A 68-Year-Old Woman With Unexplained Liver Enzyme Elevation and Active Chronic Hepatitis: Beware of Drug-Induced Autoimmune-Like Hepatitis

This patient's case history (void of protected health information) was discussed in a multidisciplinary meeting including hepatologists (LD, MG), a pathologist (DK), an immunologist (EP) with NC as moderator. We summarize the case history and discussion in the following article. A 68-year-old woman presented with abdominal pain, nausea, and loss of appetite that progressively worsened over the month before presentation. She was in her usual state of health leading up to this presentation without any recent illnesses, travel, or new medications or supplements. Her past medical history was notable for a remote stroke, hypertension, migraine headaches, idiopathic urticaria, asthma, osteoarthritis, osteoporosis, and recurrent urinary tract infections. Her surgical history included hysterectomy with bladder suspension 20 years ago. She had a known drug allergy to penicillin, causing hives. She was a nonsmoker and drank 1 alcoholic beverage 3–4 times a week. Her family history was notable for a brother who required surgery for liver cysts in adulthood and a younger brother with an enlarged liver. She had 3 healthy children. She did not take any herbal or dietary supplements. She has been on a stable medication regimen that included meloxicam for 1 year; clopidogrel, verapamil, and sumatriptan for 3 years; nitrofurantoin and alendronate for 4 years; and estrogen for 20 years. On physical examination, she had a body mass index of 32 kg/m2, was afebrile and normotensive with a resting heart rate of 85 beats per minute and no respiratory distress. She was anicteric with an unremarkable head and neck examination, and no evidence of lymphadenopathy. Her cardiopulmonary examination was normal. Her abdomen was soft and nontender with no hepatosplenomegaly. She had no peripheral edema, no rash, and no stigmata of chronic liver disease. Pertinent laboratory findings showed alanine aminotransferase (ALT) of 255 IU/L (upper limit of normal [ULN], 45 IU/L) and aspartate aminotransferase (AST) of 202 (ULN 45 IU/L), with normal alkaline phosphatase and total bilirubin. She had normal complete blood count, basic metabolic panel, creatine phosphokinase, amylase, and lipase. A computed tomography scan of the abdomen was only remarkable for fatty infiltration of the liver. Serologies for acute and chronic hepatitis A, B, and C were negative, and hepatitis C RNA was undetectable. The antinuclear and antimitochondrial antibody tests were negative, but the antismooth muscle antibody was positive with a titer of 1:80. The IgG and IgM levels were only borderline elevated. Iron studies and alpha-1 antitrypsin and ceruloplasmin levels were normal. Upon further review, she had mild liver enzyme elevations dating back to 6 months before her presentation. Her ALT fluctuated between 79 and 115 IU/L, and her AST fluctuated between 53 and 72 IU/L, with normal alkaline phosphatase and bilirubin at all times. Her symptoms persisted as did the elevated liver enzymes when retested 6 weeks after presentation (ALT, 170 IU/L; and AST, 160 IU/L; with a normal alkaline phosphatase and bilirubin). At that point, a liver biopsy was performed, which showed chronic hepatitis with severe interface hepatitis and portal to central bridging necrosis. The inflammation was predominantly lymphocytic with clusters of plasma cells at the interface and rare eosinophils. In addition to the bridging necrosis, there was perivenular inflammation and necrosis around many central veins. In areas of bridging necrosis there was early portal to central bridging fibrosis (Figure 1). Only minimal, macrovesicular steatosis was present without features of steatohepatitis. There was no bile duct injury or bile stasis. Question: What is the most likely etiology of the liver injury?A.Idiopathic autoimmune hepatitis (AIH).B.Drug-induced liver injury (DILI) from nitrofurantoin.C.DILI from meloxicam.D.DILI from alendronate. Look on page 261 for the answer and see the Gastroenterology website (www.gastrojournal.org) for more information on submitting to Gastro Grand Rounds. The correct answer is B. NC: The patient subsequently had consultation with a hepatologist who suspected DILI. The nitrofurantoin (NTF) was discontinued and, despite the autoimmune features, she was not treated with corticosteroids because she had no severe features and