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Long-term sequelae of drug-induced liver injury

  • Einar S. Björnsson
    Correspondence
    Corresponding author. Address: The National University Hospital of Iceland, 101 Reykjavik, Iceland, Tel.: 543 6180, fax 543-4834.
    Affiliations
    Faculty of Medicine, University of Iceland, Iceland

    Department of Gastroenterology, Landspitali University Hospital Reykjavik, Iceland
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  • Raul J. Andrade
    Correspondence
    Departamento de Medicina, Facultad de Medicina, Boulevard Louis Pasteur nº 32, 29071-Málaga Spain; Tel.: +34 658259338.
    Affiliations
    Unidad de Gestión Clínica de Enfermedades Digestivas, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Malaga, Spain

    Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
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Published:October 21, 2021DOI:https://doi.org/10.1016/j.jhep.2021.10.011

      Summary

      Drug-induced liver injury (DILI) has a very variable clinical and biochemical phenotype and differs widely in severity, from mild injury to life-threatening liver failure. Chronic injury has also been reported to occur at a variable frequency, ranging from 3.4% to 39%, 6-12 months after discontinuing the implicated agent. This wide range is probably related to various definitions of chronic liver injury and variable selection of patients. The long-term sequalae of this chronic injury in terms of morbidity and mortality are unclear, although rare vanishing bile duct syndrome is associated with an unfavourable prognosis, with increased risk of chronic liver failure and need for liver transplantation. Other forms of long-term sequalae associated with DILI are progressive fibrosis, autoimmune-like hepatitis, secondary sclerosing cholangitis, sinusoidal obstruction syndrome and, as a common final stage, the development of cirrhosis, portal hypertension and its complications. Immune checkpoint inhibitors, which can cause an autoimmune-like phenotype have also recently been shown to cause sclerosing cholangitis with cytotoxic T CD8+ cell infiltration in biliary tracts. DILI has been shown to have a significant impact on health-related quality of life but very little is known about its psychological consequences in the long-term. Further investigations with structured long-term follow-up and periodic quality of life surveys are needed to assess the impact of DILI on psychological outcomes, particularly in those with chronic sequelae.

      Keywords

      Introduction

      Drug-induced liver injury (DILI) is a liver disorder that has many faces, encompassing a variety of clinical and pathological syndromes and ranging in severity from mild asymptomatic liver injury, with rapid recovery after discontinuing the implicated agent, to life-threatening acute liver failure.
      European Association for the Study of the Liver
      EASL clinical practice guidelines: drug-induced liver injury.
      Many cases are in the middle of this spectrum with long-standing jaundice, itching and severe lethargy for weeks or months after diagnosis. It is well documented that the vast majority of patients with DILI recover clinically, biochemically and histologically.
      • Hoofnagle J.H.
      • Bjornsson E.S.
      Drug induced liver injury: types and phenotypes.
      In some patients, however, the biochemical and sometimes histological recovery is very slow and in a smaller proportion the biochemical abnormalities persist for more than 6 months (and even more than 12 months in some cases) after the diagnosis of DILI.
      • Ortega-Alonso A.
      • Andrade R.J.
      Chronic liver injury induced by drugs and toxins.
      Cases have been reported where liver injury has led to cirrhosis and other structural changes in the hepatobiliary system, such as secondary sclerosing cholangitis. Severe DILI induced by prolonged drug therapy may induce progressive liver disease in a proportion of individuals who can suffer from long-term sequelae of DILI.
      • Bessone F.
      • Robles-Diaz M.
      • Hernandez N.
      • Medina-Caliz I.
      • Lucena M.I.
      • Andrade R.J.
      Assessment of serious acute and chronic idiosyncratic drug-induced liver injury in clinical practice.
      In addition, DILI can present as a “chronic” phenotype like those of autoimmune hepatitis (AIH) or sinusoidal obstruction syndrome.
      • Hoofnagle J.H.
      • Bjornsson E.S.
      Drug induced liver injury: types and phenotypes.
      Finally, even though patients recover from the acute phase, DILI can induce persistent psychological distress. This review will try to answer the question of what kind of, and in what proportion, long-term consequences can occur in patients diagnosed with DILI, addressing in more detail some of the chronic sequelae that have emerged thanks to cohort studies published in the last 20 years.

      Frequency of chronic liver test abnormalities after DILI

      In probably the first study analysing the natural history of DILI, patients were identified through a histological database.
      • Aithal P.
      • Day C.
      The natural history of histologically proved drug induced liver disease.
      A total of 13/33 (39%) who were followed-up for a median of 5 years had significant persistent liver test abnormalities and/or on changes on hepatic imaging.
      • Aithal P.
      • Day C.
      The natural history of histologically proved drug induced liver disease.
      The majority of patients presented with jaundice and 3 with hepatic failure. Interestingly an important factor that predicted persistence or the development of chronicity was continued exposure to the implicated drug. Only including patients with clinically significant DILI who underwent a liver biopsy might have created a selection bias, with another important limitation being the interpretation of abnormal scans.
      Further studies have not revealed similarly high proportions of patients with chronicity (Table 1). Subsequent studies have reported chronicity occurring in 3.4%-18% of cases, but follow-up has been very variable.
      • Andrade R.J.
      • Lucena M.I.
      • Kaplowitz N.
      • García-Muņoz B.
      • Borraz Y.
      • Pachkoria K.
      • et al.
      Outcome of acute idiosyncratic drug-induced liver injury: long-term follow-up in a hepatotoxicity registry.
      • Björnsson E.
      • Kalaitzakis E.
      • Av Klinteberg V.
      • Alem N.
      • Olsson R.
      Long-term follow-up in patients with mild to moderate drug-induced liver injury.
      • Chalasani N.
      • Fontana R.J.
      • Bonkovsky H.L.
      • Watkins P.B.
      • Davern T.
      • Serrano J.
      • et al.
      Causes, clinical features, and outcomes from a prospective study of drug induced liver injury in the United States.
      • Björnsson E.
      • Davidsdottir L.
      The long-term follow-up after idiosyncratic drug-induced liver injury with jaundice.
      • Fontana R.J.
      • Hayashi P.H.
      • Gu J.
      • Reddy K.R.
      • Barnhart H.
      • Watkins P.B.
      • et al.
      Idiosyncratic drug-induced liver injury is associated with substantial morbidity and mortality within 6 months from onset.
      • Fontana R.J.
      • Hayashi P.H.
      • Barnhart H.
      • Kleiner D.E.
      • Reddy K.R.
      • Chalasani N.
      • et al.
      Persistent liver biochemistry abnormalities are more common in older patients and those with cholestatic drug induced liver injury.
      • Medina-Caliz I.
      • Robles-Diaz M.
      • Garcia-Muñoz B.
      • Stephens C.
      • Ortega-Alonso A.
      • Garcia-Cortes M.
      • et al.
      Definition and risk factors for chronicity following acute idiosyncratic drug-induced liver injury.
      • Chalasani N.
      • Bonkovsky H.L.
      • Fontana R.J.
      • Lee W.
      • Stolz A.
      • Talwalkar J.
      • et al.
      Features and outcomes of 899 patients with drug-induced liver injury: the DILIN prospective study.
      Generally, the shorter the follow-up, the higher the proportion of patients with abnormal liver tests (Table 1). It has been well documented that it takes longer to recover from cholestatic liver injury than hepatocellular injury.
      • Andrade R.J.
      • Lucena M.I.
      • Kaplowitz N.
      • García-Muņoz B.
      • Borraz Y.
      • Pachkoria K.
      • et al.
      Outcome of acute idiosyncratic drug-induced liver injury: long-term follow-up in a hepatotoxicity registry.
      • Björnsson E.
      • Kalaitzakis E.
      • Av Klinteberg V.
      • Alem N.
      • Olsson R.
      Long-term follow-up in patients with mild to moderate drug-induced liver injury.
      • Chalasani N.
      • Fontana R.J.
      • Bonkovsky H.L.
      • Watkins P.B.
      • Davern T.
      • Serrano J.
      • et al.
      Causes, clinical features, and outcomes from a prospective study of drug induced liver injury in the United States.
      • Björnsson E.
      • Davidsdottir L.
      The long-term follow-up after idiosyncratic drug-induced liver injury with jaundice.
      • Fontana R.J.
      • Hayashi P.H.
      • Gu J.
      • Reddy K.R.
      • Barnhart H.
      • Watkins P.B.
      • et al.
      Idiosyncratic drug-induced liver injury is associated with substantial morbidity and mortality within 6 months from onset.
      • Fontana R.J.
      • Hayashi P.H.
      • Barnhart H.
      • Kleiner D.E.
      • Reddy K.R.
      • Chalasani N.
      • et al.
      Persistent liver biochemistry abnormalities are more common in older patients and those with cholestatic drug induced liver injury.
      • Medina-Caliz I.
      • Robles-Diaz M.
      • Garcia-Muñoz B.
      • Stephens C.
      • Ortega-Alonso A.
      • Garcia-Cortes M.
      • et al.
      Definition and risk factors for chronicity following acute idiosyncratic drug-induced liver injury.
      • Chalasani N.
      • Bonkovsky H.L.
      • Fontana R.J.
      • Lee W.
      • Stolz A.
      • Talwalkar J.
      • et al.
      Features and outcomes of 899 patients with drug-induced liver injury: the DILIN prospective study.
      Table 1Studies reporting the frequency of abnormal liver tests after acute DILI, showing definition of chronicity, number of patients, duration of follow-up and proportion of patients with abnormal liver tests.
      Reference, study designDefinition of chronicityNumber of patientsFollow-up mean/median or rangeProportion of abnormal liver tests after DILI
      Aithal and Day 1999
      • Aithal P.
      • Day C.
      The natural history of histologically proved drug induced liver disease.


      Retrospective study
      Liver tests elevated/scan abnormal335 years39%
      Andrade et al. 2006
      • Andrade R.J.
      • Lucena M.I.
      • Kaplowitz N.
      • García-Muņoz B.
      • Borraz Y.
      • Pachkoria K.
      • et al.
      Outcome of acute idiosyncratic drug-induced liver injury: long-term follow-up in a hepatotoxicity registry.


      Prospective study
      Liver tests elevated >6 months49320 months5.7%
      Björnsson et al. 2007
      • Björnsson E.
      • Kalaitzakis E.
      • Av Klinteberg V.
      • Alem N.
      • Olsson R.
      Long-term follow-up in patients with mild to moderate drug-induced liver injury.


      Retrospective study
      Liver tests elevated >6 months5048 months6%
      Chalasani et al. 2008
      • Chalasani N.
      • Fontana R.J.
      • Bonkovsky H.L.
      • Watkins P.B.
      • Davern T.
      • Serrano J.
      • et al.
      Causes, clinical features, and outcomes from a prospective study of drug induced liver injury in the United States.


      Prospective study
      Liver tests elevated >6 months300>6 months13.6%
      Björnsson et al. 2009
      • Björnsson E.
      • Davidsdottir L.
      The long-term follow-up after idiosyncratic drug-induced liver injury with jaundice.


      Retrospective study
      Liver tests elevated68510 years3.4%
      Fontana et al. 2014
      • Fontana R.J.
      • Hayashi P.H.
      • Gu J.
      • Reddy K.R.
      • Barnhart H.
      • Watkins P.B.
      • et al.
      Idiosyncratic drug-induced liver injury is associated with substantial morbidity and mortality within 6 months from onset.


      Prospective study
      Liver tests elevated >6 months59824 months18.9%
      Fontana et al. 2015
      • Fontana R.J.
      • Hayashi P.H.
      • Barnhart H.
      • Kleiner D.E.
      • Reddy K.R.
      • Chalasani N.
      • et al.
      Persistent liver biochemistry abnormalities are more common in older patients and those with cholestatic drug induced liver injury.


      Prospective study
      Liver tests elevated at 12 months59824 months12%
      Chalasani et al. 2015
      • Chalasani N.
      • Bonkovsky H.L.
      • Fontana R.J.
      • Lee W.
      • Stolz A.
      • Talwalkar J.
      • et al.
      Features and outcomes of 899 patients with drug-induced liver injury: the DILIN prospective study.


      Prospective study
      Liver tests elevated >6 months89918%
      Medina-Caliz et al. 2016
      • Medina-Caliz I.
      • Robles-Diaz M.
      • Garcia-Muñoz B.
      • Stephens C.
      • Ortega-Alonso A.
      • Garcia-Cortes M.
      • et al.
      Definition and risk factors for chronicity following acute idiosyncratic drug-induced liver injury.


