PURPOSE:Radiotherapy can be used as a bridge therapy prior to liver transplantation. Radiotherapy generates immune reactions involving T cells, which are the main effectors of acute cellular rejection after transplantation. Here, we investigated the impact of radiotherapy on acute cellular rejection. MATERIALS AND METHODS:We retrospectively reviewed the data of oncological patients who benefited from liver transplantation. Patients who received radiotherapy prior to liver transplantation ("RT cohort", n=17) were compared to a matched cohort ("NoRTmatched cohort", n=17) obtained through propensity score-matching analysis of the total non-irradiated cohort ("NoRTall" cohort, n=136). The acute cellular rejection was evaluated using the Banff score for rejection (mild:<5, moderate: 5-6, and severe: 7-9) obtained on an early post-transplantation biopsy. Overall and disease-free survival were reported for patients with hepatocellular carcinoma. RESULTS:Median Banff scores was significantly lower for the RT cohort compared to the NoRTall cohort (2.5 versus 5, respectively, P=0.043) but this statistical difference was eliminated after comparison with the NoRTmatched cohort (median: 4, P=0.62). The 5-year overall and disease-free survival rates were 62 % and 69 %, respectively, for hepatocellular carcinoma patients of the RT cohort (n=14) and did not differ from the 5-year overall (83 %, P=0.15) and disease-free survival rates (90 %, P=0.05) of those of the NoRTmatched cohort (n=16). CONCLUSION:Radiotherapy given prior to liver transplantation did not impact the rate or severity of acute cellular rejection. Furthermore, overall and disease-free survival rates were not impacted by radiotherapy.

Background & Aims Incidental hepatocellular carcinoma (iHCC) on cirrhotic liver specimens is not rare. The aim of this study was to evaluate prevalence and outcomes of liver transplant recipients (LTRs) with iHCC. We compared this group to cirrhotic patients who underwent liver transplantation (LT) for previously known hepatocellular carcinoma (pkHCC) or tumor-free end-stage liver disease (ESLD). Methods We retrospectively reviewed 268 cirrhotic patients who underwent LT at our center between 2010 and 2020. Patient selection was made according to the indication for LT and histopathological analyses of surgical specimens (tumor-free ESLD, hepatocellular carcinoma (HCC)). Results were compared using Fisher's exact or Mann-Whitney U tests as appropriate. We used the Kaplan-Meier method to analyze the rate of death and log-rank tests to compare survival curves. Results The prevalence of iHCC was 12%. Alcohol-related liver disease was more frequent in iHCC LTRs than in the other groups (p=0.046). iHCC patients spent more time on the waiting list than patients with tumor-free ESLD cirrhosis (Ci) (12.2 months vs. 3.5 months; p=0.04). Five-year overall survival of iHCC LTRs was significantly reduced compared to the survival of Ci LTRs (44% vs. 87%, p=0.028). Conclusions The prevalence of iHCC within LT candidates is significant. iHCC LTRs show a lower survival rate than Ci LTRs, but a reduced rate of tumor recurrence compared to pkHCC LTRs. HCC screening protocol of ESLD LT candidates might include a larger use of high-resolution imaging techniques and iHCC LTRs should be approached as pkHCC LTRs with regards to postoperative imaging follow-up. SUMMARY Prevalence of incidental hepatocellular carcinoma is considerable among LT candidates. These patients have a lower survival rate than recipients with tumor-free ESLD cirrhosis. Optimizing screening methods for hepatocellular carcinoma in cirrhotic patients awaiting liver transplantation could improve their prognosis.

BACKGROUND & AIMS:In October 2021, France and Belgium launched a joint prospective drug-induced liver injury (DILI) network (Réseau d'Etude Francophone de l'Hépatotoxicité des Produits de Santé - REFHEPS), which aims to collect liver toxicity data. Here, we present the clinical characteristics, outcome, histological features, and culprit drugs responsible for cases with DILI collected from January 2022 to June 30, 2024. METHODS:Demographics, clinical presentation, histological findings, and outcome of prospectively recruited cases with DILI in the REFHEPS were analyzed. Case definition and severity of DILI were established according to the criteria of RUCAM and Drug-Induced Liver Injury Network (DILIN) criteria. RESULTS:A total of 322 cases met the inclusion criteria for DILI, including 42 cases related to paracetamol. The current study focused on the 280 patients with idiosyncratic DILI. Our study highlights sex- and age-related differences: females were younger (57 vs 59.7 years; P = .047) and more likely to develop hepatocellular DILI (60% vs 45.5%; P = .02), whereas disease severity and outcomes were similar across sexes. In patients over 65 years, DILI had a later onset, was more cholestatic, and tended to be less symptomatic. A major finding is that anticancer drugs, particularly immune checkpoint inhibitors, account for most DILI cases (68.9%). CONCLUSIONS:The REFHEPS registry collected 322 cases in 2.5 years. The study of the 280 idiosyncratic cases of DILI shows sex and age-related differences as reported in previous registries. The most significant difference compared with older registries is the predominance of anticancer drugs causing liver injury, demonstrating the emergence of "new" side effects associated with the use of innovative therapies, especially immune checkpoint inhibitors.

