Acute cholestatic hepatitis in a patient with metastatic melanoma.

A 52-year-old patient with metastatic melanoma was admitted to our hospital in February 2017 for fatigue, fever and jaundice. The melanoma was initially resected, but the patient experienced several recurrences. In April 2016, it was stage IV, with multiple localizations (cerebral and pulmonary). The patient was treated with radiotherapy and received pembrolizumab (anti-PD-1 immunotherapy) between June and December 2016. Because of tumor progression, ipilimumab (anti-CTLA4) was introduced on the 3rd of January 2017. On examination, temperature was 38.5 °C and she had icteric sclera. The abdomen was soft with mild discomfort on the upper right quadrant. Blood test results were as follows: white blood cell count 3.4x109/L, hemoglobin 8.8 g/dl, platelets 53,000/μl, alanine aminotransferase 242 IU/L (upper limit of normal [ULN], 35 IU/L), aspartate aminotransferase 174 IU/L (ULN, 35 IU/L), prothrombin time 82%, total bilirubin 58 μmol/L (ULN, <17 μmol/L), direct bilirubin 47 μmol/L (ULN, <6 μmol/L), alkaline phosphatase 768 IU/L (ULN, <98 IU/L), gamma-glutamyltransferase 896 (ULN, <36 IU/L), albumin 22 g/L, ferritin 48.269 μg/L (ULN, <290 μg/L), IgG 6.10 g/L (6.78-12.6), anti-nuclear antibodies 1:80, speckled pattern. Hepatitis A, B, C, E serologies were negative, including hepatitis B, C, E PCR. At admission, the patient was taking the following drugs: prednisone 20 mg/day, levetiracetam twice daily, hydroxyzine once daily. No new treatment was introduced in the past 3 months except for ipilimumab. The patient also reported no travel in the past year. A contrast-enhanced CT scan showed non-dysmorphic hepatomegaly without tumor, normal biliary ducts and no splenomegaly. A liver biopsy was performed (Fig. 1). 1.Q Fever2.CMV hepatitis3.Immune checkpoint inhibitor toxicity4.EBV hepatitis Liver biopsy revealed periportal and lobular hepatitis with fibrin-ring granulomas. This particular finding is usually associated with Q fever, but can be found in the case of Epstein-Barr virus (EBV), cytomegalovirus (CMV), viral hepatitis A, mycobacterial infections, lymphoma, vasculitis and typhoid fever. Human immunodeficiency virus serology, EBV, CMV, herpes simplex and HHV6 PCR were negative. Regarding Q fever, which is caused by the gram-negative C. burnetii with a mammalian reservoir (sheep, goats, cattle), she had no animal exposure and Coxiella burnetii serologies were negative. Because all other possible etiologies of the cholestatic hepatitis were ruled out, immunotherapy-induced liver toxicity was considered. The Roussel-UCLAF Causality Assessment Methods (RUCAM) scale score helps in assessing the likelihood of an association between a drug and liver toxicity. The patient had a RUCAM score of 8 (probable). The patient received two injections of anti-CTLA4 and the interval between the last anti-PD1 dose (December 2016) and the first anti-CTLA4 dose (January 2017) was about 4 weeks, meaning that both drugs were active at the time of the liver injury. Prednisone was increased up to 1 mg/kg/day with an improvement of the liver tests and resolution of the fever. She was discharged and the corticosteroids were slowly tapered with no recurrence of hepatitis. Immune-checkpoint inhibitor (ICI)-induced liver toxicity is clinically, biologically and histologically heterogenous. There are three presentations of ICI-induced hepatotoxicity: hepatic, cholangitic and mixed. The hepatic profile is histologically characterized by an acute hepatitis with spotty or confluent necrosis that prevails in the centrilobular zone. The inflammatory infiltration predominantly comprises lymphocytes and histocytes, often organized into microgranulomas. Immune-related cholangiopathy can affect both small and large bile ducts mimicking sclerosing cholangitis with strictures and upstream dilatations. Histology is characterized by either an acute cholangitis with polynuclear neutrophil infiltration or by a lymphocytic cholangitis; periductal fibrosis and bile duct obliteration have been reported. Interestingly, immune-related cholangiopathy seems to be associated with the use of anti-PD1 ICI and seems to respond poorly to immunosuppression.[1]Berry P. Kotha S. Zen Y. Papa S. El Menabawey T. Webster G. et al.Immune checkpoint inhibitor-related cholangiopathy: novel clinicopathological description of a multi-centre cohort.Liver Int. 2023 Jan; 43: 147-154Crossref PubMed Scopus (8) Google Scholar Fibrin-ring granulomas are a histological feature of immune-related liver toxicity that can guide the diagnosis.[2]Everett J. Srivastava A. Misdraji J. Fibrin ring granulomas in checkpoint inhibitor-induced hepatitis.Am J Surg Pathol. 2017; 41: 134-137Crossref PubMed Scopus (58) Google Scholar,[3]De Martin E. Michot J.M. Papouin B. Champiat S. Mateus C. Lambotte O. et al.Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors.J Hepatol. 2018 Jun; 68: 1181-1190Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar They have been associated with the use of anti-CTLA4 ICI both in monotherapy and in combination with anti-PD1. Liver biopsy is recommended in the most severe cases (grade 3 and 4 according to the Common Toxicity Criteria for Adverse Events (CTCAE) of the National Cancer Institute using version 5.0 classification),[4]Haanen J. Obeid M. Spain L. Carbonnel F. Wang Y. Robert C. et al.Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.Ann Oncol. 2022 Dec; 33: 1217-1238Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar to confirm the diagnosis and to rule out a misdiagnosed chronic liver disease. Combined immunotherapy is associated with a higher rate of immune-related adverse events, including hepatic toxicity, compared with monotherapy, and it is described in up to 25% of treated patients. Therefore, sequential oncological therapy needs to be considered when evaluating a possible relationship between an ICI and the onset of hepatitis. As for all other drug-induced liver injuries, an accurate causality assessment, in order to exclude all other causes of acute hepatitis, is paramount. Even if the ICI-induced liver toxicity is usually non severe, cases of fulminant hepatitis have been reported, accounting for less than 0.5% of treated patients. The assessment of the severity of liver injury is extremely important as it determines which patients should be treated with immunosuppressive drugs. Indeed, the severity of the liver injury should be based on the increase of bilirubin and the international normalized ratio. Corticosteroids are the first-line treatment for ICI-induced hepatitis. Their administration should be tailored to individuals and they might not be needed systematically, as spontaneous improvement, even for grade III and IV CTCAE hepatitis, has been reported. In case liver tests do not improve or worsen on maximum doses of corticosteroids, a second-line immunosuppressive drug (such as mycophenolate mofetil) is recommended. For immune-related cholangiopathy or mixed forms, ursodeoxycholic acid should be used, alone or in association with an immunosuppressive drug.[4]Haanen J. Obeid M. Spain L. Carbonnel F. Wang Y. Robert C. et al.Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.Ann Oncol. 2022 Dec; 33: 1217-1238Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar The authors received no financial support for this article. The authors declare that they have no competing interest. Please refer to the accompanying ICMJE disclosure forms for further details. EDM: conceived and wrote the manuscript; ALB, CG: provided histological images and their description; ER: provided clinical data; DS: reviewed the manuscript. 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