[Gastroenterology and hepatology: what's new in 2023]. / Gastroentérologie et hépatologie: ce qui a changé en 2023.

2023 has been marked by numerous advancements in the fields of hepatology, liver transplantation, gastroenterology, and interventional endoscopy. These developments hold the promise of changing our daily practice while enhancing the diagnosis and treatment of various hepatic and gastroenterological conditions. Additionally, the European Association for the Study of the Liver (EASL) has issued recommendations for the management of hepatitis delta, acute-on-chronic liver failure, liver diseases of pregnancy, and intrahepatic cholangiocarcinoma. Risankizumab was approved by Swiss Authorities for patients with Crohn's disease and dupilumab was approved for patients with eosinophilic esophagitis. The European Society of Gastrointestinal Endoscopy (ESGE) has revised its recommendations regarding Barrett's esophagus.

2023 a été marquée par de nombreuses avancées dans le domaine de l'hépatologie, de la transplantation hépatique, de la gastroentérologie et de l'endoscopie interventionnelle. Ces développements promettent de changer notre pratique quotidienne dans le but d'améliorer le diagnostic et le traitement de nombreuses affections hépatiques et gastroentérologiques. En outre, la Société européenne d'hépatologie (EASL) a émis des recommandations pour la prise en charge de l'hépatite delta, de l'insuffisance hépatique aiguë sur chronique, des complications hépatiques de la grossesse et du cholangiocarcinome intrahépatique. Le risankizumab a été approuvé par Swissmedic pour le traitement de la maladie de Crohn et le dupilumab pour les patients avec œsophagite à éosinophiles. La Société européenne d'endoscopie a mis à jour ses recommandations concernant l'œsophage de Barrett.

Inborn errors of type I interferon immunity in patients with symptomatic acute hepatitis E.

BACKGROUND AND AIMS: The clinical spectrum of human infection by HEV ranges from asymptomatic to severe acute hepatitis. Furthermore, HEV can cause diverse neurological manifestations, especially Parsonage-Turner syndrome. Here, we used a large-scale human genomic approach to search for genetic determinants of severe clinical presentations of HEV infection. APPROACH AND RESULTS: We performed whole genome sequencing in 3 groups of study participants with PCR-proven acute HEV infection: (1) 24 patients with symptomatic acute hepatitis E; (2) 12 patients with HEV-associated Parsonage-Turner syndrome; and (3) 16 asymptomatic blood donors (controls). For variant calling and annotation, we used GATK4 best practices followed by Variant Effect Predictor (VEP) and Annovar. For variant classification, we implemented the American College of Medical Genetics and Genomics/Association for Molecular Pathology Bayesian classification framework in R. Variants with a probability of pathogenicity >0.9 were considered damaging. We used all genes with at least 1 damaging variant as input for pathway enrichment analyses.We observed a significant enrichment of type I interferon response pathways in the symptomatic hepatitis group: 10 out of 24 patients carried a damaging variant in one of 9 genes encoding either intracellular viral sensors ( IFIH1 , DDX58 , TLR3 , POLR3B , POLR3C ) or other molecules involved in type I interferon response [interferon regulatory factor 7 ( IRF7 ), MYD88 , OAS3 , GAPDH ]. We did not find any enriched pathway in the Parsonage-Turner syndrome group or in the controls. CONCLUSIONS: Our results highlight the essential role of type I interferon in preventing symptomatic acute hepatitis E.

Body composition and short-term mortality in patients critically ill with acute-on-chronic liver failure.