      Prospective study
      Liver tests elevated at 12 months2981-3 years8%
      DILI, drug-induced liver injury.
      There is currently no consensus on the criteria for “chronic DILI” and the long-term consequences on liver-related morbidity and mortality have not been well established. In a prospective study from the Spanish Hepatotoxicity Registry, the most appropriate cut-off to define chronic DILI was reported to be 1 year.
      • Medina-Caliz I.
      • Robles-Diaz M.
      • Garcia-Muñoz B.
      • Stephens C.
      • Ortega-Alonso A.
      • Garcia-Cortes M.
      • et al.
      Definition and risk factors for chronicity following acute idiosyncratic drug-induced liver injury.
      Risk factors for chronicity in mulitivariate analysis were found to be older age, dyslipidaemia and the severity of the acute DILI episode, with severity having the highest odds ratio (=14.2).
      • Medina-Caliz I.
      • Robles-Diaz M.
      • Garcia-Muñoz B.
      • Stephens C.
      • Ortega-Alonso A.
      • Garcia-Cortes M.
      • et al.
      Definition and risk factors for chronicity following acute idiosyncratic drug-induced liver injury.
      Interestingly, liver biopsies in patients considered to have chronic liver injury revealed biliary ductal lesions in 2 cases and cirrhosis in 7 cases.
      • Medina-Caliz I.
      • Robles-Diaz M.
      • Garcia-Muñoz B.
      • Stephens C.
      • Ortega-Alonso A.
      • Garcia-Cortes M.
      • et al.
      Definition and risk factors for chronicity following acute idiosyncratic drug-induced liver injury.
      However, decompensated liver disease was not reported. Most previous studies have not reported whether the patients with “chronic DILI” developed cirrhosis or liver-related mortality.
      • Aithal P.
      • Day C.
      The natural history of histologically proved drug induced liver disease.
      • Andrade R.J.
      • Lucena M.I.
      • Kaplowitz N.
      • García-Muņoz B.
      • Borraz Y.
      • Pachkoria K.
      • et al.
      Outcome of acute idiosyncratic drug-induced liver injury: long-term follow-up in a hepatotoxicity registry.
      • Björnsson E.
      • Kalaitzakis E.
      • Av Klinteberg V.
      • Alem N.
      • Olsson R.
      Long-term follow-up in patients with mild to moderate drug-induced liver injury.
      • Chalasani N.
      • Fontana R.J.
      • Bonkovsky H.L.
      • Watkins P.B.
      • Davern T.
      • Serrano J.
      • et al.
      Causes, clinical features, and outcomes from a prospective study of drug induced liver injury in the United States.
      ,
      • Fontana R.J.
      • Hayashi P.H.
      • Gu J.
      • Reddy K.R.
      • Barnhart H.
      • Watkins P.B.
      • et al.
      Idiosyncratic drug-induced liver injury is associated with substantial morbidity and mortality within 6 months from onset.
      ,
      • Fontana R.J.
      • Hayashi P.H.
      • Barnhart H.
      • Kleiner D.E.
      • Reddy K.R.
      • Chalasani N.
      • et al.
      Persistent liver biochemistry abnormalities are more common in older patients and those with cholestatic drug induced liver injury.
      In a retrospective follow-up study from Sweden, survivors with drug-induced jaundice were analysed in terms of hospitalisation over a mean follow-up of 10 years.
      • Björnsson E.
      • Davidsdottir L.
      The long-term follow-up after idiosyncratic drug-induced liver injury with jaundice.
      This is by far the longest follow-up study on the long-term sequelae of prolonged DILI, wherein 23/685 (3.4%) patients were hospitalised for liver disease and 5 died of liver-related causes.
      • Björnsson E.
      • Davidsdottir L.
      The long-term follow-up after idiosyncratic drug-induced liver injury with jaundice.
      Cirrhosis developed in 8 patients, 5 of whom did not have a specific cause of cirrhosis (in whom DILI might have contributed).
      • Björnsson E.
      • Davidsdottir L.
      The long-term follow-up after idiosyncratic drug-induced liver injury with jaundice.
      However, given the retrospective nature of the study it was difficult to draw firm conclusions regarding the aetiology of cirrhosis. In line with the study of Aithal and Day
      • Aithal P.
      • Day C.
      The natural history of histologically proved drug induced liver disease.
      on chronic DILI, the longer duration of drug therapy before suspicion of DILI was found to be a risk factor for development of liver-related morbidity and mortality during follow-up.
      • Björnsson E.
      • Davidsdottir L.
      The long-term follow-up after idiosyncratic drug-induced liver injury with jaundice.
      Interestingly, a protracted course of DILI was more common in patients with cholestatic or mixed liver injury. In that study, after a median follow-up of 13 years, all patients with this type of injury except one had normal liver tests at the last follow-up.
      • Björnsson E.
      • Davidsdottir L.
      The long-term follow-up after idiosyncratic drug-induced liver injury with jaundice.
      In a large cohort (n = 1,136) of young patients (<25 years) who received chemotherapy for solid tumours at the University of Michigan, 160 (14%) developed liver injury during the course of their disease, with DILI occurring in 4%.
      • Cardenas V.
      • Mankuzhy N.
      • Mody R.
      • McCaffery H.
      • Fontana R.J.
      • DiPaola F.
      Incidence and sequelae of liver injury among children treated for solid tumors: analysis of a large single-center prospective cohort.
      Most patients had mild hepatocellular injury and all patients recovered completely from their liver injury.
      • Cardenas V.
      • Mankuzhy N.
      • Mody R.
      • McCaffery H.
      • Fontana R.J.
      • DiPaola F.
      Incidence and sequelae of liver injury among children treated for solid tumors: analysis of a large single-center prospective cohort.
      DILI usually resolves after discontinuation of the implicated agent but can in rare instances lead to acute liver failure or chronic injury.

      DILI leading to autoimmune hepatitis

      DILI can be associated with autoimmune features – with positive auto-antibodies, such as ANA (anti-nuclear antibody) and SMA (smooth muscle antibodies), and elevated IgG – similar to those observed in patients with AIH. Some drugs have been shown to convincingly induce what has been termed drug-induced AIH (DIAIH), whereas several other drugs reported to cause DIAIH might be innocent bystanders.
      Hepatic metabolism of some drugs has been shown to create reactive metabolites which can bind to cellular proteins such as plasma membrane cytochrome P450 leading to neoantigens and autoimmune targets in drug-induced hepatitis.
      • Robin M.A.
      • Le Roy M.
      • Descatoire V.
      • Pessayre D.
      Plasma membrane cytochromes P450 as neoantigens and autoimmune targets in drug-induced hepatitis.
      ,
      • Beaune P.H.
      • Bourdi M.
      Autoantibodies against cytochromes P-450 in drug-induced autoimmune hepatitis.
      The underlying pathophysiology has been recognised for some drugs such as hydralazine.
      • Siegmund W.
      • Franke G.
      • Biebler K.E.
      • Donner I.
      • Kallwellis R.
      • Kairies M.
      • et al.
      The influence of the acetylator phenotype for the clinical use of dihydralazine.
      ,
      • Bourdi M.
      • Tinel M.
      • Beaune P.H.
      • Pessayre D.
      Interactions of dihydralazine with cytochromes P4501A: a possible explanation for the appearance of anti-cytochrome P4501A2 autoantibodies.
      A recent study from the DILIN group in the US aimed to characterise the prominent autoimmune features of DILI caused by nitrofurantoin, minocycline, methyldopa, or hydralazine,
      • de Boer Y.S.
      • Kosinski A.S.
      • Urban T.J.
      • Zhao Z.
      • Long N.
      • Chalasani N.
      • et al.
      Features of autoimmune hepatitis in patients with drug- induced liver injury.
      all of which have a well-documented ability to induce DIAIH.
      • Stricker B.H.
      • Blok A.P.
      • Claas F.H.
      • Van Parys G.E.
      • Desmet V.J.
      Hepatic injury associated with the use of nitrofurans: a clinicopathological study of 52 reported cases.
      • Gough A.
      • Chapman S.
      • Wagstaff K.
      • Emery P.
      • Elias E.
      Minocycline induced autoimmune hepatitis and systemic lupus erythematosus-like syndrome.
      • Björnsson E.
      • Talwalkar J.
      • Treeprasertsuk S.
      • Kamath P.S.
      • Takahashi N.
      • Sanderson S.
      • et al.
      Drug-induced autoimmune hepatitis: clinical characteristics and prognosis.
      In the study by de Boer et al. approximately 90% of cases occurred in females, and 74% had hepatocellular injury.
      • de Boer Y.S.
      • Kosinski A.S.
      • Urban T.J.
      • Zhao Z.
      • Long N.
      • Chalasani N.
      • et al.
      Features of autoimmune hepatitis in patients with drug- induced liver injury.
      Most patients with nitrofurantoin- and minocycline-induced DILI and approximately 50% with methyldopa- and hydralazine-induced DILI had autoimmune features resembling AIH.
      • de Boer Y.S.
      • Kosinski A.S.
      • Urban T.J.
      • Zhao Z.
      • Long N.
      • Chalasani N.
      • et al.
      Features of autoimmune hepatitis in patients with drug- induced liver injury.
      Interestingly, these autoimmune markers were found to decrease as liver injury improved and patients were not carriers of the most common HLA alleles found in patients with genuine AIH.
      • de Boer Y.S.
      • Kosinski A.S.
      • Urban T.J.
      • Zhao Z.
      • Long N.
      • Chalasani N.
      • et al.
      Features of autoimmune hepatitis in patients with drug- induced liver injury.
      In a study from the Mayo clinic, characterising DIAIH (mostly caused by nitrofurantoin and minocycline) among patients diagnosed with AIH, clinical, biochemical and histological features were very similar in DIAIH and genuine AIH.
      • Björnsson E.
      • Talwalkar J.
      • Treeprasertsuk S.
      • Kamath P.S.
      • Takahashi N.
      • Sanderson S.
      • et al.
      Drug-induced autoimmune hepatitis: clinical characteristics and prognosis.
      The only significant difference between them was the absence of relapse after discontinuation of corticosteroids in the DIAIH group, compared to a relapse rate of 65% in the genuine AIH group.
      • Björnsson E.
      • Talwalkar J.
      • Treeprasertsuk S.
      • Kamath P.S.
      • Takahashi N.
      • Sanderson S.
      • et al.
      Drug-induced autoimmune hepatitis: clinical characteristics and prognosis.
      A similar lack of relapse after discontinuation of immunosuppression was observed for liver injury associated with other drugs with a well-documented ability to induce DIAIH, such as imatinib and infliximab.
      • Björnsson E.S.
      • Gunnarsson B.I.
      • Gröndal G.
      • Jonasson J.G.
      • Einarsdottir R.
      • Ludviksson B.R.
      • et al.
      The risk of drug-induced liver injury from Tumor Necrosis Factor (TNF)-alpha-antagonists.
      ,
      • Björnsson E.
      • Bergmann O.
      • Jonasson J.G.
      • Grondal G.
      • Gudbjornsson B.
      • Olafsson S.
      Drug-induced autoimmune hepatitis: response to corticosteroids and lack of relapse after cessation of steroids.
      Abnormal liver tests 6 to 12 months after cessation of the suspected causative agent have been reported to occur in 3.4% to 39% of patients.
      Several studies have demonstrated a relationship between the occurrence of DILI and autoimmune disease development.
      • Björnsson E.
      • Davidsdottir L.
      The long-term follow-up after idiosyncratic drug-induced liver injury with jaundice.
      ,
      • Ohmoto K.
      • Yamamoto S.
      Drug-induced liver injury associated with antinuclear antibodies.
      • Sugimoto K.
      • Ito T.
      • Yamamoto N.
      • Shiraki K.
      Seven cases of autoimmune hepatitis that developed after drug-induced liver injury.
      • Lucena M.I.
      • Kaplowitz N.
      • Hallal H.
      • Castiella A.
      • García-Bengoechea M.
      • Otazua P.
      • et al.
      Recurrent drug-induced liver injury (DILI) with different drugs in the Spanish Registry: the dilemma of the relationship to autoimmune hepatitis.
      Ohmoto et al. found that patients diagnosed with DILI who were ANA positive were more likely to have other autoimmune diseases and be female than other patients with DILI.
      • Ohmoto K.
      • Yamamoto S.
      Drug-induced liver injury associated with antinuclear antibodies.
      Interestingly, in a long-term follow-up (mean of 6 years) of patients with DILI and concomitant jaundice, AIH developed in 5/23 (22%) patients who had been hospitalised for liver disease, all of whom were female.
      • Björnsson E.
      • Davidsdottir L.
      The long-term follow-up after idiosyncratic drug-induced liver injury with jaundice.
      In agreement with these results, in 7 patients who had been diagnosed with DILI in a Japanese study, autoimmune features developed later in the course with increased ANA titres and IgG levels.
      • Sugimoto K.
      • Ito T.
      • Yamamoto N.
      • Shiraki K.
      Seven cases of autoimmune hepatitis that developed after drug-induced liver injury.
      Finally, along the same lines, Lucena et al. observed that among patients with at least 2 episodes of DILI caused by different drugs, 4/9 (44%) presented with AIH in the second episode.
      • Lucena M.I.
      • Kaplowitz N.
      • Hallal H.
      • Castiella A.
      • García-Bengoechea M.
      • Otazua P.
      • et al.
      Recurrent drug-induced liver injury (DILI) with different drugs in the Spanish Registry: the dilemma of the relationship to autoimmune hepatitis.
      It is still unclear if this is DILI unmasking genuine AIH or DILI with autoimmune features, but it clearly exceeds the chance of association reported by the Spanish DILI Registry.
      • Lucena M.I.
      • Kaplowitz N.
      • Hallal H.
      • Castiella A.
      • García-Bengoechea M.
      • Otazua P.
      • et al.
      Recurrent drug-induced liver injury (DILI) with different drugs in the Spanish Registry: the dilemma of the relationship to autoimmune hepatitis.
      It is not currently clear how DIAIH can be reliably distinguished from genuine AIH, based on histology, immunological features, HLA genotype or lack of relapse after discontinuation of corticosteroids. This issue has important implications not only for clinical management but also for drug development.