Autoimmune diseases of the liver and biliary tract require timely and accurate diagnosis. This study evaluates the D-tek panel (D-Tek, Mons, Belgium) of 10 immunodot antigens for its effectiveness in diagnosing autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC). We retrospectively analysed serum samples from 111 patients who had undergone routine testing, including indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assays (ELISA), to confirm or exclude autoimmune liver or biliary tract disease. The panel tested for M2/nPDC, M2/OGDC-E2, M2/BCOADC-E2, M2/PDC-E2, gp210, sp100, LKM1, LC1, SLA, and F-actin antigens. Results showed that all positive IIF+ELISA results were confirmed by the immunodot panel, except for two samples from patients who had never been diagnosed with AIH. The immunodot test identified over 20 additional autoantibodies in samples initially negative by IIF, corroborated by laboratory imaging and medical history. The immunodot technique proved to be a quick, sensitive, and specific method with high overall accuracy. This study suggests that the immunodot technique may be an effective screening and confirmatory method for autoimmune liver diseases, potentially improving diagnostic efficiency and accuracy in clinical practice.

Nearly all medications carry the risk of drug-induced liver injury (DILI). Idiosyncratic reactions are rare and poorly predictable, and the mechanisms are not always well understood. Pirfenidone is an oral antifibrotic drug used to treat idiopathic pulmonary fibrosis. While elevation of liver enzymes is a common adverse reaction during therapy, it rarely leads to discontinuation or reduction of the drug. Although isolated cases of liver damage or liver failure have been reported, they are infrequent. This report presents the case of a 70-year-old woman with known idiopathic pulmonary fibrosis, depression, hypothyroidism, and hypercholesterolemia who presented at our emergency department with jaundice, anorexia, and asthenia. The patient’s medication regimen included lamotrigine, simvastatin, levothyroxine, and pirfenidone, which had been introduced 6 months prior. Laboratory testing revealed elevated liver enzyme levels consistent with acute hepatocellular hepatitis. Following a medical workup, which included anamnesis, laboratory testing, iconographic investigations, and liver biopsy, we concluded that the patient had suffered from pirfenidone-induced liver injury. Pirfenidone was withdrawn, and liver tests gradually improved. The purpose of this clinical case report is to highlight this rare adverse reaction and to make clinicians aware of its assessment and management. In 2018, only one other case of severe liver failure leading to the death of the patient was reported. Early detection of potential DILI during the workup is crucial to discontinue the suspected medication promptly. Any drug-induced hepatitis must be reported for registration.

Background & Aims: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are the cornerstone of systemic therapy for patients with hormone receptor -positive, HER2-negative (HR+/HER2-) metastatic breast cancer. In the various therapeutic studies with CDK4/6 inhibitors, elevations in liver tests were more frequent than in the control groups. The mechanism of CDK4/6 inhibitor -induced liver toxicity is not well understood; moreover, natural history and appropriate management are poorly described. Methods: We conducted a retrospective study, collecting cases of CDK4/6 hepatitis from the REFHEPS (R & eacute;seau Francophone pour l'& eacute;tude de l'HEpatotoxicit & eacute; des Produits de Sant & eacute;) database. Results: In this study, we report on 22 cases of hepatitis induced by CDK4/6 inhibitors (ribociclib, n = 19 and abemaciclib, n = 3). According to the CTCAE classification, all hepatitis cases were grade 3 or 4. Twelve (54.6%) patients had a liver biopsy showing acute centrilobular hepatitis with foci of necrosis and lymphocytic infiltrate. Nine (40.9%) patients were treated with corticosteroids for resolution of hepatitis. In three cases, another CDK4/6 inhibitor could be resumed after resolution of the hepatitis without recurrence. Conclusions: CDK4/6 inhibitor -induced hepatitis is poorly described in the literature but there are several arguments pointing out that these drugs should be included in the DI-ALH (drug -induced autoimmune-like hepatitis) category. (c) 2024 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Gene therapy is being successfully developed for the treatment of several genetic disorders. Various methods of gene transfer have been developed to enable the production of the deficient enzyme or protein. One of the most important is adeno-associated virus vectors, which have been shown to be viable for use in in vivo gene therapy. Several gene therapies have already been approved. They are also promising for acquired diseases. Important examples include gene therapy for haemophilia A and B, X-linked myotubular myopathy, spinal muscular atrophy and several liver diseases such as Criggler-Najjar disease, alpha-1 antitrypsin deficiency and Fabry disease. However, the introduction of a foreign compound into hepatocytes leads to hepatic reactions with heterogeneous phenotypic expression and a wide spectrum of severity, ranging from mild transaminase elevation to acute liver failure. Several mechanisms appear to be involved in liver injury, including an immune response, but also direct toxicity depending on the method of gene transfer. As a result, the incidence, expression and severity of liver injury vary from indication to indication and from patient to patient. Patients treated for haemophilia A are more prone to transaminase elevation than those treated for haemophilia B. Corticosteroids are successfully used to correct liver reactions but also to prevent degradation of the transferred gene and loss of therapeutic activity. The aim of this review is to describe the risk of liver injury according to the indication for gene therapy and the short- and long-term management currently proposed to prevent or correct liver reactions in clinical practice.

