checkpoint with features 1 per of for of for dose and duration not but can be in months with by 50 use cases with 1 for 14 once from other medications and patients or use to with for to a of to in and with acute liver DILI, liver drug reaction with and immune checkpoint not of In to general be for For example, are data clinical with for with to In addition, be of for patients with hepatotoxicity because of its and is a of from that and use been with in patients with following with Guidance statements and with idiosyncratic DILI with an acute