Background & Aims: Body composition is sex dependent and associated with an increased mortality risk in patients with cirrhosis. We evaluated whether it was also associated with short-term mortality in patients critically ill with acute-on-chronic liver failure (ACLF). Patients and methods: We retrospectively included all patients with cirrhosis and ACLF hospitalised in the intensive care unit (ICU) of Lausanne University Hospital between 2010 and 2019 for whom an abdominal computed tomography (CT) scan performed ±7 days from admission was available. Patients from the ICU of Paul Brousse University Hospital admitted between 2017 and 2020 served as an external cohort. All body composition parameters at the third lumbar vertebral level (L3) were quantified using a deep learning-based method. Results: In total, 192 patients from Lausanne were included. Median age was 62 years and 28-day survival rate was 58.2%. In males, variables independently associated with 28-day mortality on days 1 and 3 were Chronic Liver Failure Consortium (CLIF-C) ACLF-lactate and sarcopenia. In females, CLIF-C ACLF-lactate on days 1 and 3 was the only predictor of 28-day survival. We derived two scores combining sarcopenia and the CLIF-C ACLF-lactate score on days 1 and 3, with area under the receiver operating characteristic outperforming the CLIF-C ACLF-lactate score alone in male but not in female patients. Comparable results were found in the external cohort of 58 patients and supported the sex specificity of the performance of the model. Patients with sarcopenia had increased risks of invasive fungal infection and renal replacement therapy. Conclusion: Sarcopenia was associated with 28-day mortality in male but not in female patients critically ill with ACLF. Although screening for sarcopenia could impact the management of male patients, further studies are needed in female cohorts to investigate whether other body composition parameters are associated with outcomes. Impact and implications: Body composition, easily assessed by CT, is altered in patients with cirrhosis and associated with outcome; it has never been investigated in patients critically ill with ACLF. The results of the present study, underlining the benefit of sarcopenia evaluation to improve prognosis prediction in males critically ill with ACLF, are of importance for physicians managing such patients to optimise the decision-making process toward continued treatment, liver transplantation, or limitation of care. In a wider sense, besides the number and course of organ failures, the results recall the weight of the general condition of males with ACLF at admission to ICU. In females critically ill with ACLF, in analyses limited by the sample size, none of the body composition parameters was associated with short-term mortality independently of organ failures; this suggests that the number and course of organ failures are the main determinant of mortality in these patients.

The current and future burden of hepatitis B in Switzerland: a modelling study.

BACKGROUND AND AIMS: Chronic hepatitis B infection (defined as sustained detection of hepatitis B virus [HBV] surface antigen [HBsAg] protein in serum) is a leading cause of cirrhosis, hepatocellular carcinoma and liver-related deaths. A situation analysis carried out by the Swiss Federal Office of Public Health estimated the HBsAg prevalence in Switzerland to be 0.53% (95% CI: 0.32-0.89%) in 2015 (~44,000 cases). A lower prevalence of chronic HBV in the younger generation and the adoption of universal coverage in the first year of life are expected to decrease the burden of HBV; however, a number of people in key populations (including migrants) remain undiagnosed and untreated, and infected individuals remain at risk of progressing to cirrhosis, hepatocellular carcinoma and death. Our primary objective was to examine the current and estimate the future disease burden of HBV in Switzerland and the impact of migration. The secondary objective was to estimate the impact of changing future treatment numbers. METHODS: A modelling study was performed using an existing, validated model (PRoGReSs Model) applied to the Swiss context. Model inputs were selected through a literature search and expert consensus. Population data from the Federal Statistical Office were used alongside prevalence data from the Polaris Observatory to estimate the number of HBV infections among people born abroad. The PRoGReSs Model was populated with and calibrated to the available data and what-if scenarios were developed to explore the impact of intervention on the future burden of disease. A Monte Carlo simulation was used to estimate 95% uncertainty intervals (95% UIs). RESULTS: In 2020, there were an estimated 50,100 (95% UI: 47,500-55,000) HBsAg+ cases among people born abroad. Among people born in Switzerland, there were approximately 62,700 (UI: 58,900-68,400) total HBV infections (0.72% [UI: 0.68-0.79%] prevalence). Prevalence among infants and children under the age of 5 were both <0.1%. By 2030, prevalence of HBV is expected to decrease, although morbidity and mortality will increase. Increasing diagnosis (90%) and treatment (80% of those eligible) to meet the global health sector strategy on viral hepatitis programme targets could prevent 120 cases of hepatocellular carcinoma and 120 liver-related deaths. CONCLUSIONS: Thanks to the historical vaccination programmes and the continued rollout of universal 3-dose coverage in the first year of life, Switzerland is expected to exceed the global health sector strategy targets for the reduction of incidence. While overall prevalence is decreasing, the current diagnosis and treatment levels remain below global health sector strategy targets.

The combination of non-contrast abbreviated MRI and alpha foetoprotein has high performance for hepatocellular carcinoma screening.