Autoimmune gastritis (AIG) is a prominent risk factor for pernicious anemia (PA) and gastric neoplasia. This study aimed to investigate the clinicopathological characteristics of AIG patients in China, with a focus on those who had positive anti-intrinsic factor antibodies (AIFA).A total of 103 AIG patients who were diagnosed between January 2018 and August 2022 were reviewed in a large academic tertiary teaching hospital. Patients were divided into two groups based on the presence or absence of AIFA, and their serologic and histopathological characteristics were analyzed.The mean age of the 103 AIG patients was 54.16±11.92 years (range 23–79), with 69 (66.99%) being women. AIFA were present in 28.16% of patients. Patients with AIFA-positive had a higher risk of PA than those with AIFA-negative, as demonstrated by a larger mean corpuscular volume (MCV), lower hemoglobin level, and lower vitamin B-12 level (P<0.05). There were no statistically significant differences in gastric histopathology, gastrin level, and pepsinogen level when patients were divided into AIFA-positive and AIFA-negative group. Of the 103 cases, 34 (33.01%) were concomitant with other autoimmune diseases, with autoimmune thyroid diseases being the most common (25.24%, 26/103). Thyroid peroxidase antibody, which accounted for 45.45% (25/55), was the most prevalent thyroid antibody, followed by anti-thyroglobulin antibody (34.55%, 19/55), thyroid stimulating antibody (12.73%, 7/55), and thyrotropin receptor antibody (3.64%, 2/55).This study highlights the increased risk of severe anemia in AIFA-positive AIG patients, particularly for PA. Clinicians should consider the presence of AIFA as a warning sign for PA and prioritize early diagnosis and appropriate treatment to prevent serious complications.

BACKGROUND AND AIMS:Cystic fibrosis liver disease (CFLD) is the third leading cause of death in patients with cystic fibrosis (CF). We aim to determine the prevalence of CFLD in a cohort of adult patients with CF and to characterise liver involvement in this population highlighting the importance of histological diagnosis.METHODS:We retrospectively studied a cohort of patients with CF. Inclusion criteria were age ≥ 18 and minimum 1 year of follow-up. We excluded lung transplant patients. CFLD was defined as having 2 out of 3 criteria: persistent elevation of transaminases and/or gamma-glutamyltransferase; abnormal ultrasound; and abnormal transient elastography. Non-invasive fibrosis biomarkers were calculated in CFLD patients. Adult-onset CFLD (Ad-CFLD) was defined as CFLD ≥18 years. Severe CFLD (s-CFLD) was defined as CFLD with cirrhosis and/or portal hypertension.RESULTS:We included 113 patients. Median age was 29 years, 58 were male. Forty patients had CFLD. Median age at CFLD diagnosis was 10 years. Twenty-one patients had s-CFLD. Two s-CFLD patients had nodular regenerative hyperplasia, 1 had hepatocellular carcinoma and 4 underwent liver transplantation. Six patients had ad-CFLD. Both CFLD and s-CFLD groups were compared to a non-CFLD group. The CFLD group had significantly more males (p = 0.034). S-CFLD group had worse pulmonary function (p = 0.015).CONCLUSION:Thirty five percent of adult patients with CF, mainly males, had CFLD. Nineteen percent had s-CFLD and had worse pulmonary function. With recent reports unravelling different pathophysiological mechanisms in CFLD, we believe it is important to better characterise liver involvement using liver biopsy.

In the last 5 years, the landscape of oncologic treatment has been deeply modified with the development and use of immune checkpoint inhibitors (ICIs) that exert their antitumoral effect by reverting the exhausted phenotype of tumor-infiltrating lymphocytes. This innovative therapeutic strategy has widely changed the prognosis of some advanced neoplastic diseases such as melanoma and lung cancer, providing durable remission for a significant number of patients. Unfortunately, immune-related adverse events (irAEs), especially ICI-induced hepatitis, may be very severe in some cases, impairing the prognosis of the patient. Guidelines available today on the diagnosis and management of ICI-induced hepatitis are mainly based on expert opinions and case series. This lack of large data is explained not only by the low incidence of hepatic adverse events but also by their clinical heterogeneity and variable severity. In this article, we will review the clinical, biological, and histological characteristics of ICI-induced liver injury. We will discuss the current knowledge on their pathological mechanisms and their therapeutic strategy based on immunosuppressive treatment for more severe cases. Regarding severity assessment, we will discuss the gap between the oncologist and the hepatologist's point of view, highlighting the need for multidisciplinary management. While initially developed for notably less frequent diseases than neoplastic ones, gene therapy is going to be a revolution for the treatment of diseases not responding to pharmacological therapy. Limited but growing data describe liver injury after the administration of such therapy whose exact physiopathology remains unknown. In this article, we will discuss the available data supporting the role of gene therapies in the onset of drug-induced liver injury and related mechanisms. We will describe the clinical context, the biological and histological features, and the management currently proposed.