liver enzymes rapidly declined, decreasing by >50% within 1 month and normalizing within 3 months of drug discontinuation. The liver enzymes continued to be normal 6 months after the onset of the liver injury. All other medications were continued during this time without interruption. NC: Dr Dara, what do you think is the most likely etiology of the liver injury here and can you provide an overview for us? LD: This is highly likely a case of drug-induced autoimmune-like hepatitis (DI-ALH) from the patient's long-standing NTF use. The common viral hepatitides were ruled out and we even have an HCV RNA. The biopsy is suggestive of an AIH-like pathology in this case. The pattern of enzyme elevations is hepatocellular. One key factor we consider in cases of hepatotoxicity is the duration of time a patient has been on a drug until the onset of symptoms or laboratory abnormalities, called latency. Direct hepatotoxins like acetaminophen typically have short latencies (hours to days), whereas idiosyncratic toxins have a longer latency. This is thought to be due to the time it takes for the immune system to be activated. NTF is one of the few drugs that has a very long latency, meaning a patient can be on it for many months and even years before they develop or manifest hepatotoxicity. The other medications that can be considered in the differential, meloxicam and alendronate, have much shorter latencies, and can be associated with mild liver enzyme elevations, are less common causes of DILI, and do not have a classic AIH-like presentation.1LiverToxClinical and Research Information on Drug-Induced Liver Injury. LiverTox, Bethesda, MD2012Google Scholar When faced with multiple drugs to consider, a detailed history of drug initiation or dose escalation is informative. The patients may not recall this precisely, but the pharmacy can be an excellent resource in these cases. In addition, it is important to specifically ask the patient about recent infections (tooth infections, sinus, bronchitis, etc) and antibiotic courses that could have since been discontinued. Another important factor when multiple drugs are implicated is stopping the most likely drug and rechecking the liver tests. A positive dechallenge defined as decrease of liver enzymes with drug cessation makes the diagnosis more likely. In clinical practice, it is often difficult to distinguish the most likely agent if the patient is on multiple drugs that have a similar pattern of injury. Sometimes, we end up stopping multiple drugs, especially in severe cases—think hepatotoxicity with antituberculosis medications where both INH and rifampin may be held. Or in this case, if she was on a statin, we would stop the NTF and the statin both, because either can present with DI-ALH. Here, NTF was the more likely culprit given the very long latency (∼4 years), an autoimmune hepatitis-like phenotype, and normalization of liver enzymes with stopping NTF (dechallenge). Of course, idiopathic AIH is also in the differential diagnosis. Idiosyncratic DILI can be caused by a number of medications and herbal agents and is rare, unpredictable, and not dose dependent. DI-ALH is a phenotype of DILI that resembles idiopathic AIH, but is associated with certain medications.2Andrade R.J. Aithal G.P. de Boer Y.S. et al.Nomenclature, diagnosis and management of drug-induced autoimmune-like hepatitis (DI-ALH): an expert opinion meeting report.J Hepatol. 2023; 79: 853-866Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar DI-ALH classically occurs with drugs such as NTF, infliximab, and minocycline, although >40 drugs such as statins, hydralazine, and methyldopa have been implicated.2Andrade R.J. Aithal G.P. de Boer Y.S. et al.Nomenclature, diagnosis and management of drug-induced autoimmune-like hepatitis (DI-ALH): an expert opinion meeting report.J Hepatol. 2023; 79: 853-866Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar In the US Drug-Induced Liver Injury Network (DILIN), about 8% had a DI-ALH phenotype, and other DILI registries have also observed this phenotype in 3%–9% of cases.2Andrade R.J. Aithal G.P. de Boer Y.S. et al.Nomenclature, diagnosis and management of drug-induced autoimmune-like hepatitis (DI-ALH): an expert opinion meeting report.J Hepatol. 2023; 79: 853-866Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 3Stephens C. Robles-Diaz M. Medina-Caliz I. et al.Comprehensive analysis and insights gained from long-term experience of the Spanish DILI Registry.J Hepatol. 