Development and validation of pFIB scores for exclusion of significant liver fibrosis in pediatric MASLD.

BACKGROUND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent pediatric liver disease, yet accurate risk scores for referral of children/adolescents with suspected clinically significant liver fibrosis are currently lacking. APPROACH RESULTS: Clinical and biochemical variables were collected in a prospective cohort of 327 children and adolescents with severe obesity, in whom liver fibrosis was evaluated by transient elastography. Logistic regression was performed to establish continuous (pFIB-c) and simplified (pFIB-6) diagnostic scores that accurately exclude significant (≥F2) fibrosis. Performance for each was compared to established non-invasive fibrosis scores. These scores were validated in elastography (n=504) and multiple biopsy-proven MASLD (n=261) cohorts. Patient sex, ethnicity, weight z-score, HOMA-IR index, ALT, and presence of hypertension were included in the scores. The pFIB-c and pFIB-6 exhibited good discriminatory capacity (c-statistic of 0.839 and 0.826), outperforming existing indices. Negative predictive values (NPV) were >90% for both scores in the derivation and elastography validation cohorts. Performance in the histological cohorts varied (AUROCs for the pFIB-c between 0.710 and 0.770), as the scores were less accurate when applied to populations in tertiary referral centers characterized by a high prevalence of significant fibrosis and high ALT levels. CONCLUSIONS: Analyzing several cohorts totaling approximately 1100 children and adolescents, we developed novel risk scores incorporating readily available clinical variables. In accordance with the aim of excluding pediatric MASLD-associated fibrosis, the scores performed better in non-selected cohorts of children and adolescents living with obesity than in patients referred to tertiary liver units.

Osteopontin characterizes bile duct-associated macrophages and correlates with liver fibrosis severity in primary sclerosing cholangitis.

BACKGROUND AND AIMS: Primary sclerosing cholangitis (PSC) is an immune-mediated cholestatic liver disease for which pharmacological treatment options are currently unavailable. PSC is strongly associated with colitis and a disruption of the gut-liver axis, and macrophages are involved in the pathogenesis of PSC. However, how gut-liver interactions and specific macrophage populations contribute to PSC is incompletely understood. APPROACH AND RESULTS: We investigated the impact of cholestasis and colitis on the hepatic and colonic microenvironment, and performed an in-depth characterization of hepatic macrophage dynamics and function in models of concomitant cholangitis and colitis. Cholestasis-induced fibrosis was characterized by depletion of resident KCs, and enrichment of monocytes and monocyte-derived macrophages (MoMFs) in the liver. These MoMFs highly express triggering-receptor-expressed-on-myeloid-cells-2 ( Trem2 ) and osteopontin ( Spp1 ), markers assigned to hepatic bile duct-associated macrophages, and were enriched around the portal triad, which was confirmed in human PSC. Colitis induced monocyte/macrophage infiltration in the gut and liver, and enhanced cholestasis-induced MoMF- Trem2 and Spp1 upregulation, yet did not exacerbate liver fibrosis. Bone marrow chimeras showed that knockout of Spp1 in infiltrated MoMFs exacerbates inflammation in vivo and in vitro , while monoclonal antibody-mediated neutralization of SPP1 conferred protection in experimental PSC. In human PSC patients, serum osteopontin levels are elevated compared to control, and significantly increased in advanced stage PSC and might serve as a prognostic biomarker for liver transplant-free survival. CONCLUSIONS: Our data shed light on gut-liver axis perturbations and macrophage dynamics and function in PSC and highlight SPP1/OPN as a prognostic marker and future therapeutic target in PSC.

Further pharmacological and genetic evidence for the efficacy of PlGF inhibition in cancer and eye disease.

Our findings that PlGF is a cancer target and anti-PlGF is useful for anticancer treatment have been challenged by Bais et al. Here we take advantage of carcinogen-induced and transgenic tumor models as well as ocular neovascularization to report further evidence in support of our original findings of PlGF as a promising target for anticancer therapies. We present evidence for the efficacy of additional anti-PlGF antibodies and their ability to phenocopy genetic deficiency or silencing of PlGF in cancer and ocular disease but also show that not all anti-PlGF antibodies are effective. We also provide additional evidence for the specificity of our anti-PlGF antibody and experiments to suggest that anti-PlGF treatment will not be effective for all tumors and why. Further, we show that PlGF blockage inhibits vessel abnormalization rather than density in certain tumors while enhancing VEGF-targeted inhibition in ocular disease. Our findings warrant further testing of anti-PlGF therapies.