      Secondary sclerosing cholangitis due to DILI

      Biliary tract changes have been reported after treatment with certain drugs.
      • Dikengil A.
      • Siskind B.N.
      • Morse S.S.
      • Swedlund A.
      • Bober-Sorcinelli K.E.
      • Burrell M.I.
      Sclerosing cholangitis from intraarterial floxuridine.
      • Ludwig J.
      • Kim C.H.
      • Wiesner R.H.
      • Krom R.A.
      Floxuridine-induced sclerosing cholangitis: an ischemic cholangiopathy?.
      • Aldrighetti L.
      • Arru M.
      • Ronzoni M.
      • Salvioni M.
      • Villa E.
      • Ferla G.
      Extrahepatic biliary stenoses after hepatic arterial infusion (HAI) of floxuridine (FUdR) for liver metastases from colorectal cancer.
      • Phongkitkarun S.
      • Kobayashi S.
      • Varavithya V.
      • Huang X.
      • Curley S.A.
      • Chamsangavej C.
      Bile duct complications of hepatic arterial infusion chemotherapy evaluated by helical CT.
      • Sandrasegaran K.
      • Alazmi W.M.
      • Tann M.
      • Fogel E.L.
      • McHenry L.
      • Lehman G.A.
      Chemotherapy-induced sclerosing cholangitis.
      • Schwab G.P.
      • Wetscher G.J.
      • Vogl W.
      • Redmond E.
      Methimazole-induced cholestatic liver injury, mimicking sclerosing cholangitis.
      • Horsley-Silva J.L.
      • Dow E.N.
      • Menias C.O.
      • Smith M.L.
      • Carballido E.M.
      • Lindor K.
      • et al.
      Docetaxel induced sclerosing cholangitis.
      • Seto W.K.
      • Ng M.
      • Chan P.
      • Oi-Lin Ng I.
      • Chi-Wai Cheung S.
      • Fan-Ngai Hung I.
      • et al.
      Ketamine-induced cholangiopathy: a case report.
      • Lo R.S.
      • Krishnamoorthy R.
      • Freeman J.G.
      • Austin A.S.
      Cholestasis and biliary dilatation associated with chronic ketamine abuse: a case series.
      • Turkish A.
      • Luo J.J.
      • Lefkowitch J.H.
      Ketamine abuse, biliary tract disease, and secondary sclerosing cholangitis.
      • Lui K.L.
      • Lee W.K.
      • Li M.K.
      Ketamine-induced cholangiopathy.
      • Knooihuizen S.A.I.
      • Aday A.
      • Lee W.M.
      Ketamine-induced sclerosing cholangitis (KISC) in a critically ill patient with COVID-19.
      The first reports appeared in the 1980s and were mainly seen in patients receiving treatment for liver metastases by intra-arterial infusion of cytotoxic agents such as floxuridine, which suggested a rather local toxic effect of the drug in bile ducts.
      • Dikengil A.
      • Siskind B.N.
      • Morse S.S.
      • Swedlund A.
      • Bober-Sorcinelli K.E.
      • Burrell M.I.
      Sclerosing cholangitis from intraarterial floxuridine.
      • Ludwig J.
      • Kim C.H.
      • Wiesner R.H.
      • Krom R.A.
      Floxuridine-induced sclerosing cholangitis: an ischemic cholangiopathy?.
      • Aldrighetti L.
      • Arru M.
      • Ronzoni M.
      • Salvioni M.
      • Villa E.
      • Ferla G.
      Extrahepatic biliary stenoses after hepatic arterial infusion (HAI) of floxuridine (FUdR) for liver metastases from colorectal cancer.
      • Phongkitkarun S.
      • Kobayashi S.
      • Varavithya V.
      • Huang X.
      • Curley S.A.
      • Chamsangavej C.
      Bile duct complications of hepatic arterial infusion chemotherapy evaluated by helical CT.
      • Sandrasegaran K.
      • Alazmi W.M.
      • Tann M.
      • Fogel E.L.
      • McHenry L.
      • Lehman G.A.
      Chemotherapy-induced sclerosing cholangitis.
      Case reports have also involved systemic therapy for other drugs.
      • Schwab G.P.
      • Wetscher G.J.
      • Vogl W.
      • Redmond E.
      Methimazole-induced cholestatic liver injury, mimicking sclerosing cholangitis.
      ,
      • Horsley-Silva J.L.
      • Dow E.N.
      • Menias C.O.
      • Smith M.L.
      • Carballido E.M.
      • Lindor K.
      • et al.
      Docetaxel induced sclerosing cholangitis.
      An interesting and convincing case report described sclerosing cholangitis in a patient treated with the chemotherapy agent docetaxel.
      • Horsley-Silva J.L.
      • Dow E.N.
      • Menias C.O.
      • Smith M.L.
      • Carballido E.M.
      • Lindor K.
      • et al.
      Docetaxel induced sclerosing cholangitis.
      Elevated liver tests indicative of cholestatic injury prompted imaging, which revealed diffuse intrahepatic biliary dilatation with multifocal narrowing and dilatations of the intrahepatic bile ducts.
      • Horsley-Silva J.L.
      • Dow E.N.
      • Menias C.O.
      • Smith M.L.
      • Carballido E.M.
      • Lindor K.
      • et al.
      Docetaxel induced sclerosing cholangitis.
      Docetaxel was discontinued and liver biopsy showed subacute bile duct obstructive lesions, eosinophilic infiltration, canalicular cholestasis and bile duct stricturing. Five months later, imaging studies were still consistent with secondary sclerosing cholangitis.
      • Horsley-Silva J.L.
      • Dow E.N.
      • Menias C.O.
      • Smith M.L.
      • Carballido E.M.
      • Lindor K.
      • et al.
      Docetaxel induced sclerosing cholangitis.
      The authors speculated that drug-drug interactions had led to increased hepatic accumulation of reactive metabolites in the liver, but docetaxel undergoes extensive hepatic metabolism.
      • Horsley-Silva J.L.
      • Dow E.N.
      • Menias C.O.
      • Smith M.L.
      • Carballido E.M.
      • Lindor K.
      • et al.
      Docetaxel induced sclerosing cholangitis.
      Several reports have shown that ketamine can cause sclerosing cholangitis with diffuse biliary strictures both intra-and extrahepatically, which has mainly been reported in association with abuse of ketamine.
      • Seto W.K.
      • Ng M.
      • Chan P.
      • Oi-Lin Ng I.
      • Chi-Wai Cheung S.
      • Fan-Ngai Hung I.
      • et al.
      Ketamine-induced cholangiopathy: a case report.
      • Lo R.S.
      • Krishnamoorthy R.
      • Freeman J.G.
      • Austin A.S.
      Cholestasis and biliary dilatation associated with chronic ketamine abuse: a case series.
      • Turkish A.
      • Luo J.J.
      • Lefkowitch J.H.
      Ketamine abuse, biliary tract disease, and secondary sclerosing cholangitis.
      • Lui K.L.
      • Lee W.K.
      • Li M.K.
      Ketamine-induced cholangiopathy.
      However, recently ketamine-induced sclerosing cholangitis was reported in a patient with COVID-19 who received ketamine as a sedative in the intensive care unit.
      • Knooihuizen S.A.I.
      • Aday A.
      • Lee W.M.
      Ketamine-induced sclerosing cholangitis (KISC) in a critically ill patient with COVID-19.
      The patient was difficult to sedate and received ketamine for 15 days i.v. and then orally for 5 additional days; the patient developed intrahepatic dilatation and a dilated common bile duct with distal narrowing.
      • Knooihuizen S.A.I.
      • Aday A.
      • Lee W.M.
      Ketamine-induced sclerosing cholangitis (KISC) in a critically ill patient with COVID-19.
      The study by Gudnason et al. was the first investigating bile duct abnormalities in unselected patients with DILI.
      • Gudnason H.O.
      • Björnsson H.K.
      • Gardarsdottir M.
      • Thorisson H.M.
      • Olafsson S.
      • Bergmann O.M.
      • et al.
      Secondary sclerosing cholangitis in patients with drug-induced liver injury.
      The motivation for that study was the development of multiple intrahepatic biliary strictures and strictures in the hilar region in a 40-year-old woman shortly after an operation for a benign oesophageal tumour. This was considered secondary to either sevoflurane or ceftriaxone (Fig. 1A). Follow-up imaging was repeated 3 months later and despite the patient having normal liver tests by this time, cholangiographic features were still abnormal – with biliary strictures (Fig. 1B).
      Figure thumbnail gr1
      Fig. 1Imaging features of varying presentations of DILI.
      (A) MRC in the patient with DILI due to either drug sevoflurane or ceftriaxone. Multiple strictures are shown in the bile ducts. (B) New MRC 3 months later in the same patient still showing strictures. (C) Magnetic resonance imaging in a patient with nitrofurantoin-induced liver injury showing confluent necrosis in both liver lobes. (D) Characteristic hyperdense amiodarone-related liver lesions are shown in a patient with decompensated cirrhosis with ascites. DILI, drug-induced liver injury; MRC, magnetic resonance cholangiography.
      Among 102 patients with DILI, magnetic resonance cholangiopancreatography (MRCP) was performed in 25 as part of the diagnostic work up prior to the diagnosis of DILI; 10/25 (40%) had cholangiographic changes.
      • Gudnason H.O.
      • Björnsson H.K.
      • Gardarsdottir M.
      • Thorisson H.M.
      • Olafsson S.
      • Bergmann O.M.
      • et al.
      Secondary sclerosing cholangitis in patients with drug-induced liver injury.
      A total of 9 out of 10 had biliary strictures and dilatations were observed in the intra- and/or extrahepatic biliary system in 8.
      • Gudnason H.O.
      • Björnsson H.K.
      • Gardarsdottir M.
      • Thorisson H.M.
      • Olafsson S.
      • Bergmann O.M.
      • et al.
      Secondary sclerosing cholangitis in patients with drug-induced liver injury.
      The findings, showing involvement of the common bile duct, are in line with those observed in ketamine-induced secondary sclerosing cholangitis.
      • Seto W.K.
      • Ng M.
      • Chan P.
      • Oi-Lin Ng I.
      • Chi-Wai Cheung S.
      • Fan-Ngai Hung I.
      • et al.
      Ketamine-induced cholangiopathy: a case report.
      • Lo R.S.
      • Krishnamoorthy R.
      • Freeman J.G.
      • Austin A.S.
      Cholestasis and biliary dilatation associated with chronic ketamine abuse: a case series.
      • Turkish A.
      • Luo J.J.
      • Lefkowitch J.H.
      Ketamine abuse, biliary tract disease, and secondary sclerosing cholangitis.
      • Lui K.L.
      • Lee W.K.
      • Li M.K.
      Ketamine-induced cholangiopathy.
      • Knooihuizen S.A.I.
      • Aday A.
      • Lee W.M.
      Ketamine-induced sclerosing cholangitis (KISC) in a critically ill patient with COVID-19.
      Liver histology, available in 4 patients in the study by Gudnason et al. showed mostly canalicular cholestasis as well as portal hepatitis with acute and chronic hepatitis.
      • Gudnason H.O.
      • Björnsson H.K.
      • Gardarsdottir M.
      • Thorisson H.M.
      • Olafsson S.
      • Bergmann O.M.
      • et al.
      Secondary sclerosing cholangitis in patients with drug-induced liver injury.
      The patients with DILI who developed secondary sclerosing cholangitis all had cholestatic liver injury, and more frequently had jaundice and prolonged liver injury in comparison with those who did not have evidence of biliary changes.
      • Gudnason H.O.
      • Björnsson H.K.
      • Gardarsdottir M.
      • Thorisson H.M.
      • Olafsson S.
      • Bergmann O.M.
      • et al.
      Secondary sclerosing cholangitis in patients with drug-induced liver injury.
      Limitations of this study included the fact that only approximately one-quarter of patients had undergone MRCP and follow-up MRCPs were not performed in most patients.
      Cholestatic DILI is the most common type associated with a protracted course of liver injury.
      These results were reproduced by Ahmad et al. from the DILIN prospective cohort study, wherein they detected 4 patients with secondary sclerosing-like abnormalities out of 56 patients (7%) who had been investigated by MRCP.
      • Ahmad J.
      • Rossi S.
      • Rodgers S.K.
      • Ghabril M.
      • Fontana R.J.
      • Stolz A.
      • et al.
      Sclerosing cholangitis like changes on magnetic resonance cholangiography in patients with drug induced liver injury.
      However, the proportion of patients with potential secondary cholangitis might have been underestimated as only a small minority of patients with DILI were investigated with MRCP.
      Immunotherapy, and in particularly immune checkpoint inhibitors, are increasingly being used for the treatment of several types of malignancies.
      • O'Day S.J.
      • Maio M.
      • Chiarion-Sileni V.
      • Gajewski T.F.
      • Pehamberger H.
      • Bondarenko I.N.
      • et al.
      Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study.
      These drugs have revolutionised the treatment of many cancer types, such as advanced malignant melanoma, but are associated with various immune-mediated adverse effects, including liver injury.
      • Larkin J.
      • Chiarion-Sileni V.
      • Gonzalez R.
      • Grob J.J.
      • Cowey C.L.
      • Lao C.D.
      • et al.
      Combined nivolumab and ipilimumab or monotherapy in untreated melanoma.
      Most patients with immune-mediated liver injury due to checkpoint inhibitors present with predominantly hepatocellular injury with histological features of hepatitis.
      • Shah P.
      • Sundaram V.
      • Bjornsson E.S.
      Biologic and checkpoint inhibitor-induced liver injury: a systematic literature review.
      ,
      • Miller E.D.
      • Abu-Sbeih H.
      • Styskel B.
      • Nogueras Gonzalez G.M.
      • Blechacz B.
      • Naing A.
      • et al.
      Clinical characteristics and adverse impact of hepatotoxicity due to immune checkpoint inhibitors.
