Guideline sources The following summarized guidelines for the evaluation and management of drug-induced liver injury are prepared by our editorial team based on guidelines from the American Association for the Study of Liver Diseases (AASLD 2022), the American College of Gastroenterology (ACG 2021), the American Gastroenterological Association (AGA 2021), and the European Association for the Study of the Liver (EASL 2019). 1 2 3 4 6 7 7 8 Definition DILI is acute/chronic liver injury characterized by abnormalities in liver function. 6 Epidemiology DILI is mostly caused by antibiotics (amoxicillin-clavulanate; 45.4%), herbal and dietary supplements (16.1%), cardiovascular agents (9.8%), CNS agents (9.1%), anti-neoplastic agents (5.5%), and analgesics (paracetamol overdose; 3.7%). 7 Disease course Clinical manifestations of DILI include jaundice, rashes, acute hepatitis, Stevens-Johnson syndrome, AIH, coagulopathies, hepatic encephalopathy. Progression may lead to chronic liver https://web.pathway.md/diseases/recwmnTv3HE0qONJ3 1/11 6/29/23, 10:21 PM Drug-induced liver injury Pathway disease with fibrosis, cirrhosis, necessitating liver transplantation. 7 Prognosis and risk of recurrence The mortality rate associated with DILI is 7.6%. 8 Calculator Calculator Calculat King's College Criteria for aceta Updated Roussel Uclaf Causality Update Guidelines 1. Screening and diagnosis Indications for monitoring: educate patients to report untoward symptoms to their healthcare providers for early detection of DILI, as well as obtain prospective clinical and laboratory monitoring with certain high-risk drugs (such as immune checkpoint inhibitors, isoniazid, and methotrexate). E Show 7 more Patterns of injury: Recognize that: direct hepatotoxins, such as acetaminophen, can cause liver injury in nearly all exposed patients once a threshold dose or duration of use is exceeded indirect hepatotoxins are generally independent of the dose administered and have a variable latency and manifestations arising from the biological action of the drug on the liver and/or host immune system 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, and is believed to arise from an aberrant adaptive host immune response to the drug and/or its metabolites. (Guidance statement). E Show 2 more Causality assessment: As per AASLD 2022 guidelines, use structured causality assessment instruments incorporating the dose, duration, and timing of suspect drug and other concomitant drug or herbal and dietary supplement product use, assessment of the laboratory, radiological, and histological features at presentation, and exclusion of competing causes of liver injury. E Show 4 more As per EASL 2019 guidelines, consider using the CIOMS/RUCAM scale to assess causality and guide a systematic and objective evaluation of patients with suspected DILI. C Diagnostic criteria: Define clinically significant DILI as any one of the following: serum AST or ALT > 5 ULN, or ALP > 2 ULN (or pre-treatment baseline if the baseline is abnormal) on 2 separate occasions total serum bilirubin > 2.5 mg/dL along with elevated AST, ALT, or ALP levels https://web.pathway.md/diseases/recwmnTv3HE0qONJ3 2/11 6/29/23, 10:21 PM Drug-induced liver injury Pathway INR > 1.5 with elevated AST, ALT, or ALP levels. E Differential diagnosis: exclude alternative causes of liver injury in all patients with DILI, including testing for viral hepatitis, metabolic liver disease, AIH, and pancreaticobiliary disease. E 2. Classification and risk stratification Classification: As per AASLD 2022 guidelines, classify idiosyncratic DILI by the R-value at presentation (R = ALT:ULN/ALP:ULN; hepatocellular if R 5, mixed if 2 < R < 5, and cholestatic if R 2) to help guide the evaluation of alternative causes of liver injury. E As per EASL 2019 guidelines, classify DILI as hepatocellular, cholestatic or mixed according to the pattern of elevation of liver enzymes based on the first set of laboratory tests available in relation to the clinical event. B Risk factors: As per AASLD 