2021; 75: 86-97Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 4de Boer Y.S. Kosinski A.S. Urban T.J. et al.Features of autoimmune hepatitis in patients with drug-induced liver injury.Clin Gastroenterol Hepatol. 2017; 15: 103-112.e2Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar DI-ALH from NTF (NTF-ALH), which comprised 3.5% of cases in the DILIN cohort between 2004 and 2021, can present at any time during the course of treatment, although patients that have a longer exposure, present with more severe liver injury, and can have features of chronic hepatitis.5Chalasani N. Li Y.J. Dellinger A. et al.Clinical features, outcomes, and HLA risk factors associated with nitrofurantoin-induced liver injury.J Hepatol. 2023; 78: 293-300Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar This patient was on NTF for 4 years. Although latency beyond 1 year is less common with methyldopa and hydralazine, long latency is common in DI-ALH owing to agents such as NTF, minocycline, and statins. NTF-ALH occurs mostly in women who take NTF long term for recurrent urinary tract infection and presents with a hepatocellular pattern of injury.2Andrade R.J. Aithal G.P. de Boer Y.S. et al.Nomenclature, diagnosis and management of drug-induced autoimmune-like hepatitis (DI-ALH): an expert opinion meeting report.J Hepatol. 2023; 79: 853-866Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar,4de Boer Y.S. Kosinski A.S. Urban T.J. et al.Features of autoimmune hepatitis in patients with drug-induced liver injury.Clin Gastroenterol Hepatol. 2017; 15: 103-112.e2Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar,5Chalasani N. Li Y.J. Dellinger A. et al.Clinical features, outcomes, and HLA risk factors associated with nitrofurantoin-induced liver injury.J Hepatol. 2023; 78: 293-300Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar The AST to ALT ratio can be >1, although this was not the case here, and a sizable number of patients can present with advanced liver disease (bridging fibrosis and cirrhosis) or massive/submassive and bridging hepatic necrosis, leading to death or need for liver transplantation.5Chalasani N. Li Y.J. Dellinger A. et al.Clinical features, outcomes, and HLA risk factors associated with nitrofurantoin-induced liver injury.J Hepatol. 2023; 78: 293-300Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar NC: Dr Ghabril, what is your approach to evaluating a patient with suspected DILI? MG: Unfortunately, DILI lacks a definitive diagnostic test and is a diagnosis of exclusion, which requires a high index of suspicion when there is a temporal association with a drug or herbal supplement. Key to this diagnosis is ruling out competing etiologies of liver injury by systematic history taking and diagnostic workup. A detailed medication history is crucial and, although in this case a prescription medication was identified, it is equally important to elicit a detailed history of herbal and dietary supplement use, which are an increasing cause for DILI worldwide. An understanding of the expected phenotype of liver injury owing to a particular agent also helps in diagnosing DILI. Diagnostic testing encompasses viral serologies, autoantibodies, as well as imaging studies to assess the liver, its vascular system and the biliary system (Table 1).6Vuppalanchi R. Ghabril M. Review article: clinical assessment of suspected drug-induced liver injury and its management.Aliment Pharmacol Ther. 2022; 56: 1516-1531Crossref PubMed Scopus (2) Google Scholar A liver biopsy is recommended as part of the diagnostic algorithm if liver enzymes do not rapidly improve with dechallenge or whenever a competing etiology such as AIH is suspected (Figure 2). The liver biopsy provides valuable information on the chronicity, grade, and pattern of inflammation and can be used to exclude other etiologies of liver disease and should precede starting immunosuppression in suspected DI-ALH.2Andrade R.J. Aithal G.P. de Boer Y.S. et al.Nomenclature, diagnosis and management of drug-induced autoimmune-like hepatitis (DI-ALH): an expert opinion meeting report.J Hepatol. 