      However, recently a large number of cases presenting with clinical, biochemical and histological evidence of secondary sclerosing cholangitis have been reported.
      • Doherty G.J.
      • Duckworth A.M.
      • Davies S.E.
      • Mells G.F.
      • Brais R.
      • Harden S.V.
      • et al.
      Severe steroid-resistant anti-PD1 T-cell checkpoint inhibitor-induced hepatotoxicity driven by biliary injury.
      • Gelsomino F.
      • Vitale G.
      • D'Errico A.
      • Bertuzzi C.
      • Andreone P.
      • Ardizzoni A.
      Nivolumab-induced cholangitic liver disease: a novel form of serious liver injury.
      • Kawakami H.
      • Tanizaki J.
      • Tanaka K.
      • Haratani K.
      • Hayashi H.
      • Takeda M.
      • et al.
      Imaging and clinicopathological features of nivolumab-related cholangitis in patients with non-small cell lung cancer.
      • Gelsomino F.
      • Vitale G.
      • Ardizzoni A.
      A case of nivolumab-related cholangitis and literature review: how to look for the right tools for a correct diagnosis of this rare immune-related adverse event.
      • Cho J.H.
      • Sun J.M.
      • Lee S.H.
      • Ahn J.S.
      • Park K.
      • Ahn M.J.
      Late-onset cholecystitis with cholangitis after avelumab treatment in non-small cell lung cancer.
      • Hamoir C.
      • de Vos M.
      • Clinckart F.
      • Nicaise G.
      • Komuta M.
      • Lanthier N.
      Hepatobiliary and pancreatic: nivolumab-related cholangiopathy.
      • Kashima J.
      • Okuma Y.
      • Shimizuguchi R.
      • Chiba K.
      Bile duct obstruction in a patient treated with nivolumab as second-line chemotherapy for advanced non-small-cell lung cancer: a case report.
      • Kuraoka N.
      • Hara K.
      • Terai S.
      • Yatabe Y.
      • Horio Y.
      Peroral cholangioscopy of nivolumab-related (induced) ulcerative cholangitis in a patient with non-small cell lung cancer.
      • Ogawa K.
      • Kamimura K.
      • Terai S.
      Antiprogrammed cell death-1 immunotherapy-related secondary sclerosing cholangitis.
      • Noda-Narita S.
      • Mizuno S.
      • Noguchi S.
      • Watanabe K.
      • Nakai Y.
      • Koike K.
      • et al.
      Development of mild drug-induced sclerosing cholangitis after discontinuation of nivolumab.
      • Kono M.
      • Sakurai T.
      • Okamoto K.
      • Masaki S.
      • Nagai T.
      • Komeda Y.
      • et al.
      Efficacy and safety of chemotherapy following anti-PD1 antibody therapy for gastric cancer: a case of sclerosing cholangitis.
      • Sawada K.
      • Shonaka T.
      • Nishikawa Y.
      • Hasegawa K.
      • Hayashi H.
      • Hasebe T.
      • et al.
      Successful treatment of nivolumab-related cholangitis with prednisolone: a case report and review of the literature.
      • Zen Y.
      • Chen Y.Y.
      • Jeng Y.M.
      • Tsai H.W.
      • Yeh M.M.
      Immune-related adverse reactions in the hepatobiliary system: second-generation check-point inhibitors highlight diverse histological changes.
      • McClure T.
      • Cui W.
      • Asadi K.
      • John T.
      • Testro A.
      Case of nivolumab-induced sclerosing cholangitis: lessons from long-term follow-up.
      • Nabeshima S.
      • Yamasaki M.
      • Matsumoto N.
      • Takaki S.
      • Nishi Y.
      • Kawamoto K.
      • et al.
      Atezolizumab-induced Sclerosing Cholangitis in a patient with lung cancer: a case report.
      In contrast with the most commonly reported hepatitis-like pattern, these patients have a cholestatic pattern of injury, with diffuse biliary duct dilatation and thickening of the bile ducts.
      • Doherty G.J.
      • Duckworth A.M.
      • Davies S.E.
      • Mells G.F.
      • Brais R.
      • Harden S.V.
      • et al.
      Severe steroid-resistant anti-PD1 T-cell checkpoint inhibitor-induced hepatotoxicity driven by biliary injury.
      • Gelsomino F.
      • Vitale G.
      • D'Errico A.
      • Bertuzzi C.
      • Andreone P.
      • Ardizzoni A.
      Nivolumab-induced cholangitic liver disease: a novel form of serious liver injury.
      • Kawakami H.
      • Tanizaki J.
      • Tanaka K.
      • Haratani K.
      • Hayashi H.
      • Takeda M.
      • et al.
      Imaging and clinicopathological features of nivolumab-related cholangitis in patients with non-small cell lung cancer.
      • Gelsomino F.
      • Vitale G.
      • Ardizzoni A.
      A case of nivolumab-related cholangitis and literature review: how to look for the right tools for a correct diagnosis of this rare immune-related adverse event.
      • Cho J.H.
      • Sun J.M.
      • Lee S.H.
      • Ahn J.S.
      • Park K.
      • Ahn M.J.
      Late-onset cholecystitis with cholangitis after avelumab treatment in non-small cell lung cancer.
      • Hamoir C.
      • de Vos M.
      • Clinckart F.
      • Nicaise G.
      • Komuta M.
      • Lanthier N.
      Hepatobiliary and pancreatic: nivolumab-related cholangiopathy.
      • Kashima J.
      • Okuma Y.
      • Shimizuguchi R.
      • Chiba K.
      Bile duct obstruction in a patient treated with nivolumab as second-line chemotherapy for advanced non-small-cell lung cancer: a case report.
      • Kuraoka N.
      • Hara K.
      • Terai S.
      • Yatabe Y.
      • Horio Y.
      Peroral cholangioscopy of nivolumab-related (induced) ulcerative cholangitis in a patient with non-small cell lung cancer.
      • Ogawa K.
      • Kamimura K.
      • Terai S.
      Antiprogrammed cell death-1 immunotherapy-related secondary sclerosing cholangitis.
      • Noda-Narita S.
      • Mizuno S.
      • Noguchi S.
      • Watanabe K.
      • Nakai Y.
      • Koike K.
      • et al.
      Development of mild drug-induced sclerosing cholangitis after discontinuation of nivolumab.
      • Kono M.
      • Sakurai T.
      • Okamoto K.
      • Masaki S.
      • Nagai T.
      • Komeda Y.
      • et al.
      Efficacy and safety of chemotherapy following anti-PD1 antibody therapy for gastric cancer: a case of sclerosing cholangitis.
      • Sawada K.
      • Shonaka T.
      • Nishikawa Y.
      • Hasegawa K.
      • Hayashi H.
      • Hasebe T.
      • et al.
      Successful treatment of nivolumab-related cholangitis with prednisolone: a case report and review of the literature.
      • Zen Y.
      • Chen Y.Y.
      • Jeng Y.M.
      • Tsai H.W.
      • Yeh M.M.
      Immune-related adverse reactions in the hepatobiliary system: second-generation check-point inhibitors highlight diverse histological changes.
      • McClure T.
      • Cui W.
      • Asadi K.
      • John T.
      • Testro A.
      Case of nivolumab-induced sclerosing cholangitis: lessons from long-term follow-up.
      • Nabeshima S.
      • Yamasaki M.
      • Matsumoto N.
      • Takaki S.
      • Nishi Y.
      • Kawamoto K.
      • et al.
      Atezolizumab-induced Sclerosing Cholangitis in a patient with lung cancer: a case report.
      Biliary tract dilatation without biliary obstruction is observed in almost 80% of cases according to a recent review.
      • Onoyama T.
      • Takeda Y.
      • Yamashita T.
      • Hamamoto W.
      • Sakamoto Y.
      • Koda H.
      • et al.
      Programmed cell death-1 inhibitor-related sclerosing cholangitis: a systematic review.
      Furthermore, in 30% of patients, multiple strictures were seen intrahepatically and diffuse hypertrophy was found in the extrahepatic bile ducts in the vast majority of cases (>90%).
      • Onoyama T.
      • Takeda Y.
      • Yamashita T.
      • Hamamoto W.
      • Sakamoto Y.
      • Koda H.
      • et al.
      Programmed cell death-1 inhibitor-related sclerosing cholangitis: a systematic review.
      The long-term consequences of secondary sclerosing cholangitis remain to be established.
      Endoscopic biopsies from the thickening bile ducts have shown lymphocytic infiltration with predominantly CD8+T-cytotoxic cells.
      • Doherty G.J.
      • Duckworth A.M.
      • Davies S.E.
      • Mells G.F.
      • Brais R.
      • Harden S.V.
      • et al.
      Severe steroid-resistant anti-PD1 T-cell checkpoint inhibitor-induced hepatotoxicity driven by biliary injury.
      ,
      • Kawakami H.
      • Tanizaki J.
      • Tanaka K.
      • Haratani K.
      • Hayashi H.
      • Takeda M.
      • et al.
      Imaging and clinicopathological features of nivolumab-related cholangitis in patients with non-small cell lung cancer.
      ,
      • Hamoir C.
      • de Vos M.
      • Clinckart F.
      • Nicaise G.
      • Komuta M.
      • Lanthier N.
      Hepatobiliary and pancreatic: nivolumab-related cholangiopathy.
      • Kashima J.
      • Okuma Y.
      • Shimizuguchi R.
      • Chiba K.
      Bile duct obstruction in a patient treated with nivolumab as second-line chemotherapy for advanced non-small-cell lung cancer: a case report.
      • Kuraoka N.
      • Hara K.
      • Terai S.
      • Yatabe Y.
      • Horio Y.
      Peroral cholangioscopy of nivolumab-related (induced) ulcerative cholangitis in a patient with non-small cell lung cancer.
      • Ogawa K.
      • Kamimura K.
      • Terai S.
      Antiprogrammed cell death-1 immunotherapy-related secondary sclerosing cholangitis.
      ,
      • McClure T.
      • Cui W.
      • Asadi K.
      • John T.
      • Testro A.
      Case of nivolumab-induced sclerosing cholangitis: lessons from long-term follow-up.
      ,
      • Nabeshima S.
      • Yamasaki M.
      • Matsumoto N.
      • Takaki S.
      • Nishi Y.
      • Kawamoto K.
      • et al.
      Atezolizumab-induced Sclerosing Cholangitis in a patient with lung cancer: a case report.
      Thus, accumulating literature on sclerosing cholangitis developing in patients treated with immune checkpoint inhibitors has increased our knowledge of this form of DILI considerably. For the first time since drug-induced secondary sclerosing cholangitis was reported,
      • Dikengil A.
      • Siskind B.N.
      • Morse S.S.
      • Swedlund A.
      • Bober-Sorcinelli K.E.
      • Burrell M.I.
      Sclerosing cholangitis from intraarterial floxuridine.
      • Ludwig J.
      • Kim C.H.
      • Wiesner R.H.
      • Krom R.A.
      Floxuridine-induced sclerosing cholangitis: an ischemic cholangiopathy?.
      • Aldrighetti L.
      • Arru M.
      • Ronzoni M.
      • Salvioni M.
      • Villa E.
      • Ferla G.
      Extrahepatic biliary stenoses after hepatic arterial infusion (HAI) of floxuridine (FUdR) for liver metastases from colorectal cancer.
      • Phongkitkarun S.
      • Kobayashi S.
      • Varavithya V.
      • Huang X.
      • Curley S.A.
      • Chamsangavej C.
      Bile duct complications of hepatic arterial infusion chemotherapy evaluated by helical CT.
      • Sandrasegaran K.
      • Alazmi W.M.
      • Tann M.
      • Fogel E.L.
      • McHenry L.
      • Lehman G.A.
      Chemotherapy-induced sclerosing cholangitis.
      • Schwab G.P.
      • Wetscher G.J.
      • Vogl W.
      • Redmond E.
      Methimazole-induced cholestatic liver injury, mimicking sclerosing cholangitis.
      • Horsley-Silva J.L.
      • Dow E.N.
      • Menias C.O.
      • Smith M.L.
      • Carballido E.M.
      • Lindor K.
      • et al.
      Docetaxel induced sclerosing cholangitis.
      • Seto W.K.
      • Ng M.
      • Chan P.
      • Oi-Lin Ng I.
      • Chi-Wai Cheung S.
      • Fan-Ngai Hung I.
      • et al.
      Ketamine-induced cholangiopathy: a case report.
      • Lo R.S.
      • Krishnamoorthy R.
      • Freeman J.G.
      • Austin A.S.
      Cholestasis and biliary dilatation associated with chronic ketamine abuse: a case series.
      • Turkish A.
      • Luo J.J.
      • Lefkowitch J.H.
      Ketamine abuse, biliary tract disease, and secondary sclerosing cholangitis.
      • Lui K.L.
      • Lee W.K.
      • Li M.K.
      Ketamine-induced cholangiopathy.
      • Knooihuizen S.A.I.
      • Aday A.
      • Lee W.M.
      Ketamine-induced sclerosing cholangitis (KISC) in a critically ill patient with COVID-19.
      • Gudnason H.O.
      • Björnsson H.K.
      • Gardarsdottir M.
      • Thorisson H.M.
      • Olafsson S.
      • Bergmann O.M.
      • et al.
      Secondary sclerosing cholangitis in patients with drug-induced liver injury.
      • Ahmad J.
      • Rossi S.
      • Rodgers S.K.
      • Ghabril M.
      • Fontana R.J.
      • Stolz A.
      • et al.
      Sclerosing cholangitis like changes on magnetic resonance cholangiography in patients with drug induced liver injury.
      biliary tract histology has been available and has almost invariably demonstrated infiltration of cytotoxic T CD8+ lymphocytes, suggesting that an alteration in the balance between effector and regulatory T cells is associated with immune-mediated hepatobiliary injury. There is no standard treatment for this adverse reaction and although corticosteroids have frequently been tried, a recent systematic review reported a mean response rate of only around 11.5%.
      • Onoyama T.
      • Takeda Y.
      • Yamashita T.
      • Hamamoto W.
      • Sakamoto Y.
      • Koda H.
      • et al.
      Programmed cell death-1 inhibitor-related sclerosing cholangitis: a systematic review.
      Since the prognosis of patients with advanced cancer is generally dismal it is unlikely that the natural history of immune checkpoint inhibitor-associated sclerosing cholangitis can be established.