OBJECTIVES: This study aimed to compare two abbreviated MRI (AMRI) protocols to complete MRI for HCC detection: non-contrast (NC)-AMRI without/with alpha foetoprotein (AFP) and dynamic contrast-enhanced (Dyn)-AMRI. METHODS: This retrospective single-center study included 351 patients (M/F: 264/87, mean age: 57y) with chronic liver disease, who underwent MRI for HCC surveillance between 2014 and 2020. Two reconstructed AMRI sets were obtained based on complete MRI: NC-AMRI (T2-weighted imaging (WI) + diffusion-WI) and Dyn-AMRI (T2-WI + dynamic T1-WI) and were assessed by 2 radiologists who reported all suspicious lesions, using LI-RADS/adapted LI-RADS classification. The reference standard was based on all available patient data. Inter-reader agreement was assessed and MRI diagnostic performance was compared to the reference standard. RESULTS: The reference standard demonstrated 83/351 HCC-positive patients (prevalence: 23.6%, median size: 22 mm, and positive MRIs: 83/631). Inter-reader agreement was substantial for all sets. Sensitivities of Dyn-AMRI and complete MRI (both 92.8%) were similar, higher than NC-AMRI (72.3%, p < 0.001). Specificities were not different between sets. NC-AMRI + AFP (92.8%) had similar sensitivity to Dyn-AMRI and complete MRI. In patients with small size HCCs (≤ 2 cm), sensitivities of Dyn-AMRI (85.3%) and complete MRI (88.2%) remained similar (p = 0.564), also outperforming NC-AMRI (52.9%, p < 0.05). NC-AMRI + AFP had similar sensitivity (88.2%) to Dyn-AMRI and complete MRI (p = 0.706 and p = 1, respectively). CONCLUSIONS: Dyn-AMRI has similar diagnostic performance to complete MRI for HCC detection, while both outperform NC-AMRI, especially for small size HCCs. NC-AMRI + AFP demonstrates similar sensitivity to Dyn-AMRI and complete MRI. CLINICAL RELEVANCE STATEMENT: Due to the low sensitivity of ultrasound for hepatocellular screening, new screening methods are needed. Abbreviated MRI (AMRI) is a candidate, especially non-contrast AMRI with serum alpha foetoprotein as the acquisition time is low, without the need for contrast medium injection. KEY POINTS: • Dynamic contrast-enhanced abbreviated MRI using extracellular gadolinium-based contrast agent and complete MRI have similar diagnostic performance for hepatocellular carcinoma detection in an at-risk population. • Non-contrast abbreviated MRI with alpha foetoprotein has similar diagnostic performance to dynamic contrast-enhanced abbreviated MRI and complete MRI, including when considering small size hepatocellular carcinoma ≤ 2 cm. • Non-contrast abbreviated MRI and dynamic contrast-enhanced abbreviated MRI can be performed in 7 and 10 min, excluding patient setup time.

[Gastroenterology and hepatology: what's new in 2022]. / Gastroentérologie et hépatologie : ce qui a changé en 2022.

The field of gastroenterology and hepatology is evolving constantly. In 2022, numerous landmark studies have been published in all its subspecialities including hepatology, functional diseases, interventional endoscopy, and inflammatory bowel disease. Among the most significant advances are the antiviral treatment for hepatitis D, the new Chicago classification version 4 for esophageal motility disorders, the first biological treatment for eosinophilic esophagitis, a randomized controlled trial about the efficacy of screening colonoscopy, novel endoscopic techniques such as G-POEM or endoscopic sleeve gastrectomy, and emerging IBD therapies such as ozanimod, upadacitinib or anti-IL23 antibodies.

La gastroentérologie et l'hépatologie sont des disciplines variées et en pleine évolution. Durant l'année 2022, plusieurs études marquantes ont été publiées dans les domaines de l'hépatologie, des maladies fonctionnelles, de l'endoscopie et des maladies inflammatoires chroniques de l'intestin (MICI). Les avancées les plus importantes sont le traitement antiviral contre l'hépatite D, la nouvelle classification de Chicago version 4 pour les troubles moteurs œsophagiens, le traitement biologique de l'œsophagite à éosinophiles, l'efficacité de la coloscopie de dépistage, de nouvelles techniques endoscopiques comme le G-POEM ou la gastrectomie endoscopique et des nouveaux médicaments pour les MICI comme l'ozanimod, l'upadacitinib ou les anticorps anti-IL-23.

Marked weight loss on liraglutide 3.0 mg: Real-life experience of a Swiss cohort with obesity.