2023; 79: 853-866Abstract Full Text Full Text PDF PubMed Scopus (11) Google ScholarTable 1Laboratory Tests and Hepatobiliary Imaging in the Workup for Possible Drug-induced Liver InjuryLaboratory tests Anti-hepatitis A IgM antibody Anti-hepatitis C antibody and hepatitis C RNA Hepatitis B surface antigen, anti-hepatitis B core antibody, anti-hepatitis B core IgM antibody Anti-hepatitis E IgM antibody Antinuclear antibody Smooth muscle antibody Antimitochondrial M2 antibody (in patients with features of cholestasis) Immunoglobulin G serum quantification Immunoglobulin M serum quantification (in patients with features of cholestasis)Additional laboratory studies to consider if above are negative Anti-cytomegalovirus IgM antibody or cytomegalovirus PCR Anti-hepatitis E IgG antibody and/or hepatitis E PCR Anti-Epstein-Barr virus IgM or Epstein-Barr virus PCR Herpes simplex virus PCR Varicella PCR Adenovirus PCRLiver Biopsy A liver biopsy is not always necessary. In cases of suspected autoimmune hepatitis a liver biopsy is required. With suspected primary biliary cholangitis and PSC, a biopsy may be necessary. In patients with worsening liver disease without a diagnosis a liver biopsy may be helpful in establishing a diagnosis.Specialized testing depending on clinical scenario In patents with underlying liver disease or unusual features suggesting inherited metabolic liver disease such as hemochromatosis, alpha-1 antitrypsin deficiency and Wilson disease perform disease specific tests.Imaging studies to rule out vascular diseases, stones, tumors, and structural causes of liver enzyme abnormalities Liver ultrasound with Doppler studies Abdominal computerized tomography scan (often adds information regarding structural and vascular (clots) lesions, and features of portal hypertension) Magnetic resonance cholangiopancreatography (usually reserved for suspected stone, PSC, obstruction) Endoscopic retrograde cholangiopancreatography (usually reserved for suspected stone, PSC, obstruction) Consider echocardiography if heart failure or congestive hepatopathy is suspectedPCR, polymerase chain reaction; PSC, primary sclerosing cholangitis. Open table in a new tab PCR, polymerase chain reaction; PSC, primary sclerosing cholangitis. Causality assessment tools such as the Roussel Uclaf Causality Assessment Method (RUCAM) use a weighted point system consisting of temporal associations, drug signatures, risk factors, competing diagnoses, exposure to concomitant drugs, prior reports of hepatotoxicity, and rechallenge to adjudicate DILI in a structured format. These tools are not used in clinical practice and have limitations, namely, interobserver variability.7Rockey D.C. Seeff L.B. Rochon J. et al.Causality assessment in drug-induced liver injury using a structured expert opinion process: comparison to the Roussel-Uclaf causality assessment method.Hepatology. 2010; 51: 2117-2126Crossref PubMed Scopus (278) Google Scholar Additional tools such as the recently described Revised Electronic Causality Assessment Model (RECAM) are available as an online calculator.8Hayashi P.H. Lucena M.I. Fontana R.J. et al.A revised electronic version of RUCAM for the diagnosis of DILI.Hepatology. 2022; 76: 18-31Crossref PubMed Scopus (40) Google Scholar Both RUCAM and RECAM are comprehensive tools that are valuable in performing a complete workup regardless of clinical experience in the area of hepatotoxicity. Both tools incorporate the role of latency and course of injury with dechallenge in hepatocellular and nonhepatocellular DILI. However, limitations exist, such as when multiple agents are being considered. Clinical judgement and expert opinion are still superior to these tools. NC: Dr Dara, how would one distinguish DI-ALH from idiopathic AIH? LD: That is an excellent question. It is often difficult to distinguish the 2 disorders because there are no specific biomarkers for either condition. The majority of cases of DI-ALH have an acute presentation while idiopathic AIH presents acutely in less than 20% of cases.9Mack C.L. Adams D. Assis D.N. et al.Diagnosis and management of autoimmune hepatitis in adults and children: 2019 practice guidance and guidelines from the American Association for the Study of Liver Diseases.Hepatology. 2020; 72: 671-722Crossref PubMed Scopus (411) Google Scholar Antinuclear antibodies are positive in ≤75% of DI-ALH and antismooth muscle antibodies in 52-60%.2Andrade R.J. Aithal G.P. de Boer Y.S. et al.Nomenclature, diagnosis and management of drug-induced autoimmune-like hepatitis (DI-ALH): an expert opinion meeting report.J Hepatol. 2023; 79: 853-866Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar,4de Boer Y.S. Kosinski A.S. Urban T.J. et al.Features of autoimmune hepatitis in patients with drug-induced liver injury.Clin Gastroenterol Hepatol. 