      Vanishing bile duct syndrome associated with drug therapy

      As stated above, in general, persistence of biochemical abnormalities is more common in cholestatic liver injury than in mixed or hepatocellular injury.
      • Björnsson E.
      • Davidsdottir L.
      The long-term follow-up after idiosyncratic drug-induced liver injury with jaundice.
      ,
      • Fontana R.J.
      • Hayashi P.H.
      • Barnhart H.
      • Kleiner D.E.
      • Reddy K.R.
      • Chalasani N.
      • et al.
      Persistent liver biochemistry abnormalities are more common in older patients and those with cholestatic drug induced liver injury.
      That said, the vast majority of patients with cholestatic DILI will recover completely within 12 months or more.
      • Fontana R.J.
      • Hayashi P.H.
      • Barnhart H.
      • Kleiner D.E.
      • Reddy K.R.
      • Chalasani N.
      • et al.
      Persistent liver biochemistry abnormalities are more common in older patients and those with cholestatic drug induced liver injury.
      However, recovery can be very slow, particularly if there is severe destruction, loss and disappearance of bile ducts, which has been referred to as vanishing bile duct syndrome (VBDS).
      • Ludwig J.
      Idiopathic adulthood ductopenia: an update.
      ,
      • Degott C.
      • Feldmann G.
      • Larrey D.
      • Durand-Schneider A.M.
      • Grange D.
      • Machayekhi J.P.
      • et al.
      Drug-induced prolonged cholestasis in adults: a histological semiquantitative study demonstrating progressive ductopenia.
      The definition of ductopenia has been put forward as a loss of biliary (interlobular) ducts which are seen in less than 50% of portal tracts.
      • Ludwig J.
      • Wiesner R.H.
      • LaRusso N.F.
      Idiopathic adulthood ductopenia. A cause of chronic cholestatic liver disease and biliary cirrhosis.
      VBDS has mainly been reported in patients with jaundice and prolonged cholestasis for months or years.
      • Desmet V.
      Vanishing bile duct syndrome in drug-induced liver disease.
      • Olsson R.
      • Wiholm B.E.
      • Sand C.
      • Hultcrantz R.
      • Myrhed M.
      Liver damage from flucloxacillin, cloxacillin and dicloxacillin.
      • Forbes G.M.
      • Jeffrey G.P.
      • Shilkin K.B.
      • Reed W.D.
      Carbamazepine hepatotoxicity: another cause of the vanishing bile duct syndrome.
      • Moradpour D.
      • Altorfer J.
      • Flury R.
      • Greminger P.
      • Meyenberger C.
      • Jost R.
      • et al.
      Chlorpromazine-induced vanishing bile duct syndrome leading to biliary cirrhosis.
      • Davies M.H.
      • Harrison R.F.
      • Elias E.
      • Hübscher S.G.
      Antibiotic-associated acute vanishing bile duct syndrome: a pattern associated with severe, prolonged, intrahepatic cholestasis.
      Some of these patients developed biliary cirrhosis, which can lead to the requirement for a liver transplantation or death.
      • Olsson R.
      • Wiholm B.E.
      • Sand C.
      • Hultcrantz R.
      • Myrhed M.
      Liver damage from flucloxacillin, cloxacillin and dicloxacillin.
      ,
      • Moradpour D.
      • Altorfer J.
      • Flury R.
      • Greminger P.
      • Meyenberger C.
      • Jost R.
      • et al.
      Chlorpromazine-induced vanishing bile duct syndrome leading to biliary cirrhosis.
      ,
      • Ishii M.
      • Miyasaki Y.
      • Yamamoto T.
      • Miura M.
      • Ueno Y.
      • Takahashi T.
      • et al.
      A case of drug-induced ductopenia resulting in fatal biliary cirrhosis.
      However, the reversibility of VBDS has also been described.
      • Ramos A.M.
      • Gayotto L.C.
      • Clemente C.M.
      • Mello E.S.
      • Luz K.G.
      • Freitas M.L.
      Reversible vanishing bile duct syndrome induced by carbamazepine.
      ,
      • Vuppalanchi R.
      • Chalasani N.
      • Saxena R.
      Restoration of bile ducts in drug-induced vanishing bile duct syndrome due to zonisamide.
      Long-term sequelae of DILI include cirrhosis, autoimmune-like hepatitis, secondary sclerosing cholangitis, sinusoidal obstruction syndrome and vanishing bile duct syndrome.
      Bonkovski et al. recently reported on patients with DILI who were found to have bile duct loss (from the DILIN cohort).
      • Bonkovsky H.L.
      • Kleiner D.
      • Gu J.
      • Odin J.
      • Russo M.
      • Navarro V.
      • et al.
      Clinical presentation and outcomes of bile duct loss caused by drugs and dietary supplements.
      In the first 10 years, of approximately 1,050 patients, 34% had a liver biopsy of whom 7% (n = 26) had bile duct loss. A total of 14/26 (54%) had severe bile duct loss (<50% of portal areas with bile ducts) whereas the rest had mild bile duct loss. Jaundice was present in 96% (all but one) of the patients with VBDS, whereas 70% of the total DILIN cohort had jaundice. Similarly, almost 80% of these patients had itching in comparison to 54% in the total cohort.
      • Bonkovsky H.L.
      • Kleiner D.
      • Gu J.
      • Odin J.
      • Russo M.
      • Navarro V.
      • et al.
      Clinical presentation and outcomes of bile duct loss caused by drugs and dietary supplements.
      Interestingly, the hepatic activity index was not significantly different between patients with and without bile duct loss and the most common histological pattern demonstrated relatively mild inflammation. There was a trend toward less inflammation in patients with unfavourable outcomes vs. those with favourable outcomes. Of major importance was the observation that bile ducts were present in only 17% of portal areas in the biopsies of patients with poor outcome but in 64% of portal areas in those with better outcome. The only predictor of poor outcome was degree of bile duct loss on biopsy.
      In general, the prognosis of patients with bile duct loss was unfavourable. Overall, a liver-related mortality rate of 19% was observed in patients with bile duct loss compared to overall mortality of 6.2% (half of which was liver related) in 899 patients with DILI.
      • Bonkovsky H.L.
      • Kleiner D.
      • Gu J.
      • Odin J.
      • Russo M.
      • Navarro V.
      • et al.
      Clinical presentation and outcomes of bile duct loss caused by drugs and dietary supplements.
      Overall, 2/26 (8%) required liver transplantation compared to only 4% in the total DILIN cohort. Elevated liver tests at 6 months of follow-up were found in 94% of the patients with bile duct loss compared to 47% of patients known to have other histological patterns. Although the prognosis of most patients with liver injury due to checkpoint inhibitors is favourable, fatal cholestatic injury characterised by bile duct injury and VBDS was reported in a patient who still had a tumour response.
      • Thorsteinsdottir T.
      • Loitegard T.
      • Reims H.M.
      • Porojnicu A.C.
      Fatal cholestatic liver injury during treatment with PD1 immune checkpoint inhibitor for malignant melanoma.
      Another case of VBDS due to checkpoint inhibitors has also been reported.
      • Doherty G.J.
      • Duckworth A.M.
      • Davies S.E.
      • Mells G.F.
      • Brais R.
      • Harden S.V.
      • et al.
      Severe steroid-resistant anti-PD1 T-cell checkpoint inhibitor-induced hepatotoxicity driven by biliary injury.