OBJECTIVE: This study investigated the effectiveness of liraglutide 3.0 mg daily in combination with a standardized multidisciplinary intervention on body weight and body composition changes in a real-life setting. METHODS: A prospective, observational cohort study design was used. Adult patients with BMI > 35 kg/m2 , or BMI > 28 kg/m2 with greater than or equal to one metabolic comorbidity, were included (n = 54, 65% women). Liraglutide treatment was covered by Swiss health insurance. Clinical and biological data were collected at baseline, 4 months, and 10 months. Body composition was assessed by dual-energy x-ray absorptiometry at baseline and 10 months. RESULTS: At 10 months, mean (SD) percentage weight loss (WL%) was -12.4% (5.5%) or -14.1 (6.6) kg. WL% was ≥5% in 87% of patients at 4 months and in 96% at 10 months. WL% was higher in women (-9.5% [3.1%] vs. men -7.2% [2.5%], p = 0.02) at 4 months and persisted at 10 months (-13.7% [5.2%] vs. -9.6% [5.1%], p = 0.006). WL% was associated with baseline percentage fat mass but not with age or BMI. Body composition showed a decrease in fat mass, visceral adipose tissue, and absolute lean mass. CONCLUSIONS: In a real-world setting, liraglutide 3.0 mg led to beneficial changes in WL and body composition, with a greater impact in women.

Systematic comparison with autoimmune liver disease identifies specific histological features of immune checkpoint inhibitor-related adverse events.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have become a mainstay of cancer treatment. Their immune-boosting quality has one major drawback, their proclivity to induce a broad array of immune-related adverse events (irAEs) affecting, among others, the liver and sharing some similarities with classic autoimmune liver diseases (AILD).We aimed to compare clinical, laboratory and histological features of patients with liver-related irAEs and AILD. METHODS: We systematically compared liver irAEs with AILD, namely autoimmune hepatitis (AIH) and primary biliary cholangitis, regarding their clinical, laboratory, and histological features. RESULTS: Twenty-seven patients with liver irAEs (ICI group) and 14 patients with AILD were identified. We observed three distinct ICI-induced histological liver injury patterns: hepatitic (52%), cholangitic (19%), and mixed (29%). When comparing the ICI and AILD groups, centrilobular injury as well as granuloma formation were more prevalent in the former (p=0.067 and 0.002, respectively). CD4+/CD8+ T cell ratios were heterogeneous between the two groups, without statistically significant difference but with a trend toward increased CD8+ T cells among hepatitic irAEs as compared with AIH. Pattern of liver function test alteration was predictive for the type of irAEs but did not correlate with histological severity. CONCLUSIONS: Liver irAEs have broad clinical, laboratory and histological presentations. Histological features of irAEs and AILD are distinct, likely underpinning their different immunological mechanisms.

[Short telomere syndrome in adults: a rare entity that should be evoked]. / Syndrome des télomères courts chez l'adulte†: une entité rare qu'il faut savoir évoquer.

Short telomere syndrome (STS) is a group of rare, often underrecognized, diseases caused by defects in telomere-maintenance genes, leading to abnormal telomere shortening and associated with diverse multi-organ manifestations. In pediatric patients, STS typically presents with mucocutaneous or gastrointestinal lesions, bone marrow failure and neoplasia. In adulthood, aplastic bone marrow disease, liver disease and pulmonary fibrosis are classic clinical manifestations. At present, medical treatment options for STS remain limited. Danazol, a synthetic androgenic hormone, can slow down telomere shortening and thus limit the progression of the disease. Finally, hematopoietic, hepatic and pulmonary transplantation, sometimes combined, may be discussed in a multidisciplinary setting in certain situations.

Le syndrome des télomères courts (STC) est un groupe de maladies rares dues à un défaut dans les gènes de maintenance des télomères, provoquant leur raccourcissement anormal et des manifestations cliniques multiorganiques. Dans l'enfance, le STC se présente par des lésions mucocutanées et gastro-intestinales, une insuffisance médullaire et des néoplasies. À l'âge adulte, une atteinte médullaire aplasiante, hépatique, et une fibrose pulmonaire sont des manifestations cliniques classiques. Les options thérapeutiques pour le STC restent limitées. Le danazol, une hormone androgène synthétique, permet, parfois, de freiner le raccourcissement télomérique et de limiter la progression de la maladie. Finalement, les transplantations hématopoïétique, hépatique et pulmonaire sont discutées dans certaines situations de manière multidisciplinaire.

Partial lipodystrophy, severe dyslipidaemia and insulin resistant diabetes as early signs of Werner syndrome.