2017; 15: 103-112.e2Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar Among patients with NTF-ALH, the percentage of antinuclear antibodies or antismooth muscle antibodies positivity increases with longer duration of therapy.5Chalasani N. Li Y.J. Dellinger A. et al.Clinical features, outcomes, and HLA risk factors associated with nitrofurantoin-induced liver injury.J Hepatol. 2023; 78: 293-300Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar It is important to note that many patients may not have either autoantibody; therefore, the absence of the antibodies does not rule out NTF-ALH. Interestingly in DI-ALH the autoantibodies are predominantly from the IgM subclass, whereas in idiopathic AIH, autoantibodies are from both IgM and IgG subclasses.10Lammert C. Zhu C. Lian Y. et al.Exploratory study of autoantibody profiling in drug-induced liver injury with an autoimmune phenotype.Hepatol Commun. 2020; 4: 1651-1663Crossref PubMed Scopus (18) Google Scholar Unlike AIH, where antibodies persist, in DI-ALH antibodies declined at the 6-month follow-up when the drug is discontinued.10Lammert C. Zhu C. Lian Y. et al.Exploratory study of autoantibody profiling in drug-induced liver injury with an autoimmune phenotype.Hepatol Commun. 2020; 4: 1651-1663Crossref PubMed Scopus (18) Google Scholar Only 25% of DI-ALH patients present with an IgG of >1.1× ULN.4de Boer Y.S. Kosinski A.S. Urban T.J. et al.Features of autoimmune hepatitis in patients with drug-induced liver injury.Clin Gastroenterol Hepatol. 2017; 15: 103-112.e2Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar Histological features of autoimmune liver injury are common to both, but advanced fibrosis is more common with idiopathic AIH. In general, drugs associated with DI-ALH, such as infliximab, can present with histologic features of AIH, but typically lack significant fibrosis.11Bjornsson H.K. Gudbjornsson B. Bjornsson E.S. Infliximab-induced liver injury: clinical phenotypes, autoimmunity and the role of corticosteroid treatment.J Hepatol. 2022; 76: 86-92Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar However, this does not apply to NTF-ALH, where 40% of patients with long-term use can present with advanced fibrosis.5Chalasani N. Li Y.J. Dellinger A. et al.Clinical features, outcomes, and HLA risk factors associated with nitrofurantoin-induced liver injury.J Hepatol. 2023; 78: 293-300Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar The most important difference between these 2 entities, is the resolution of liver injury upon drug discontinuation alone or needing immunosuppression only temporarily. This contrasts sharply with idiopathic AIH, where spontaneous remissions are rare and long-term immunosuppression is required. The HLA risk-alleles for idiopathic AIH are absent in patients with DI-ALH.4de Boer Y.S. Kosinski A.S. Urban T.J. et al.Features of autoimmune hepatitis in patients with drug-induced liver injury.Clin Gastroenterol Hepatol. 2017; 15: 103-112.e2Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar The contrasting features of DI-ALH and idiopathic AIH are summarized in Table 2.Table 2Comparison Between DI-ALH and AIHDI-ALHAIHGenderDepends on the implicated agent. In case of nitrofurantoin, minocycline and methyldopa, it is mostly in women. However, no specific sex preponderance for other agents such as statins and infliximab.Mostly women.AgeDepends on the implicated agent.Primarily middle aged, but can show a bimodal peak.BiochemistriesHepatocellularHepatocellularHLA DRB1∗03:01 and HLA DRB1∗04:01Absent.Can be present.AutoantibodiesDepending on the implicated agent, ANA and/or ASMA can be present in up to 80% patients.ANA and/or ASMA positive in 80% of patients. Anti-LKM is present in type2 AIH.SeverityDepending on the implicated agent, it can present as chronic hepatitis, cirrhosis, or acute liver injury.Primarily chronic injury, but can present as acute liver failure or as cirrhosis and end stage liver disease.HistologyLymphoplasmacytic infiltrate and interface hepatitis. Central vein inflammation can be seen. Fibrosis is uncommon except with agents such as nitrofurantoin. Granulomas and cholestasis have been reported but rare.Lymphoplasmacytic infiltrate and interface hepatitis. Central vein inflammation can be seen. Fibrosis and evidence of chronicity often seen. No granulomas and no cholestasis should be seen unless patient has AIH- primary biliary cholangitis variant syndrome.Natural