2022 guidelines, recognize that: the daily dose of a medication, its lipophilicity, and the extent of hepatic metabolism influence the risk of causing DILI insufficient evidence to confirm subject age, gender, race, and ethnicity as reliable risk factors for DILI susceptibility some drugs are more likely to cause DILI in older patients (such as amoxicillin-clavulanate, isoniazid), whereas others are more commonly implicated in pediatric patients (such as valproate, minocycline) medical comorbidities, such as obesity and diabetes, are associated with increased incidence and severity of DILI with specific drugs insufficient evidence regarding the role of alcohol, tobacco, and diet in DILI susceptibility patients with preexisting liver disease are at increased risk of developing liver injury with selected drugs (such as methotrexate and anti-tuberculosis therapy) and poor outcomes with a DILI episode PTPN22 gene polymorphism is a risk factor for DILI across multiple drugs and major ethnic groups. E As per EASL 2019 guidelines: Recognize that: age is a contributing factor determining the susceptibility to DILI secondary to particular drugs, and contributing to the phenotype of the disease B female sex is a risk factor for DILI associated with specific drugs B female sex is associated with a greater risk of drug-induced ALF B ethnicity is a risk factor for DILI A chronic hepatitis B and C are risk factors for DILI from anti-human immunodeficiency virus and anti-tuberculosis therapy B regular alcohol intake is a contributing factor to DILI associated with specific drugs such as isoniazid, methotrexate and halothane. B https://web.pathway.md/diseases/recwmnTv3HE0qONJ3 3/11 6/29/23, 10:21 PM Drug-induced liver injury Pathway components of metabolic syndrome are risk factors for the occurrence and the degree of drug-associated fatty liver disease in patients treated with tamoxifen and methotrexate. A Recognize the following properties of drugs conferring a risk for DILI: a daily dose of > 100 mg whatever the drug predominant hepatic metabolism by cytochrome P450 enzymes formation of reactive metabolites dual inhibition of mitochondria and bile salt export pump function. B Risks of rechallenge: As per AASLD 2022 guidelines, avoid offering rechallenge with the suspect drug unless the anticipated benefit is high for a severe or life-threatening condition. D As per ACG 2021 guidelines, do not re-expose patients with DILI to a drug thought likely to have caused hepatotoxicity, especially if the initial liver injury was associated with significant aminotransferase elevation (such as > 5 times the ULN, Hy's law, or jaundice). An exception to this recommendation are life-threatening situations where there is no suitable alternative. D As per EASL 2019 guidelines, recognize that liver injury caused by unintentional rechallenge in clinical practice confers a higher risk of mortality/liver transplantation than the initial DILI episode. B Show 2 more Prognosis: As per AASLD 2022 guidelines, recognize that most adult and pediatric patients with idiosyncratic DILI present with an acute liver injury phenotype (symptomatic or asymptomatic) typically resolves within 6 months of onset without long-term sequelae in 80% of cases. E Show 4 more As per ACG 2021 guidelines, consider using a prognostic model consisting of Model for End- Stage Liver Disease, Charlson comorbidity index, and serum albumin in clinical practice for predicting 6-month mortality in patients presenting with suspected DILI. C As per EASL 2019 guidelines: Recognize that a very small proportion of patients develops chronic liver disease as a potential consequence of idiosyncratic drug-induced liver disease. B Consider using Hy's law to identify patients at risk of progressing severe DILI in the setting of clinical trials. Recognize that thresholds for interrupting or stopping treatment with a study drug, as recommended by the U.S. FDA, are intended as guidelines for studies in drug development. Consider adapting these thresholds depending