      Cirrhosis and other structural hepatic changes induced by DILI

      Although probably very rare, biliary cirrhosis can develop in patients who have experienced severe and prolonged cholestatic injury.
      • Olsson R.
      • Wiholm B.E.
      • Sand C.
      • Hultcrantz R.
      • Myrhed M.
      Liver damage from flucloxacillin, cloxacillin and dicloxacillin.
      ,
      • Moradpour D.
      • Altorfer J.
      • Flury R.
      • Greminger P.
      • Meyenberger C.
      • Jost R.
      • et al.
      Chlorpromazine-induced vanishing bile duct syndrome leading to biliary cirrhosis.
      ,
      • Ishii M.
      • Miyasaki Y.
      • Yamamoto T.
      • Miura M.
      • Ueno Y.
      • Takahashi T.
      • et al.
      A case of drug-induced ductopenia resulting in fatal biliary cirrhosis.
      ,
      • Droste H.T.
      • de Vries R.A.
      Chronic hepatitis caused by lisinopril.
      Liver fibrosis and the development of cirrhosis are well-documented adverse effects of methotrexate.
      • Whiting-O'Keefe Q.E.
      • Fye K.H.
      • Sack K.D.
      Methotrexate and histologic hepatic abnormalities: a meta-analysis.
      In the past, regular liver biopsies were recommended in patients who used methotrexate long-term. It is unclear what proportion of patients under methotrexate therapy might develop severe liver fibrosis or cirrhosis, as the published range is wide (0–26%).
      • Aithal G.
      Hepatotoxicity related to methotrexate.
      This wide range might be partly attributable to sampling error associated with the use of liver histology to illustrate fibrosis and cirrhosis, which most of the previous studies relied on.
      • Dawwas M.F.
      • Aithal G.P.
      End-stage methotrexate-related liver disease is rare and associated with features of the metabolic syndrome.
      Decompensated liver disease from methotrexate seems very rare.
      • Dawwas M.F.
      • Aithal G.P.
      End-stage methotrexate-related liver disease is rare and associated with features of the metabolic syndrome.
      Among approximately 159,000 patients listed for liver transplantation in the US, from 1987-2011, only 117 (0.07%) had methotrexate-induced liver injury.
      • Dawwas M.F.
      • Aithal G.P.
      End-stage methotrexate-related liver disease is rare and associated with features of the metabolic syndrome.
      Compared to patients with other causes of end-stage liver disease, those with methotrexate-induced injury were more likely to have features of the metabolic syndrome, similar to patients with NASH.
      • Dawwas M.F.
      • Aithal G.P.
      End-stage methotrexate-related liver disease is rare and associated with features of the metabolic syndrome.
      Other studies have also found diabetes mellitus and obesity to be risk factors for methotrexate-induced liver injury.
      • Malatjalian D.A.
      • Ross J.B.
      • Williams C.N.
      • Colwell S.J.
      • Eastwood B.J.
      Methotrexate hepatotoxicity in psoriatics: report of 104 patients from Nova Scotia, with analysis of risks from obesity, diabetes and alcohol consumption during long term follow-up.
      ,
      • Rosenberg P.
      • Urwitz H.
      • Johannesson A.
      • Lindholm J.
      • Kinnman N.
      • Hultcrantz R.
      Psoriasis patients with diabetes type 2 are at high risk of developing liver fibrosis during methotrexate treatment.
      A number of other drugs that cause DILI have been associated with the development of cirrhosis.
      • Stricker B.H.
      • Blok A.P.
      • Claas F.H.
      • Van Parys G.E.
      • Desmet V.J.
      Hepatic injury associated with the use of nitrofurans: a clinicopathological study of 52 reported cases.
      ,
      • Black M.
      • Mitchell J.R.
      • Zimmerman H.J.
      • Ishak K.G.
      • Epler G.R.
      Isoniazid-associated hepatitis in 114 patients.
      • Utili R.
      • Boitnott J.K.
      • Zimmerman H.J.
      Dantrolene-associated hepatic injury. Incidence and character.
      • Sharp J.R.
      • Ishak K.G.
      • Zimmerman H.J.
      Chronic active hepatitis and severe hepatic necrosis associated with nitrofurantoin.
      • Arranto A.J.
      • Sotaniemi E.A.
      Histologic follow-up of alpha-methyldopa-induced liver injury.
      • Kronborg I.J.
      • Evans D.T.
      • Mackay I.R.
      • Bhathal P.S.
      Chronic hepatitis after successive halothane anesthetics.
      • Guigui B.
      • Perrot S.
      • Berry J.P.
      • Fleury-Feith J.
      • Martin N.
      • Métreau J.M.
      • et al.
      Amiodarone-induced hepatic phospholipidosis: a morphological alteration independent of pseudoalcoholic liver disease.
      • Lewis J.H.
      • Ranard R.C.
      • Caruso A.
      • Jackson L.K.
      • Mullick F.
      • Ishak K.G.
      • et al.
      Amiodarone hepatotoxicity: prevalence and clinicopathologic correlations among 104 patients.
      • Mazeika P.K.
      • Ford M.J.
      Chronic active hepatitis associated with diclofenac sodium therapy.
      • Eckstein R.P.
      • Dowsett J.F.
      • Lunzer M.R.
      Flucloxacillin induced liver disease: histopathological findings at biopsy and autopsy.
      • Chatrenet P.
      • Regimbeau C.
      • Ramain J.P.
      • Penot J.
      • Bruandet P.
      [Chronic active cirrhogenic hepatitis induced by fenofibrate].
      • Pineda J.A.
      • Larrauri J.
      • Macias J.
      • Hernández A.
      • Guijarro J.
      • Sayago M.
      • et al.
      Rapid progression to liver cirrhosis of toxic hepatitis due to ebrotidine.
      • Jeserich M.
      • Ihling C.
      • Allgaier H.P.
      • Berg P.A.
      • Heilmann C.
      Acute liver failure due to enalapril.
      • Anania F.A.
      • Rabin L.
      Terbinafine hepatotoxicity resulting in chronic biliary-ductopenia and portal fibrosis.
      • Yeung E.
      • Wong F.S.
      • Wanless I.R.
      • Shiota K.
      • Guindi M.
      • Joshi S.
      • et al.
      Ramipril-associated hepatotoxicity.
      • Volbeda F.
      • Jonker A.M.
      • Vecht J.
      • Groeneveld P.H.
      [Liver cirrhosis due to chronic use of nitrofurantoin].
      • Oikawa H.
      • Maesawa C.
      • Sato R.
      • Oikawa K.
      • Yamada H.
      • Oriso S.
      • et al.
      Liver cirrhosis induced by long-term administration of a daily low dose of amiodarone: a case report.
      • de Boer N.K.H.
      • Mulder C.J.J.
      • van Bodegraven A.A.
      Myelotoxicity and hepatotoxicity during azathioprine therapy.
      The most well documented are perhaps nitrofurantoin
      • Stricker B.H.
      • Blok A.P.
      • Claas F.H.
      • Van Parys G.E.
      • Desmet V.J.
      Hepatic injury associated with the use of nitrofurans: a clinicopathological study of 52 reported cases.
      ,
      • Sharp J.R.
      • Ishak K.G.
      • Zimmerman H.J.
      Chronic active hepatitis and severe hepatic necrosis associated with nitrofurantoin.
      and amiodarone.
      • Guigui B.
      • Perrot S.
      • Berry J.P.
      • Fleury-Feith J.
      • Martin N.
      • Métreau J.M.
      • et al.
      Amiodarone-induced hepatic phospholipidosis: a morphological alteration independent of pseudoalcoholic liver disease.
      ,
      • Lewis J.H.
      • Ranard R.C.
      • Caruso A.
      • Jackson L.K.
      • Mullick F.
      • Ishak K.G.
      • et al.
      Amiodarone hepatotoxicity: prevalence and clinicopathologic correlations among 104 patients.
      ,
      • Volbeda F.
      • Jonker A.M.
      • Vecht J.
      • Groeneveld P.H.
      [Liver cirrhosis due to chronic use of nitrofurantoin].
      The hepatotoxicity of nitrofurantoin (category A) is well documented, with more than 100 cases reported.
      • Björnsson E.S.
      • Hoofnagle J.H.
      Categorization of drugs implicated in causing liver injury: critical assessment based upon published case reports.
      The clinical, biochemical and histological phenotype of DILI due to nitrofurantoin is very variable, including acute idiosyncratic DILI, DIAIH and cirrhosis.
      • Mazeika P.K.
      • Ford M.J.
      Chronic active hepatitis associated with diclofenac sodium therapy.
      ,
      • Eckstein R.P.
      • Dowsett J.F.
      • Lunzer M.R.
      Flucloxacillin induced liver disease: histopathological findings at biopsy and autopsy.
      ,
      • de Boer N.K.H.
      • Mulder C.J.J.
      • van Bodegraven A.A.
      Myelotoxicity and hepatotoxicity during azathioprine therapy.
      ,
      • Björnsson E.S.
      • Bergmann O.M.
      • Bjornsson H.K.
      • Kvaran R.B.
      • Olafsson S.
      Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland.
      ,
      DeLeve
      Liver sinusoidal endothelial cells and liver injury.
      Interestingly, a peculiar form of nitrofurantoin-induced liver injury has been described on imaging, with confluent fibrosis and liver atrophy (Fig. 1C). Among patients with DIAIH, mainly induced by nitrofurantoin and minocycline, this type of hepatic finding on radiological imaging was only found in those with nitrofurantoin-induced injury.
      • Björnsson E.
      • Talwalkar J.
      • Treeprasertsuk S.
      • Kamath P.S.
      • Takahashi N.
      • Sanderson S.
      • et al.
      Drug-induced autoimmune hepatitis: clinical characteristics and prognosis.
      Most patients who developed cirrhosis due to amiodarone were on treatment for several years.
      • Guigui B.
      • Perrot S.
      • Berry J.P.
      • Fleury-Feith J.
      • Martin N.
      • Métreau J.M.
      • et al.
      Amiodarone-induced hepatic phospholipidosis: a morphological alteration independent of pseudoalcoholic liver disease.
      ,
      • Lewis J.H.
      • Ranard R.C.
      • Caruso A.
      • Jackson L.K.
      • Mullick F.
      • Ishak K.G.
      • et al.
      Amiodarone hepatotoxicity: prevalence and clinicopathologic correlations among 104 patients.
      ,
      • Volbeda F.
      • Jonker A.M.
      • Vecht J.
      • Groeneveld P.H.
      [Liver cirrhosis due to chronic use of nitrofurantoin].
      These patients present with decompensated cirrhosis and despite discontinuation of the drug they do not always recover from their liver disease.
      • Richer M.
      • Robert S.
      Fatal hepatotoxicity following oral administration of amiodarone.
      The characteristic hyperdense amiodarone-related liver lesion is illustrated in Fig. 1D, in a patient with decompensated cirrhosis treated with the compound for 3 years. Reports have also appeared on the rapid progression of cirrhosis in patients treated with ebrotidine, which was removed from the market due to this adverse effect.
      • Andrade R.J.
      • Lucena M.I.
      • Kaplowitz N.
      • García-Muņoz B.
      • Borraz Y.
      • Pachkoria K.
      • et al.
      Outcome of acute idiosyncratic drug-induced liver injury: long-term follow-up in a hepatotoxicity registry.
      ,
      • Pineda J.A.
      • Larrauri J.
      • Macias J.
      • Hernández A.
      • Guijarro J.
      • Sayago M.
      • et al.
      Rapid progression to liver cirrhosis of toxic hepatitis due to ebrotidine.