Bariatric surgery post-liver transplantation: A Belgian nationwide study.

Weight gain poses a rising concern post-liver transplantation (LT), and metabolic dysfunction-associated steatotic liver disease might impair graft health. The timing is crucial when considering bariatric surgery (BS) in a population with liver disease or transplantation. BS can be considered for post-LT weight gain, although the evidence is limited and the long-term outcome still uncertain. We conducted a national retrospective analysis in 5 Belgian transplant centers and included 25 patients with an LT followed by a bariatric procedure. A total of 187 LT patients without BS were included for comparison. Clinical, biochemical, and outcome data were retrospectively retrieved. In our nationwide cohort, 25 patients had undergone BS post-LT, at a median 3.5 years after LT. Twenty-one (84.0%) patients received a sleeve gastrectomy (SG). Patients were predominantly male (72.0%), with a lower age at time of transplantation compared with the non-BS population (54.5 vs. 60.6, p <0.001). Weight loss was significant and sustained, with a decrease in body mass index from 41.0±4.5 pre-BS to 32.6±5.8 1-3 years post-BS ( p <0.001) and 31.1±5.8 3-5 years post-BS ( p <0.001). Three pre-BS (12.0%) patients presented with recurrent and one (4.0%) de novo metabolic dysfunction-associated steatotic liver disease after LT, with 100% resolution post-BS ( p =0.016). Notable reductions were observed in alanine transaminase levels (40.5±28.5 U/L to 27.1±25.1 U/L post-BS, p =0.05) and HbA1c levels (6.9±1.6 to 6.0±1.4 post-BS, p <0.001). Three patients were re-transplanted, and eight patients died, of which five (20.0%) due to a nonhepatic malignancy and one (4.0%) due to liver failure. SG is the favored BS post-LT and has proven to be safe and feasible in a post-LT setting with favorable metabolic consequences. SG post-LT is a valid treatment for de novo and recurrent metabolic dysfunction-associated steatotic liver disease post-LT. Although we report on the largest cohort to date, there is still a need for larger cohorts to examine the effect of BS on patient and graft survival.

Kupffer Cells Contested as Early Drivers in the Pathogenesis of Primary Sclerosing Cholangitis.

Primary sclerosing cholangitis (PSC) is an idiopathic chronic immune-mediated cholestatic liver disease characterized by fibro-inflammatory bile duct strictures, progressive hepatobiliary fibrosis, and gut-liver axis disruption. The pathophysiology of PSC remains insufficiently characterized, which hampers the development of effective therapies. Hepatic macrophages (MFs) such as Kupffer cells (KCs) are implicated in PSC pathogenesis, but their exact role is unclear. Using the latest markers to discriminate resident KCs (ResKCs) from their monocyte-derived counterparts (MoKCs), and two models of intrahepatic and extrahepatic cholestasis, respectively, this study showed that CLEC4F+TIM4+ ResKCs were depleted after chronic cholestatic liver injury. The infiltrating CLEC4F+TIM4- MoKCs were already enriched during the acute phase of PSC. Transcriptional profiling of hepatic MF subsets during early cholestatic injury indicated that ResKCs were indeed activated and that MoKCs expressed higher levels of pro-inflammatory and proliferative markers compared with those of ResKCs. As indicated in experiments with Clec4fDTR transgenic mice, conditional depletion of KCs, before and during early cholestasis induction, had no effect on the composition of the hepatic myeloid cell pool following injury progression and did not affect disease outcomes. Taken together, these results provide new insights into the heterogeneity of the MF pool during experimental PSC and evidence that depletion of resident and activated KCs during sclerosing cholangitis does not affect disease outcome in mice.

Adipose Tissue Insulin Resistance Correlates with Disease Severity in Pediatric Metabolic Dysfunction-Associated Steatotic Liver Disease: A Prospective Cohort Study.