on individual risk-benefit assessment. C 3. Diagnostic investigations Medication history: elicit a detailed medication and herbal/dietary supplement history within the 180 days before presentation in patients with suspected DILI. E https://web.pathway.md/diseases/recwmnTv3HE0qONJ3 4/11 6/29/23, 10:21 PM Drug-induced liver injury Pathway Abdominal imaging: As per ACG 2021 guidelines, obtain abdominal imaging (ultrasound, CT and MRI) to exclude biliary tract pathology and infiltrative processes in all patients with suspected cholestatic DILI. B As per EASL 2019 guidelines, obtain abdominal ultrasound in all patients with suspected DILI. Consider obtaining additional imaging studies based on the clinical context. B Liver function tests: As per AASLD 2022 guidelines, recognize that serum markers of liver injury, such as serum AST, ALT, and ALP, are not sensitive or specific enough for early detection of DILI. E As per EASL 2019 guidelines, obtain ALT, ALP and TBIL as standard tests to define liver damage and liver dysfunction in patients with DILI. B Show 4 more Viral and serological hepatitis panel: As per ACG 2021 guidelines, obtain standard serologies and HCV-RNA to exclude acute viral hepatitis (A, B, and C) and AIH in patients with suspected hepatocellular or mixed DILI. B Show 3 more As per EASL 2019 guidelines, consider obtaining HCV-RNA and anti-HEV IgM or HEV-RNA in patients with suspected DILI to exclude acute hepatitis C and/or E, particularly in cases not compatible with the drug signature of the suspected causative agent and/or with high aminotransferase levels. C Evaluation for other liver diseases: evaluate patients with suspected hepatocellular or mixed DILI for Wilson disease and Budd-Chiari syndrome if clinically appropriate. B Genetic testing: obtain HLA genotyping in selected clinical scenarios where genetic tests assist the diagnosis and management of patients with DILI. B Show 2 more 4. Diagnostic procedures Liver biopsy: As per AASLD 2022 guidelines: Do not perform a liver biopsy for the diagnosis of idiosyncratic DILI, especially in mild and self-limited cases. Consider performing a liver biopsy in patients with a severe or protracted course of DILI and in case of diagnostic uncertainty. D Recognize that liver biopsy can help to: identify hepatotoxic drugs based on specific histological patterns and exclude concurrent liver diseases determine the mechanism of injury, for example, microvesicular steatosis and necrosis associated with the use of mitochondrial toxin fialuridine predict outcomes, for example, the presence of eosinophils and granulomas is associated with a more favorable outcome, whereas necrosis or fibrosis is associated with poorer outcomes. E https://web.pathway.md/diseases/recwmnTv3HE0qONJ3 5/11 6/29/23, 10:21 PM Drug-induced liver injury Pathway As per ACG 2021 guidelines: Perform liver biopsy if AIH remains a competing etiology and if immunosuppressive therapy is contemplated. B Consider performing liver biopsy if: there is an unrelenting rise in liver biochemistries or signs of worsening liver function despite stopping the suspected offending agent the peak ALT level has not fallen by > 50% at 30-60 days after the onset in cases of hepatocellular DILI despite stopping the suspected offending agent the peak ALP has not fallen by > 50% at 180 days in cases of cholestatic DILI despite stopping the suspected offending agent liver biochemistry abnormalities persist > 180 days, especially if associated with symptoms (such as itching) or signs (such as jaundice and hepatomegaly), to evaluate for the presence of chronic liver diseases and chronic DILI continued use or re-exposure to the implicated agent is expected. C As per EASL 2019 guidelines, consider performing liver biopsy in the evaluation of selected patients with suspected DILI, as liver histology can provide information supporting the diagnosis of DILI or an alternative. C Show 2 more Endoscopic retrograde cholangiography: consider limiting EUS to patients with suspected cholestatic