      Although cirrhosis may be the final stage of most chronic DILI phenotypes, the natural history of chronic liver disease related to DILI remains to be characterised in prospective studies.
      In the prospective study from the Spanish DILI Registry on chronic liver disease, 7 out of 16 (63%) patients in whom a liver biopsy was performed had cirrhosis. Drugs related to cirrhosis were varied and included atorvastatin, bentazepam, ebrotidine, clopidogrel/atorvastatin, amoxicillin-clavulanate/ibuprofen and ranitidine, which caused at the initial episode indistinctly hepatocellular and cholestatic patterns of damage.
      • Medina-Caliz I.
      • Robles-Diaz M.
      • Garcia-Muñoz B.
      • Stephens C.
      • Ortega-Alonso A.
      • Garcia-Cortes M.
      • et al.
      Definition and risk factors for chronicity following acute idiosyncratic drug-induced liver injury.
      Drugs that have been reported to be implicated in long-term sequelae after DILI are listed in Table 2, with corresponding references.
      Table 2Several drugs that have been reported to lead to long-term sequelae.
      Chronic DILICirrhosisVBDSDIAIHSecondary sclerosing cholangitis
      NitrofurantoinYes
      • Aithal P.
      • Day C.
      The natural history of histologically proved drug induced liver disease.
      ,
      • Björnsson E.
      • Kalaitzakis E.
      • Av Klinteberg V.
      • Alem N.
      • Olsson R.
      Long-term follow-up in patients with mild to moderate drug-induced liver injury.
      ,
      • Chalasani N.
      • Fontana R.J.
      • Bonkovsky H.L.
      • Watkins P.B.
      • Davern T.
      • Serrano J.
      • et al.
      Causes, clinical features, and outcomes from a prospective study of drug induced liver injury in the United States.
      Yes
      • Volbeda F.
      • Jonker A.M.
      • Vecht J.
      • Groeneveld P.H.
      [Liver cirrhosis due to chronic use of nitrofurantoin].
      NoYes
      • de Boer Y.S.
      • Kosinski A.S.
      • Urban T.J.
      • Zhao Z.
      • Long N.
      • Chalasani N.
      • et al.
      Features of autoimmune hepatitis in patients with drug- induced liver injury.
      ,
      • Björnsson E.
      • Talwalkar J.
      • Treeprasertsuk S.
      • Kamath P.S.
      • Takahashi N.
      • Sanderson S.
      • et al.
      Drug-induced autoimmune hepatitis: clinical characteristics and prognosis.
      No
      MinocyclineYes
      • Aithal P.
      • Day C.
      The natural history of histologically proved drug induced liver disease.
      NoNoYes
      • de Boer Y.S.
      • Kosinski A.S.
      • Urban T.J.
      • Zhao Z.
      • Long N.
      • Chalasani N.
      • et al.
      Features of autoimmune hepatitis in patients with drug- induced liver injury.
      ,
      • Björnsson E.
      • Talwalkar J.
      • Treeprasertsuk S.
      • Kamath P.S.
      • Takahashi N.
      • Sanderson S.
      • et al.
      Drug-induced autoimmune hepatitis: clinical characteristics and prognosis.
      No
      MethyldopaYes
      • Aithal P.
      • Day C.
      The natural history of histologically proved drug induced liver disease.
      NoNoYes
      • de Boer Y.S.
      • Kosinski A.S.
      • Urban T.J.
      • Zhao Z.
      • Long N.
      • Chalasani N.
      • et al.
      Features of autoimmune hepatitis in patients with drug- induced liver injury.
      ,
      • Björnsson E.
      • Talwalkar J.
      • Treeprasertsuk S.
      • Kamath P.S.
      • Takahashi N.
      • Sanderson S.
      • et al.
      Drug-induced autoimmune hepatitis: clinical characteristics and prognosis.
      No
      Amoxicillin-ClavulanateYes
      • Aithal P.
      • Day C.
      The natural history of histologically proved drug induced liver disease.
      ,
      • Andrade R.J.
      • Lucena M.I.
      • Kaplowitz N.
      • García-Muņoz B.
      • Borraz Y.
      • Pachkoria K.
      • et al.
      Outcome of acute idiosyncratic drug-induced liver injury: long-term follow-up in a hepatotoxicity registry.
      ,
      • Chalasani N.
      • Fontana R.J.
      • Bonkovsky H.L.
      • Watkins P.B.
      • Davern T.
      • Serrano J.
      • et al.
      Causes, clinical features, and outcomes from a prospective study of drug induced liver injury in the United States.
      ,
      • Fontana R.J.
      • Hayashi P.H.
      • Barnhart H.
      • Kleiner D.E.
      • Reddy K.R.
      • Chalasani N.
      • et al.
      Persistent liver biochemistry abnormalities are more common in older patients and those with cholestatic drug induced liver injury.
      ,
      • Medina-Caliz I.
      • Robles-Diaz M.
      • Garcia-Muñoz B.
      • Stephens C.
      • Ortega-Alonso A.
      • Garcia-Cortes M.
      • et al.
      Definition and risk factors for chronicity following acute idiosyncratic drug-induced liver injury.
      NoYes
      • Bonkovsky H.L.
      • Kleiner D.
      • Gu J.
      • Odin J.
      • Russo M.
      • Navarro V.
      • et al.
      Clinical presentation and outcomes of bile duct loss caused by drugs and dietary supplements.
      NoYes
      • Gudnason H.O.
      • Björnsson H.K.
      • Gardarsdottir M.
      • Thorisson H.M.
      • Olafsson S.
      • Bergmann O.M.
      • et al.
      Secondary sclerosing cholangitis in patients with drug-induced liver injury.
      FlucloxacillinYes
      • Aithal P.
      • Day C.
      The natural history of histologically proved drug induced liver disease.
      ,
      • Björnsson E.
      • Davidsdottir L.
      The long-term follow-up after idiosyncratic drug-induced liver injury with jaundice.
      ,
      • Olsson R.
      • Wiholm B.E.
      • Sand C.
      • Hultcrantz R.
      • Myrhed M.
      Liver damage from flucloxacillin, cloxacillin and dicloxacillin.
      ,
      • Davies M.H.
      • Harrison R.F.
      • Elias E.
      • Hübscher S.G.
      Antibiotic-associated acute vanishing bile duct syndrome: a pattern associated with severe, prolonged, intrahepatic cholestasis.
      Yes
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      • Wiholm B.E.
      • Sand C.
      • Hultcrantz R.
      • Myrhed M.
      Liver damage from flucloxacillin, cloxacillin and dicloxacillin.
      ,
      • Davies M.H.
      • Harrison R.F.
      • Elias E.
      • Hübscher S.G.
      Antibiotic-associated acute vanishing bile duct syndrome: a pattern associated with severe, prolonged, intrahepatic cholestasis.
      Yes
      • Olsson R.
      • Wiholm B.E.
      • Sand C.
      • Hultcrantz R.
      • Myrhed M.
      Liver damage from flucloxacillin, cloxacillin and dicloxacillin.
      ,
      • Davies M.H.
      • Harrison R.F.
      • Elias E.
      • Hübscher S.G.
      Antibiotic-associated acute vanishing bile duct syndrome: a pattern associated with severe, prolonged, intrahepatic cholestasis.
      NoNo
      AtorvastatinYes
      • Andrade R.J.
      • Lucena M.I.
      • Kaplowitz N.
      • García-Muņoz B.
      • Borraz Y.
      • Pachkoria K.
      • et al.
      Outcome of acute idiosyncratic drug-induced liver injury: long-term follow-up in a hepatotoxicity registry.
      ,
      • Medina-Caliz I.
      • Robles-Diaz M.
      • Garcia-Muñoz B.
      • Stephens C.
      • Ortega-Alonso A.
      • Garcia-Cortes M.
      • et al.
      Definition and risk factors for chronicity following acute idiosyncratic drug-induced liver injury.
      Yes
      • Medina-Caliz I.
      • Robles-Diaz M.
      • Garcia-Muñoz B.
      • Stephens C.
      • Ortega-Alonso A.
      • Garcia-Cortes M.
      • et al.
      Definition and risk factors for chronicity following acute idiosyncratic drug-induced liver injury.
      NoYes
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      • Kaplowitz N.
      • Hallal H.
      • Castiella A.
      • García-Bengoechea M.
      • Otazua P.
      • et al.
      Recurrent drug-induced liver injury (DILI) with different drugs in the Spanish Registry: the dilemma of the relationship to autoimmune hepatitis.
      Yes
      • Gudnason H.O.
      • Björnsson H.K.
      • Gardarsdottir M.
      • Thorisson H.M.
      • Olafsson S.
      • Bergmann O.M.
      • et al.
      Secondary sclerosing cholangitis in patients with drug-induced liver injury.
      ,
      • Ahmad J.
      • Rossi S.
      • Rodgers S.K.
      • Ghabril M.
      • Fontana R.J.
      • Stolz A.
      • et al.
      Sclerosing cholangitis like changes on magnetic resonance cholangiography in patients with drug induced liver injury.
      AzithromycinYes
      • Chalasani N.
      • Bonkovsky H.L.
      • Fontana R.J.
      • Lee W.
      • Stolz A.
      • Talwalkar J.
      • et al.
      Features and outcomes of 899 patients with drug-induced liver injury: the DILIN prospective study.
      NoYes
      • Bonkovsky H.L.
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      • Odin J.
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      • et al.
      Clinical presentation and outcomes of bile duct loss caused by drugs and dietary supplements.
      NoNo
      AmiodaroneYes
      • Björnsson E.
      • Kalaitzakis E.
      • Av Klinteberg V.
      • Alem N.
      • Olsson R.
      Long-term follow-up in patients with mild to moderate drug-induced liver injury.
      ,
      • Chalasani N.
      • Bonkovsky H.L.
      • Fontana R.J.
      • Lee W.
      • Stolz A.
      • Talwalkar J.
      • et al.
      Features and outcomes of 899 patients with drug-induced liver injury: the DILIN prospective study.
      Yes
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      • et al.
      Amiodarone-induced hepatic phospholipidosis: a morphological alteration independent of pseudoalcoholic liver disease.
      ,
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      Amiodarone hepatotoxicity: prevalence and clinicopathologic correlations among 104 patients.
      NoNoYes
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      • Thorisson H.M.
      • Olafsson S.
      • Bergmann O.M.
      • et al.
      Secondary sclerosing cholangitis in patients with drug-induced liver injury.
      InfliximabNoNoYes
      • Bonkovsky H.L.
      • Kleiner D.
      • Gu J.
      • Odin J.
      • Russo M.
      • Navarro V.
      • et al.
      Clinical presentation and outcomes of bile duct loss caused by drugs and dietary supplements.
      Yes
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      • Gunnarsson B.I.
      • Gröndal G.
      • Jonasson J.G.
      • Einarsdottir R.
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      • et al.
      The risk of drug-induced liver injury from Tumor Necrosis Factor (TNF)-alpha-antagonists.
      Yes
      • Gudnason H.O.
      • Björnsson H.K.
      • Gardarsdottir M.
      • Thorisson H.M.
      • Olafsson S.
      • Bergmann O.M.
      • et al.
      Secondary sclerosing cholangitis in patients with drug-induced liver injury.
      NivolumabNoNoNoNoYes
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      Successful treatment of nivolumab-related cholangitis with prednisolone: a case report and review of the literature.
      DIAIH, drug-induced autoimmune hepatitis; VBDS, vanishing bile duct syndrome.