Werner syndrome is a premature ageing disorder caused by biallelic variants in the WRN gene. WRN encodes a dual DNA helicase/exonuclease enzyme. Molecular diagnosis is commonly only made at a late disease stage in the third or fourth decade, when cardinal features have become apparent. We describe a 28 year-old woman who presented with early onset diabetes associated with partial lipodystrophy, severe dyslipidaemia and rapidly progressive liver fibrosis related to non-alcoholic steatohepatitis in the absence of progeroid features. Werner syndrome was diagnosed by trio exome analysis, which revealed compound heterozygous WRN mutations: the known variant c.1290_1293del (p.Asn430Lysfs*7) and the novel intronic splice site variant c.2732+5G>A. cDNA analysis demonstrated this to lead to in-frame skipping of exon 22, predicted to delete most of the zinc binding region of the helicase domain. We suggest that including the WRN gene in genetic analysis of early onset diabetes, lipodystrophy or dyslipidaemia would allow for the opportunity to diagnose some cases of Werner syndrome long before clinical criteria are met, thereby allowing early implementation of important primary prevention interventions.

Portal vein recanalisation alone to treat severe portal hypertension in non-cirrhotic patients with chronic extrahepatic portal vein obstruction.

Background & Aims: We aimed to evaluate long-term outcome of patients with chronic non-cirrhotic extrahepatic portal vein obstruction (CNC-EHPVO) who underwent portal vein recanalisation (PVR) without transjugular intrahepatic portosystemic shunt (TIPS) insertion and to determine factors predicting PVR failure and stent occlusion. Methods: This retrospective monocentric study included all patients who underwent PVR without TIPS insertion in the context of CNC-EHPVO between the years 2000 and 2019. Primary patency was defined by the absence of a complete stent occlusion on follow-up imaging. Results: A total of 31 patients underwent PVR with a median follow-up of 52 months (24-82 months). Indications were gastrointestinal bleeding (n = 13), abdominal pain attributed to CNC-EHPVO (n = 7), prior to abdominal surgery (n = 4), and others (n = 7). Technical success was obtained in 27 patients. PVR failure was associated with extension within the intrahepatic portal veins (p = 0.005) and recanalisation for abdominal pain (p = 0.02). Adverse events occurred in 6 patients with no mortality. Anticoagulation was administered in 21 patients after technical success of PVR. In patients with technical success, 5-year primary patency was 73% and was associated with improved muscle mass (p = 0.007) and decreased spleen volume (p = 0.01) at 1 year. Furthermore, 21 (78%) patients with PVR technical success were free of portal hypertension complication at 5 years. Conclusions: PVR without TIPS insertion was feasible and safe in selected patients with CNC-EHPVO and portal hypertension with past or expected complications. Primary patency at 5 years was obtained in 3 of 4 patients with technical success of PVR and was associated with a control of complications of CNC-EHPVO. PVR was associated with improvement of sarcopenia and decreased spleen volume at 1 year. Lay summary: Patients with chronic obstruction of the portal vein and without cirrhosis or malignancy can develop complications related to the high pressure in the venous system. The present study reports long-term favourable outcome of patients in whom the obstruction was treated with stents.

Increasing prevalence of obesity and diabetes among patients evaluated for liver transplantation in a Swiss tertiary referral center: a 10-year retrospective analysis.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is now the first cause of chronic liver disease in developed countries. We aimed to assess trends in the prevalence of obesity, type 2 diabetes mellitus (T2DM) and NAFLD in patients undergoing liver transplantation evaluation and to assess whether obese patients were less likely to be listed or had an increased drop-out rate after listing. METHODS: We conducted a retrospective study of all consecutive patients who underwent liver transplantation evaluation at a Swiss tertiary referral centre between January 2009 and March 2020. RESULTS: A total of 242 patients were included, 83% were male. The median age was 59 years (IQR, 51-64 years). The most common causes of end-stage liver disease were viral hepatitis (28%), alcoholic liver disease (21%) and NAFLD (12%). Obesity was present in 28% of our cohort, with a significant increase over time. Prevalence of type 2 diabetes mellitus followed the same trend (p = 0.02). The proportions of non-listed and listed obese patients did not differ (21% vs. 30% respectively; p = 0.3). CONCLUSIONS: The prevalence of obesity and type 2 diabetes mellitus significantly increased over our study period. Obese patients had similar chances of being listed. The landscape of liver transplantation indications is shifting towards NAFLD, highlighting the urgent need to prevent NAFLD progression.