DILI only if routine imaging including MRI or EUS is unable to exclude impacted common bile duct stones, PSC, or pancreaticobiliary malignancy. C 5. Medical management Withdrawal of offending agents: As per AASLD 2022 guidelines, discontinue the suspect drug along with supportive care of antiemetics, antipruritics, and hydration as the mainstay of management of patients with idiosyncratic DILI. E As per ACG 2021 guidelines, discontinue suspected agents promptly in patients with suspected DILI, especially when liver biochemistries are rising rapidly or there is evidence of liver dysfunction. B N-acetylcysteine: As per AASLD 2022 guidelines, consider administering a short course of IV N-acetylcysteine in hospitalized adult patients with DILI-related ALF. E As per ACG 2021 guidelines: Consider offering N-acetylcysteine for the treatment of adult patients with early-stage ALF, given its good safety profile and some evidence for efficacy in early coma stage patients, recognizing that no definitive therapies are available for idiosyncratic DILI with or without ALF. C Avoid using N-acetylcysteine in pediatric patients with severe DILI leading to ALF. D As per EASL 2019 guidelines: https://web.pathway.md/diseases/recwmnTv3HE0qONJ3 6/11 6/29/23, 10:21 PM Drug-induced liver injury Pathway Insufficient evidence to support the use of N-acetylcysteine to reduce the severity of liver injury caused by drugs other than acetaminophen. I Administer N-acetylcysteine in adult patients with idiosyncratic drug-induced ALF early in the course of disease (grade I-II). B Corticosteroids: As per AASLD 2022 guidelines, consider administering corticosteroids for 1-3 months in selected patients with idiosyncratic DILI, including patients with severe hypersensitivity features, drug reaction with eosinophilia and systemic symptoms, and autoimmune features on liver biopsy. E As per ACG 2021 guidelines, insufficient evidence to recommend for or against the use of corticosteroids in patients with DILI. Consider offering corticosteroids in a subset of patients with DILI exhibiting AIH-like features. I As per EASL 2019 guidelines, insufficient evidence to support the routine use of corticosteroids in patients with idiosyncratic DILI. I Ursodeoxycholic acid: As per AASLD 2022 guidelines, insufficient evidence to support the use of UDCA in patients with DILI, although it is presumably safe to administer. I As per EASL 2019 guidelines, insufficient evidence to support the use of UDCA to reduce the severity of liver injury. I Cholestyramine: consider administering a short course of cholestyramine to decrease the course of hepatotoxicity induced by very selected drugs, such as leflunomide and terbinafine. C Carnitine: consider administering carnitine to improve valproate hepatotoxicity. C Defibrotide: administer defibrotide in adult and pediatric patients with moderate-to-severe sinusoidal obstruction syndrome undergoing hematopoietic cell transplantation. E 6. Surgical interventions Liver transplantation: As per AASLD 2022 guidelines, transfer patients with idiosyncratic DILI-related ALF to a liver transplant center because of the low likelihood of spontaneous survival. E As per EASL 2019 guidelines, consider performing liver transplantation as a therapeutic option in patients with drug-induced ALF. C 7. Specific circumstances Patients with HDS-induced liver injury: As per AASLD 2022 guidelines: Recognize that herbal and dietary supplements can cause severe hepatotoxicity with variable clinical, laboratory, and histological phenotypes. E Recognize that: https://web.pathway.md/diseases/recwmnTv3HE0qONJ3 7/11 6/29/23, 10:21 PM Drug-induced liver injury Pathway genetic polymorphisms in the HLA region and the conditions under which a product is consumed may influence the likelihood of a patient developing herbal or dietary supplement-induced hepatotoxicity HLA-B35:01 has been associated with hepatotoxicity attributed to green tea extract in White populations and Polygonatum multiflorum hepatotoxicity in Asian populations. E