      Vascular syndromes associated with drugs

      In addition to hepatocytes, liver sinusoidal endothelial cells can, occasionally, be the target of hepatotoxic reactions to drugs and other xenobiotics. Drug-induced vascular injury can affect different vascular structures of the liver, from the small portal veins to the large hepatic veins and hence, the clinical syndromes are variable. Furthermore, several drugs can cause different types of vascular lesions and sinusoidal injury can even manifest as different liver lesions in the same individual, supporting the concept that there is a spectrum of responses to a common insult. These include sinusoidal obstruction syndrome (SOS), nodular regenerative hyperplasia (NRH), which is caused by impaired perfusion in parts of the liver leading to atrophy or hepatocyte apoptosis and to reactive hyperplasia in areas of the liver with preserved perfusion, and peliosis hepatis, which is characterised by the formation of blood-filled cysts as a result of increasing sinusoidal dilatation and SOS.
      DeLeve
      Liver sinusoidal endothelial cells and liver injury.
      Sinusoidal injury is sometimes difficult to recognise in liver biopsies, particularly when there is secondary haemorrhage and necrosis of neighbouring hepatocytes. Indeed, hepatocyte function and survival can also be secondarily affected by vascular injury.
      • Gasmi B.
      • Kleiner D.E.
      Liver histology: diagnostic and prognostic features.
      Sinusoidal obstruction syndrome formerly known as hepatic veno-occlusive disease
      • DeLeve L.D.
      • Shulman H.M.
      • McDonald G.B.
      Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease).
      represents a variety of toxic vascular liver injuries most frequently resulting in irreversible chronic liver disease, portal hypertension and its complications, even though an acute phase with transition to chronicity cannot be documented in many instances. The syndrome was first described a century ago in association with the intake of herbs containing pyrolidizidine alkaloids, which are present predominantly in Crotalaria, Heliotropium, Senecio and Symphytum (Comfrey) species,
      • Seff L.
      • Stickel F.
      • Navarro V.J.
      Hepatotoxicity of herbal and dietary supplements.
      ,
      • Larrey D.
      • Faure S.
      Herbal medicine hepatotoxicity: a new step with development of specific biomarkers.
      and since then many case reports and case series have been published worldwide accounting for an estimate of more than 8,000 cases annually, making herbal hepatotoxicity one of the most common causes of SOS.
      European Association for the Study of the Liver
      EASL clinical practice guidelines: drug-induced liver injury.
      Sinusoidal obstruction syndrome has also been reported as a complication of the cyclophosphamide-containing myeloablative regimens used in preparation for bone marrow transplantation
      • Berk P.D.
      • Popper H.
      • Krueger G.R.
      • Decter J.
      • Herzig G.
      • Graw Jr., R.G.
      Veno-occlusive disease of the liver after allogeneic bone marrow transplantation: possible association with graft-versus-host disease.
      but also in all types of stem cell transplantation irrespective of the stem cell source, type of conditioning therapy or underlying disease.
      • Kumar S.
      • DeLeve L.D.
      • Kamath P.S.
      • Tefferi A.
      Hepatic veno-occlusive disease (sinusoidal obstruction syndrome) after hematopoietic stem cell transplantation.
      A number of other drugs have been associated with SOS including long-term use of thiopurines, such as azathioprine, mercaptopurine and thioguanine, dacarbazine, and gemtuzumab.
      LiverTox
      Clinical and Research Information on Drug-Induced Liver Injury.
      Clinical features of SOS associated with herbal toxicity include ascites, tender hepatomegaly, weight gain and marked increases in transaminases and bilirubin in its acute presentation, which can potentially lead to acute liver failure and death. However, in the subacute and chronic forms of SOS secondary to prolonged intake of herbal teas (containing pyrrolidizidine alkaloids) or long-term use of thioguanines, progressive fibrosis and cirrhosis may ensue, presenting with insidious onset of fatigue or abdominal swelling and clinical features of portal hypertension, including oedema, ascites, varices, hepatic encephalopathy, muscle wasting and weakness.
      • DeLeve L.D.
      • Shulman H.M.
      • McDonald G.B.
      Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease).
      ,
      LiverTox
      Clinical and Research Information on Drug-Induced Liver Injury.
      ,
      • Helmy A.
      Review article: updates in the pathogenesis and therapy of hepatic sinusoidal obstruction syndrome.
      Nowadays, oxaliplatin-based chemotherapy – which is used as an adjuvant treatment in patients with advanced colorectal cancer and liver metastases, is a major cause of SOS, NRH and peliosis hepatis in the clinical setting. Oxaliplatin-associated SOS was first reported in 2004 in a histopathological analysis of 87 post-chemotherapy liver resection specimens, which revealed that 44 (51%) had sinusoidal dilatation and haemorrhage, related to rupture of the sinusoidal barrier; sinusoidal changes strongly correlated with the use of oxaliplatin, occurring in 34 out of 43 patients (78%).
      • Rubbia-Brandt L.
      • Audard V.
      • Sartoretti P.
      • Roth A.D.
      • Brezault C.
      • Le Charpentier M.
      • et al.
      Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer.
      Sinusoidal injury associated with oxaliplatin occurs without significant serum enzyme elevations or clinically apparent liver injury in the majority of cases.
      LiverTox
      Clinical and Research Information on Drug-Induced Liver Injury.
      Aspartate aminotransferase-to-platelet ratio index (APRI) score was identified as an independent predictor of severe SOS after oxaliplatin therapy.
      • Soubrane O.
      • Brouquet A.
      • Zalinski S.
      • Terris B.
      • Brézault C.
      • Mallet V.
      • et al.
      Predicting high grade lesions of sinusoidal obstruction syndrome related to oxaliplatin-based chemotherapy for colorectal liver metastases: correlation with post-hepatectomy outcome.
      In that study, ROC analysis showed that APRI scores above a cut-off point of 0.36 had the best accuracy for predicting high grade SOS; area under the curve, 0.85; sensitivity, 87%; specificity 69%.
      • Soubrane O.
      • Brouquet A.
      • Zalinski S.
      • Terris B.
      • Brézault C.
      • Mallet V.
      • et al.
      Predicting high grade lesions of sinusoidal obstruction syndrome related to oxaliplatin-based chemotherapy for colorectal liver metastases: correlation with post-hepatectomy outcome.
      Splenomegaly was observed in 86% of patients receiving oxaliplatin-containing adjuvant therapy in another retrospective study, which correlated with the cumulative dose of the agent being a predictor of increasing grade of hepatic sinusoidal injury in the multivariate analysis.
      • Overman M.J.
      • Maru D.M.
      • Charnsangavej C.
      • Loyer E.M.
      • Wang H.
      • Pathak P.
      • et al.
      Oxaliplatin-mediated increase in spleen size as a biomarker for the development of hepatic sinusoidal injury.
      Clinical consequences of sinusoidal injury caused by oxaliplatin include, in the short-term, a decrease of hepatic functional reserve with higher postoperative values of total bilirubin, and longer hospital stay.
      • Nakano H.
      • Oussoultzoglou E.
      • Rosso E.
      • Casnedi S.
      • Chenard-Neu M.P.
      • Dufour P.
      • et al.
      Sinusoidal injury increases morbidity after major hepatectomy in patients with colorectal liver metastases receiving preoperative chemotherapy.
      The most worrisome long-term sequelae of sinusoidal injury in association with oxaliplatin are the development of portal hypertension and its complications, variceal bleeding and ascites.
      • Slade J.H.
      • Alattar M.L.
      • Fogelman D.R.
      • Overman M.J.
      • Agarwal A.
      • Maru D.M.
      • et al.
      Portal hypertension associated with oxaliplatin administration: clinical manifestations of hepatic sinusoidal injury.
      The impact of DILI on health-related quality of life has been shown to be significant but further investigation on psychological disability in patients with DILI are clearly needed.
      The incidence of chronic (non-reversible) portal hypertension related to oxaliplatin has recently been estimated in a large retrospective cohort study of 356 patients with a mean follow-up of approximately 5 years (range: 0.2–8.1 years).
      • Cha D.I.
      • Song K.D.
      • Ha S.Y.
      • Hong J.Y.
      • Hwang J.A.
      • Ko S.E.
      Long-term follow-up of oxaliplatin-induced liver damage in patients with colorectal cancer.
      Ninety percent of patients receiving oxaliplatin-based therapy developed parenchymal heterogeneity (grade 2 or higher) on abdominal CT scans, which was absent pre-treatment and was used as a surrogate of vascular changes. These changes were reversed in 68% of patients in 1 year, but imaging findings of portal hypertension persisted and progressed until the last follow-up in 1.4% of patients (5/356).
      • Cha D.I.
      • Song K.D.
      • Ha S.Y.
      • Hong J.Y.
      • Hwang J.A.
      • Ko S.E.
      Long-term follow-up of oxaliplatin-induced liver damage in patients with colorectal cancer.
      In a retrospective analysis of resected liver specimens from patients in 2 prospective non-randomised trials (5-fluorouracil/oxaliplatin ± bevacizumab) it was evident that bevacizumab protected against the development of SOS via an unknown mechanism.
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      • Tamandl D.
      • Dorfmeister M.
      • et al.
      Bevacizumab protects against sinusoidal obstruction syndrome and does not increase response rate in neoadjuvant XELOX/FOLFOX therapy of colorectal cancer liver metastases.
      Currently, however, there are no approved drugs for the prevention or treatment of oxaliplatin-associated SOS.
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      • Zhang C.
      Oxaliplatin-induced hepatic sinusoidal obstruction syndrome.

      Psychological disability associated with DILI

      The fact that DILI is an unexpected adverse reaction to medications intended to improve health may be psychologically very distressing and patients can develop anxiety, depression and a general fear of medications and their consequences on the liver. Thus, the psychological impact of DILI might affect compliance to drug therapy, leading to discontinuation of essential drugs.
      • Andrade R.J.
      • Chalasani N.
      • Björnsson E.S.
      • Suzuki A.
      • Kullak-Ublick G.A.
      • Watkins P.B.
      • et al.
      Drug-induced liver injury.
      Physicians are also concerned about hepatotoxicity when prescribing some drug classes, which may prevent necessary therapy. A survey conducted among over 900 primary care physicians in the US showed that 71% of respondents would prescribe statins to patients with clear indication but this proportion decreased to 50% if the patient concomitantly had baseline elevated transaminases and to 40% if there was a history of underlying liver disease, although a selection bias among respondents cannot be excluded.
      • Rzouq F.S.
      • Volk M.L.
      • Hatoum H.H.
      • Talluri S.K.
      • Mummadi R.R.
      • Sood G.K.
      Hepatotoxicity fears contribute to underutilization of statin medications by primary care physicians.
      Interestingly, although frequently claimed in liability trials from a forensic perspective, the assessment of psychological disability after DILI is a neglected area of research. The experiences posted on the internet by survivors of Stevens-Johnson Syndrome and toxic epidermal necrolysis, sometimes associated with DILI, have revealed fear of recurrence, worries about its potential effects on fertility and concern about the heritability of these adverse drug reactions. Furthermore, these patients wanted to increase the awareness of the potential harms associated with drug therapy and to inform others of the suspected cause of the adverse drug reaction they experienced.
      • Butt T.F.
      • Cox A.R.
      • Oyebode J.R.
      • Ferner R.E.
      Internet accounts of serious adverse drug reactions: a study of experiences of Stevens-Johnson syndrome and toxic epidermal necrolysis.
      A multi-centre nation-wide cross-sectional study in Korea using standardized scales demonstrated higher scores of anxiety and depression in patients with toxic liver injury caused by non-commercial herbal preparations compared with healthy individuals and patients with acute non-toxic liver damage.
      • Suh J.I.
      • Sakong J.K.
      • Lee K.
      • Lee Y.K.
      • Park J.B.
      • Kim D.J.
      • et al.
      Anxiety and depression propensities in patients with acute toxic liver injury.
      This might suggest that psychological factors are behind the desire to consume folk remedies that consequently lead to hepatotoxicity, rather than anxiety and depression being a consequence of the toxic liver damage. Similarly, patients who survived paracetamol overdose-related acute liver failure reported significantly lower general health scores, and more anxiety and depression than survivors of acute liver failure of other aetiologies and a control population, but this group also had significantly higher rates of psychiatric disease and substance abuse as a premorbid condition.
      • Rangnekar A.S.
      • Ellerbe C.
      • Durkalski V.
      • McGuire B.
      • Lee W.M.
      • Fontana R.J.
      Quality of life is significantly impaired in long-term survivors of acute liver failure and particularly in acetaminophen-overdose patients.
      In fact, so far, the impact of idiosyncratic DILI on quality of life has only been assessed using the short-form-36 (SF-36) questionnaire in a long-term follow-up study from the DILIN cohort in 113 patients fulfilling chronicity criteria at 6 months after DILI onset and followed-up for up to 24 months.
      • Fontana R.J.
      • Hayashi P.H.
      • Barnhart H.
      • Kleiner D.E.
      • Reddy K.R.
      • Chalasani N.
      • et al.
      Persistent liver biochemistry abnormalities are more common in older patients and those with cholestatic drug induced liver injury.
      The questionnaire is comprised of 8 domains: physical functioning, social functioning, role limitations due to physical health, role limitations due to emotional problems, mental health, vitality, bodily pain, and general health perceptions that can be combined to create separate physical and mental health summary scores.
      • Ware Jr., J.E.
      • Sherbourne C.D.
      The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection.
      The tool was completed at the baseline and 6-, 12-, and 24-month study visits. Patients who were found to have persistent elevations in liver tests at 12 months also had significantly worse SF-36 physical summary scores at DILI onset and throughout follow-up compared to the resolvers (p <0.01).
      • Fontana R.J.
      • Hayashi P.H.
      • Barnhart H.
      • Kleiner D.E.
      • Reddy K.R.
      • Chalasani N.
      • et al.
      Persistent liver biochemistry abnormalities are more common in older patients and those with cholestatic drug induced liver injury.
      The fact that a poor SF-36 at DILI onset was associated with persistence in this study suggests that the assessment of quality of life could be important in clinical decision making in DILI and could be used to guide the closer surveillance of these patients. Clearly, further investigations on psychological disability in DILI are urgently needed (Fig. 2).
      Figure thumbnail gr2
      Fig. 2Hazards potentially contributing to impaired health status in patients with DILI.
      DILI, drug-induced liver injury.

      Conclusions and future prospects

      The persistence of abnormal liver tests after acute DILI is highly variable and might be due to different study designs and/or differences in host susceptibility or chemical composition of the implicated agent. The natural history of most chronic phenotypes following acute DILI has not been well characterised and hence more studies are needed on the natural history of patients with persistently abnormal tests beyond 6 or 12 months. The absence of specific biomarkers of DILI is an important gap that makes it impossible to distinguish the new onset of chronic liver disease, such as non-alcoholic fatty liver disease or autoimmune liver disease, from chronic DILI. Due to the relative rarity of DILI and particularly the chronic phenotype, international collaborative efforts are needed, preferably that result in prospective studies.

      Abbreviations

      ANA, anti-nuclear antibody; APRI, aminotransferase-to-platelet ratio index; DILI, drug-induced liver injury; MRCP, magnetic resonance cholangiopancreatography; NRH, nodular regenerative hyperplasia; SOS, sinusoidal obstruction syndrome; VBDS, vanishing bile duct syndrome.

      Financial support

      The authors received no financial support to produce this manuscript.

      Authors’ contributions

      The authors contributed equally to the production of this manuscript.

      Conflict of interest

      The authors declare no conflicts of interest that pertain to this work.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following is the supplementary data to this article:

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