Humoral response to SARS-CoV-2 infection among liver transplant recipients.

OBJECTIVE: Immunosuppressive agents are known to interfere with T and/or B lymphocytes, which are required to mount an adequate serologic response. Therefore, we aim to investigate the antibody response to SARS-CoV-2 in liver transplant (LT) recipients after COVID-19. DESIGN: Prospective multicentre case-control study, analysing antibodies against the nucleocapsid protein, spike (S) protein of SARS-CoV-2 and their neutralising activity in LT recipients with confirmed SARS-CoV-2 infection (COVID-19-LT) compared with immunocompetent patients (COVID-19-immunocompetent) and LT recipients without COVID-19 symptoms (non-COVID-19-LT). RESULTS: Overall, 35 LT recipients were included in the COVID-19-LT cohort. 35 and 70 subjects fulfilling the matching criteria were assigned to the COVID-19-immunocompetent and non-COVID-19-LT cohorts, respectively. We showed that LT recipients, despite immunosuppression and less symptoms, mounted a detectable antinucleocapsid antibody titre in 80% of the cases, although significantly lower compared with the COVID-19-immunocompetent cohort (3.73 vs 7.36 index level, p<0.001). When analysing anti-S antibody response, no difference in positivity rate was found between the COVID-19-LT and COVID-19-immunocompetent cohorts (97.1% vs 100%, p=0.314). Functional antibody testing showed neutralising activity in 82.9% of LT recipients (vs 100% in COVID-19-immunocompetent cohort, p=0.024). CONCLUSIONS: Our findings suggest that the humoral response of LT recipients is only slightly lower than expected, compared with COVID-19 immunocompetent controls. Testing for anti-S antibodies alone can lead to an overestimation of the neutralising ability in LT recipients. Altogether, routine antibody testing against separate SARS-CoV-2 antigens and functional testing show that the far majority of LT patients are capable of mounting an adequate antibody response with neutralising ability.

[Autoimmune hepatitis: 2021 update]. / Hépatite autoimmune : mise au point 2021.

Autoimmune hepatitis is a rare disease which can present as acute or chronic forms and can be difficult to diagnose due to its variable clinical presentation. The disease arises in genetically susceptible individuals and several triggers have been identified. The diagnosis is based on the presence of autoantibodies, elevated transaminases and serum immunoglobulin G levels as well as a compatible histology. First-line immunosuppressive treatment strategies lead to clinical remission in most patients. In case of non-response, second-line therapies can be used and in case of hepatocellular insufficiency, liver transplantation remains an excellent option.

L'hépatite autoimmune est une maladie rare, pouvant se présenter sous forme aiguë ou chronique et dont le diagnostic peut être difficile à poser en raison d'une présentation clinique variable. La maladie se développe chez des personnes génétiquement prédisposées et plusieurs événements déclencheurs ont été identifiés. Le diagnostic repose sur la présence d'autoanticorps spécifiques, d'une élévation des transaminases et des immunoglobulines G, ainsi que sur une histologie compatible. Les traitements de première ligne, immunosuppresseurs, permettent dans la plupart des cas d'obtenir une rémission clinique. En cas de non-réponse, des traitements de deuxième ligne sont disponibles et lors d'insuffisance hépatocellulaire, la transplantation hépatique reste une excellente option.

Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy.

Immunotherapy is revolutionizing cancer treatment but is often restricted by toxicities. What distinguishes adverse events from concomitant antitumor reactions is poorly understood. Here, using anti-CD40 treatment in mice as a model of TH1-promoting immunotherapy, we showed that liver macrophages promoted local immune-related adverse events. Mechanistically, tissue-resident Kupffer cells mediated liver toxicity by sensing lymphocyte-derived IFN-γ and subsequently producing IL-12. Conversely, dendritic cells were dispensable for toxicity but drove tumor control. IL-12 and IFN-γ were not toxic themselves but prompted a neutrophil response that determined the severity of tissue damage. We observed activation of similar inflammatory pathways after anti-PD-1 and anti-CTLA-4 immunotherapies in mice and humans. These findings implicated macrophages and neutrophils as mediators and effectors of aberrant inflammation in TH1-promoting immunotherapy, suggesting distinct mechanisms of toxicity and antitumor immunity.