As per ACG 2021 guidelines, encourage patients to report the use of herbal and dietary supplements to their healthcare providers, acknowledging that supplements are not subjected to the same rigorous testing for safety and efficacy as prescription medications. B Show 5 more As per EASL 2019 guidelines, consider suspecting herbal and dietary supplements as potential causative agents associated with liver injury. C Patients with chronic liver disease: exclude other more common causes of acute liver injury including a flare-up of the underlying liver disease for the diagnosis of DILI in patients with chronic liver disease. B Show 4 more Patients with specific phenotypes (autoimmune hepatitis): Obtain detailed evaluation in patients with suspected drug-induced AIH including causality assessment, serology, genetic tests and liver biopsy whenever possible. B Withdraw corticosteroids once the liver injury has resolved in patients with suspected drug- induced AIH being treated with corticosteroids, and obtain close monitoring. B Patients with specific phenotypes (secondary sclerosing cholangitis): suspect the diagnosis of drug-induced secondary sclerosing cholangitis in patients with a cholestatic pattern of DILI with slow resolution of liver injury and characteristic changes in the biliary system demonstrated on MRCP or ERCP. B Patients with specific phenotypes (granulomatous hepatitis): obtain expert evaluation of liver histology and exclude specific infections, inflammatory and immunological conditions well- recognized as causes of hepatic granulomata for the diagnosis of granulomatous hepatitis. B Patients with specific phenotypes (acute fatty liver): recognize drug-induced fatty liver based on its distinct clinicopathological characteristics in patients exposed to drugs known to interfere with mitochondrial function. B Patients with specific phenotypes (fatty liver disease): Recognize that particular drugs, such as amiodarone, methotrexate, tamoxifen and the chemotherapeutic agents 5-fluorouracil and irinotecan are risk factors for fatty liver disease. B Rely upon the benefits of the treatment against the risk of progressive liver disease when deciding to continue or withdraw these medications. B Patients with specific phenotypes, immune-related hepatotoxicity: As per AGA 2021 guidelines, obtain baseline liver tests (TBIL, ALP, AST, and ALT) and pretreatment screening for HBV (HBsAg, HBcAb, and HBsAb) in all patients undergoing immune checkpoint inhibitor therapy. Repeat liver tests before each immune checkpoint inhibitor treatment cycle, with management based on the CTCAE version 5 grade. B Show 5 more https://web.pathway.md/diseases/recwmnTv3HE0qONJ3 8/11 6/29/23, 10:21 PM Drug-induced liver injury Pathway As per EASL 2019 guidelines: Recognize that immune checkpoint inhibitors can induce immune-related hepatotoxicity in a substantial proportion of patients, with CTLA-4 inhibitors (ipilimumab) being more hepatotoxic than PD-L1 agents (nivolumab) and combination treatments carrying greater risk. A Decide on corticosteroid treatment in patients with immune-mediated hepatitis associated with immune checkpoint inhibitors by a multidisciplinary team involving hepatologists if DILI is sufficiently severe based on clinical and histological assessment. B Patients with specific phenotypes (nodular regenerative hyperplasia): consider withdrawing drugs associated with nodular regenerative hyperplasia, if possible. C Patients with specific phenotypes (liver tumors): Recognize that: oral contraceptives are risk factors for the development of hepatic adenoma. B androgens and androgenic steroids are risk factors for the development of liver tumors, particularly in the context of treating bone marrow failure. B Consider withdrawing medications where possible and obtaining continued monitoring until regression of adenoma or definitive treatment. C Patients with acetaminophen overdose (diagnosis): recognize that acetaminophen is a dose-dependent hepatotoxin causing acute pericentral liver