historyCan subside spontaneously with cessation of the implicated agent and responds well to steroids.Spontaneous remission is uncommon.ImmunosuppressionGenerally short term (<6 months). Patients can be tapered off prednisone and monitored without relapse.Long-term immunosuppression is required. If tapered off immunosuppression , most patients will relapse.AIH, idiopathic autoimmune hepatitis; ANA, antinuclear antibodies; ASMA, antismooth muscle antibodies; DI-ALH, drug-induced autoimmune-like hepatitis; KLM, liver-kidney microsome antibodies. Open table in a new tab AIH, idiopathic autoimmune hepatitis; ANA, antinuclear antibodies; ASMA, antismooth muscle antibodies; DI-ALH, drug-induced autoimmune-like hepatitis; KLM, liver-kidney microsome antibodies. NC: Dr Kleiner, what are the characteristic histologic features of NTF-DILI, and are there distinguishing features for NTF-ALH versus idiopathic AIH? DK: The histological features of NTF-DILI are well-reported, in contrast with other instances of DILI (Figure 1). The most common presentations mimic acute or chronic viral hepatitis with inflammation dominating either the parenchyma or portal areas, respectively5Chalasani N. Li Y.J. Dellinger A. et al.Clinical features, outcomes, and HLA risk factors associated with nitrofurantoin-induced liver injury.J Hepatol. 2023; 78: 293-300Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar,12Sharp J.R. Ishak K.G. Zimmerman H.J. Chronic active hepatitis and severe hepatic necrosis associated with nitrofurantoin.Ann Intern Med. 1980; 92: 14-19Crossref PubMed Scopus (141) Google Scholar (Figure 1, A). Perivenulitis can also be seen (Figure 1, B). Plasma cells, a characteristic feature of AIH, are seen in about one-half of cases (Figure 1, C), with prominent eosinophil infiltrates in a third.4de Boer Y.S. Kosinski A.S. Urban T.J. et al.Features of autoimmune hepatitis in patients with drug-induced liver injury.Clin Gastroenterol Hepatol. 2017; 15: 103-112.e2Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar Fulminant hepatitis with bridging necrosis may also be seen (Figure 1, D).5Chalasani N. Li Y.J. Dellinger A. et al.Clinical features, outcomes, and HLA risk factors associated with nitrofurantoin-induced liver injury.J Hepatol. 2023; 78: 293-300Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar Differentiating NTF-ALH from idiopathic AIH can be difficult, particularly when advanced fibrosis is present. Fibrosis is an indication of the chronic nature of the injury and is less often seen in cases of DI-ALH. However, NTF-DILI may remain subclinical for a long period of time, leading to bridging fibrosis and cirrhosis. Uncommonly, cholestatic changes, with either visible bile stasis or copper accumulation indicative of chronic cholestasis may be seen, and granulomas have been reported in isolated cases of DI-ALH.5Chalasani N. Li Y.J. Dellinger A. et al.Clinical features, outcomes, and HLA risk factors associated with nitrofurantoin-induced liver injury.J Hepatol. 2023; 78: 293-300Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar,13Sippel P.J. Agger W.A. Nitrofurantoin-induced granulomatous hepatitis.Urology. 1981; 18: 177-178Abstract Full Text PDF PubMed Scopus (25) Google Scholar Features that would be unusual in idiopathic AIH, including granulomas and cholestasis, may suggest DI-ALH if there is an appropriate suspected medication.4de Boer Y.S. Kosinski A.S. Urban T.J. et al.Features of autoimmune hepatitis in patients with drug-induced liver injury.Clin Gastroenterol Hepatol. 2017; 15: 103-112.e2Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar,14Suzuki A. Brunt E.M. Kleiner D.E. et al.The use of liver biopsy evaluation in discrimination of idiopathic autoimmune hepatitis versus drug-induced liver injury.Hepatology. 2011; 54: 931-939Crossref PubMed Scopus (249) Google Scholar NC: Dr Phillips, can we use genetic analyses to distinguish between NTF-ALH and idiopathic AIH in this clinical scenario? EP: In attempting to distinguish idiopathic AIH from DI-AIH , genetic features such as HLA class I and II typing can be helpful in conjunction with the other clinical and pathological features already mentioned. Idiopathic AIH has been most commonly associated with both HLA-DRB1∗03:01, and HLA-DRB1∗04:01 in European populations. HLA-DRB1∗03:01 occurs as part of the larger 8.1 Ancestral haplotype (HLA-A∗01:01, B∗08:01, C∗07:02, DRB1∗03:01, DQA1∗05:01, and DQB1∗02:01), which occurs in about 8% of