injury when doses of > 4 g are ingested within a 24-hour period or excessive doses over several days. E Show 2 more Patients with acetaminophen overdose (gastrointestinal decontamination): perform gastric lavage and administer activated charcoal in all patients presenting within 4 hours of a single-time-point acetaminophen overdose. E Patients with acetaminophen overdose (N-acetylcysteine): administer IV or PO N- acetylcysteine to prevent liver injury, nearly completely if administered within 12 hours of acetaminophen ingestion. E Patients with acetaminophen overdose (prognosis): recognize that the prognosis in acetaminophen-related ALF is related to the degree of encephalopathy, coagulopathy, and acidosis. E 8. Quality improvement Reporting: report all cases of suspected DILI to specialized national registries. E Clinical findings Patient demographics Symptoms Elderly age Abdominal pain Female sex Dark urine Fatigue https://web.pathway.md/diseases/recwmnTv3HE0qONJ3 9/11 6/29/23, 10:21 PM Drug-induced liver injury Pathway Fever Past medical history Generalized pruritus Antibiotics Loss of appetite Chronic liver disease Pale stools Diabetes mellitus RUQ pain Gastroesophageal varices Skin rash Nonalcoholic fatty liver disease Weight gain Obesity Medication history Social history Acetaminophen Alcohol consumption Amiodarone Amoxicillin-clavulanate Vascular exam Anti-tuberculosis medications Peripheral edema Antifungals Aspirin Integument exam Dapsone Dietary supplements Jaundice Fibrates Hematological findings Fluoroquinolones Halothane WBC count Herbal supplements Isoniazid Macrolides Minocycline NSAIDs Niacin Nitrofurantoin Phenobarbital Phenytoin Rifampin Statins TMP-SMX Vitamin A Anthropomorphic exam Malnutrition Abdominal exam Abdominal distension Ascites Hepatomegaly Splenomegaly Lab findings ALF INR https://web.pathway.md/diseases/recwmnTv3HE0qONJ3 10/11 6/29/23, 10:21 PM Drug-induced liver injury Pathway liver enzymes serum ALP serum ALT serum AST serum TBIL serum creatinine serum gamma- glutamyltransferase serum phosphate serum albumin References 1. Naga P Chalasani, Haripriya Maddur, Mark W Russo et al. ACG Clinical Guideline: Diagnosis and Management of Idiosyncratic Drug-Induced Liver Injury. Am J Gastroenterol. 2021 May 1;116 5 878 898. Open 2. Robert J Fontana, Iris Liou, Adrian Reuben et al. AASLD practice guidance on drug, herbal, and dietary supplement-induced liver injury. Hepatology. 2022 Jul 27. Open 3. European Association for the Study of the Liver, Clinical Practice Guideline Panel: Chair, Panel members et al. EASL Clinical Practice Guidelines: Drug-induced liver injury. J Hepatol. 2019 Jun;70 6 1222 1261. Open 4. Michael Dougan, Yinghong Wang, Alberto Rubio-Tapia et al. AGA Clinical Practice Update on Diagnosis and Management of Immune Checkpoint Inhibitor Colitis and Hepatitis: Expert Review. Gastroenterology. 2021 Mar;160 4 1384 1393. Open 5. J Haanen, M Obeid, L Spain et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022 Dec;33 12 1217 1238. Open 6. Jeong Ill Suh. Drug-induced liver injury. 2020 Jan;37 1 2 12.2020 Jan;37 1 2 12. Open 7. Dev Katarey, Sumita Verma. Drug-induced liver injury. Clin Med Lond). 2016 Dec; 16 Suppl 6 s104 s109. Open 8. Einar S Bjornsson, Helgi K Bjornsson. Mortality associated with drug-induced liver injury DILI . 2017 Dec 19;2 114.2017 Dec 19;2 114. Open 9. Chalasani NP, Hayashi PH, Bonkovsky HL et al. ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol. 2014 Jul;109 7 950 66. Open 10. Einar S. Bj rnsson and Helgi K. Bj rnsson. Mortality associated with drug-induced liver injury DILI . Transl Gastroenterol Hepatol. 2017; 2 114. Open 11. Jeong Ill Suh. Drug-induced liver injury. Yeungnam Univ J Med. 2020 Jan; 37 1 2 12. Open 12. Gaby Danan, Rolf Teschke. RUCAM in Drug and Herb Induced Liver Injury: The Update. Int J Mol Sci. 2015 Dec 24;17 1 14. Open 13. Shirin Ghanavatian, Armen Derian. Tizanidine. StatPearls Internet]. Treasure Island FL StatPearls Publishing. Open https://web.pathway.md/diseases/recwmnTv3HE0qONJ3 11/11