populations of Northern European ancestry and has been more generally associated with autoimmune diseases.e1Candore G. Lio D. Colonna Romano G. et al.Pathogenesis of autoimmune diseases associated with 8.1 ancestral haplotype: effect of multiple gene interactions.Autoimmun Rev. 2002; 1: 29-35Crossref PubMed Scopus (180) Google Scholar, e2Gambino C.M. Aiello A. Accardi G. et al.Autoimmune diseases and 8.1 ancestral haplotype: an update.HLA. 2018; 92: 137-143Crossref PubMed Scopus (42) Google Scholar Both HLA-DRB1∗04:01 and HLA-DRB1∗03:01 are strongly associated with but not necessary for the development of idiopathic AIH. HLA-DRB1∗03:01 is also associated with disease severity. DI-ALH has been associated with distinct class I and II associations, which are associated with a specific drug. For instance, minocycline hepatitis has been associated with HLA-B∗35:02.e3Urban T.J. Nicoletti P. Chalasani N. et al.Minocycline hepatotoxicity: clinical characterization and identification of HLA-B ∗35:02 as a risk factor.J Hepatol. 2017; 67: 137-144Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar In the case of NTF-DILI, HLA-DRB1∗11:04 was more frequent in long-term users who more commonly had clinical and laboratory features compatible with DI-ALH.5Chalasani N. Li Y.J. Dellinger A. et al.Clinical features, outcomes, and HLA risk factors associated with nitrofurantoin-induced liver injury.J Hepatol. 2023; 78: 293-300Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar This was compared with both populations controls (OR, 4.29; P = 1.15 × 10–4) and those with idiopathic autoimmune hepatitis (OR, 11.77; P = 7.76 × 10–5) and non-NTF-DILI (OR, 3.34; P = .003).5Chalasani N. Li Y.J. Dellinger A. et al.Clinical features, outcomes, and HLA risk factors associated with nitrofurantoin-induced liver injury.J Hepatol. 2023; 78: 293-300Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar NC: Dr Ghabril, how do you approach the treatment of DI-ALH? MG: Both AIH and DI-ALH are responsive to corticosteroid therapy, but many cases of DI-ALH improve just by discontinuing the implicated agent. The decision to start corticosteroids should depend on severity at presentation, the trajectory of liver enzymes with drug discontinuation, and based on the treating physician's clinical judgement. Although there are robust data in the treatment of AIH, data on the treatment of DILI, let alone DI-ALH with corticosteroids, are limited, with no randomized trials. Despite the lack of data, corticosteroids should be used in DI-ALH when the patient does not respond to dechallenge within a few days, or if there are any severe features such as acute to severe AIH (jaundice and international normalized ratio of 1.5–2.0 without encephalopathy), evidence of portal hypertension such as ascites, submassive necrosis, or parenchymal collapse on liver biopsy. In cases of acute liver failure with encephalopathy, a prompt transplant evaluation is advised (Figure 2). A recent study examined corticosteroid treatment patterns and outcomes in DILI and demonstrated significantly more common treatment in DI-ALH and with more severe liver injury reflected by transaminase elevations and hyperbilirubinemia.e4Niu H. Ma J. Medina-Caliz I. et al.Potential benefit and lack of serious risk from corticosteroids in drug-induced liver injury: an international, multicentre, propensity score-matched analysis.Aliment Pharmacol Ther. 2023; 57: 886-896Crossref PubMed Scopus (5) Google Scholar Corticosteroid therapy was not associated with worse outcomes, but rather a greater rate of normalization of liver enzymes and bilirubin levels in those with severe liver injury. There is no standardized dosing regimen for DI-ALH, but most hepatologists prescribe dosing used for idiopathic AIH (starting with 40 mg of oral prednisone). Because DI-ALH is thought to be self-limited, the goal is to completely wean off corticosteroids (enzymes permitting) as soon as possible, ideally within 3–6 months, although longer therapy may occasionally be required. The withdrawal of immunosuppression can be successfully achieved in most cases of DI-ALH, in contrast to idiopathic AIH where the majority of patients (60%–87%) relapse after corticosteroid withdrawal.9Mack C.L. Adams D. Assis D.N. et al.Diagnosis and management of autoimmune hepatitis in adults and children: 2019 practice guidance and guidelines from the American Association for the Study of Liver Diseases.Hepatology. 2020; 72: 671-722Crossref PubMed Scopus (411) Google Scholar Because there is no need for long-term immunosuppression, steroid-sparing medications such as azathioprine or mycophenolate mofetil are unnecessary unless steroid intolerance requires more rapid dose lowering or discontinuation. DI-ALH is generally not believed to recur in the absence of a rechallenge with the offending drug. However, in 1 study, ≤50% of patients with suspected DI-ALH had recurrence by 4 years.e5Garcia-Cortes M. Ortega-Alonso A. Matilla-Cabello G. et al.Clinical presentation, causative drugs and outcome of patients with autoimmune features in two prospective DILI registries.Liver Int. 2023; 43: 1749-1760Crossref PubMed Scopus (5) Google Scholar Thus follow up with serial liver enzymes is recommended initially every 2–4 weeks, and subsequently expanding to every 3–6 months for the first 2 years and yearly for 3 years. If a patient cannot be tapered off steroids or relapses upon discontinuing the immunosuppression, it is likely that the drug unmasked underlying idiopathic AIH and these patients should be considered for long-term immunosuppression. NC: Dr Ghabril, what is the prognosis of DILI, and what are the risk factors for poor outcomes? MG: Approximately 10% of patients with significant DILI die or undergo liver transplantation within 2 years,e6Hayashi P.H. Rockey D.C. Fontana R.J. et al.Death and liver transplantation within 2 years of onset of drug-induced liver injury.Hepatology. 2017; 66: 1275-1285Crossref PubMed Scopus (90) Google Scholar and the key determinants of DILI outcomes are the severity of liver injury and the burden of underlying comorbidities, including underlying chronic liver disease or cirrhosis. The presence of jaundice and/or increased Model for End-State Liver Disease scores are associated with worse outcomes in DILI. Hy's law, defined as hepatocellular DILI associated with jaundice, is associated with a 10% risk of mortality or need for liver transplantation in patients with DILI. In this case, the patient had a hepatocellular injury but a normal bilirubin, even at the peak of liver injury, and she did not develop coagulopathy or hepatic encephalopathy. A model consisting of the Model for End-State Liver Disease score, serum albumin, and the Charlson Comorbidity Index very strongly predicts 6-month mortality in patients with DILI (c-statistics for discovery and validation cohorts 0.89 and 0.91, respectively).e7Ghabril M. Gu J. Yoder L. et al.Development and validation of a model consisting of comorbidity burden to calculate risk of death within 6 months for patients with suspected drug-induced liver injury.Gastroenterology. 2019; 157: 1245-1252.e3Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar Patients with underlying chronic liver disease who develop DILI have a 3- to 4-fold higher risk of death or liver transplantion.e8Chalasani N. Bonkovsky H.L. Fontana R. et al.Features and outcomes of 899 patients with drug-induced liver injury: the DILIN Prospective Study.Gastroenterology. 2015; 148: 1340-1352.e7Abstract Full Text Full Text PDF PubMed Scopus (618) Google Scholar, e3Urban T.J. Nicoletti P. Chalasani N. et al.Minocycline hepatotoxicity: clinical characterization and identification of HLA-B ∗35:02 as a risk factor.J Hepatol. 2017; 67: 137-144Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar The patient in this case had no known underlying chronic liver disease and had a low comorbidity burden (age unadjusted Charlson Comorbidity Index of 1), which indicated an excellent prognosis. Persistently abnormal liver tests, liver imaging, or clinical features of liver disease 6 months after the onset of liver injury, referred to as chronic DILI, is an uncommon entity that sometimes develops in patients with cholestatic liver injury irrespective of bilirubin or international normalized ratio levels at presentation.e9Fontana R.J. Hayashi P.H. Gu J. et al.Idiosyncratic drug-induced liver injury is associated with substantial morbidity and mortality within 6 months from onset.Gastroenterology. 2014; 147: 96-108.e4Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar There are no data to suggest that DI-ALH is associated with an increased risk of chronic DILI, and fortunately this patient recovered completely. CME Exam 1: A 68-Year-Old Woman With Unexplained Liver Enzyme Elevation and Active Chronic Hepatitis: Beware of Drug-Induced Autoimmune-Like HepatitisGastroenterologyVol. 166Issue 2Preview Full-Text PDF