OBJECTIVES: To assess the role of adipose tissue insulin resistance (Adipo-IR) in the pathogenesis of pediatric metabolic dysfunction-associated steatotic liver disease (MASLD) and to determine Adipo-IR evolution during a lifestyle intervention program. STUDY DESIGN: In this prospective cohort study, children and adolescents with severe obesity were recruited between July 2020 and December 2022 at an inpatient pediatric rehabilitation center. Treatment consisted of dietary intervention and physical activity. Liver steatosis and fibrosis were evaluated using ultrasound examination and transient elastography with controlled attenuation parameter and liver stiffness measurement. Every 4-6 months, anthropometric measurements, serum biochemical analysis, ultrasound examination, and elastography were repeated. Adipo-IR was estimated by the product of the fasting serum insulin times the fasting free fatty acid concentration, and hepatic IR by the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), respectively. RESULTS: Of 200 patients with obesity, 56% had evidence of steatosis on ultrasound examination and 26% were diagnosed with fibrosis (≥F2). Adipo-IR increased progressively from lean controls to patients with obesity to patients with MASLD and MASLD with fibrosis. Adipo-IR was already increased in patients with only mild steatosis (P = .0403). Patients with more insulin-sensitive adipose tissue exhibited a lower liver fat content (P < .05) and serum alanine transaminase levels (P = .001). Adipo-IR correlated positively with visceral adipose tissue weight, waist circumference, and the visceral adipose tissue/gynoid adipose tissue ratio (P < .001), but not with total body fat percentage (P = .263). After 4-6 months of lifestyle management, both MASLD and Adipo-IR improved. CONCLUSIONS: Our data suggest that Adipo-IR is associated with the presence of pediatric MASLD, particularly steatosis.

Transient Kupffer cell depletion and subsequent replacement by infiltrating monocyte-derived cells does not alter the induction or progression of hepatocellular carcinoma.

Due to a combination of rapid disease progression and the lack of curative treatment options, hepatocellular carcinoma (HCC) is one of the deadliest cancers worldwide. Infiltrated, monocyte-derived, tumor-associated macrophages are known to play a role in HCC pathogenesis, but the involvement of Kupffer cells (KCs) remains elusive. Here, we used the Clec4F-diphteria toxin receptor transgenic mouse model to specifically investigate the effect of KC depletion on HCC initiation, progression and neoplastic growth following liver resection. For this purpose, several HCC mouse models with varying underlying etiologies were used and partial hepatectomy was performed. Our results show that in HCC, developed on a fibrotic or non-alcoholic steatohepatitis background, depletion of embryonic KCs at the onset of HCC induction and the subsequent replacement by monocyte-derived KCs does not affect the tumor burden, tumor microenvironment or the phenotype of isolated KCs at end-stage disease. In non-chronic liver disease-associated diethylnitrosamine-induced HCC, ablation of Clec4F+ KCs did not alter tumor progression or neoplastic growth following liver resection. Our results show that temporal ablation of resident KCs does not impact HCC pathogenesis, neither in the induction phase nor in advanced disease, and indicate that bone marrow-derived KCs are able to swiftly repopulate the available KC niche and adopt their phenotype.

Viral clade is associated with severity of symptomatic genotype 3 hepatitis E virus infections in Belgium, 2010-2018.

BACKGROUND & AIMS: HEV genotype (gt) 3 infections are prevalent in high-income countries and display a wide spectrum of clinical presentations. Host - but not viral - factors are reported to be associated with worse clinical outcomes. METHODS: Demographic, clinical, and biochemical data laboratory-confirmed HEV infections (by PCR and/or a combination of IgM and IgG serology) at the Belgian National Reference Centre between January 2010 and June 2018 were collected using standardised case report forms. Genotyping was based on HEV open reading frame 2 sequences. Serum CXCL10 levels were measured by a magnetic bead-based assay. H&E staining was performed on liver biopsies. RESULTS: A total of 274 HEV-infected individuals were included. Subtype assignment was possible for 179/218 viraemic cases, confirming gt3 as dominant with an almost equal representation of clades abchijklm and efg. An increased hospitalisation rate and higher peak serum levels of alanine aminotransferase, bilirubin, and alkaline phosphatase were found in clade efg-infected individuals in univariate analyses. In multivariable analyses, clade efg infections remained more strongly associated with severe disease presentation than any of the previously identified host risk factors, being associated with a 2.1-fold higher risk of hospitalisation (95% CI 1.1-4.4, p = 0.034) and a 68.2% higher peak of bilirubin levels (95% CI 13.3-149.9, p = 0.010), independently of other factors included in the model. In addition, acute clade efg infections were characterised by higher serum CXCL10 levels (p = 0.0005) and a more pronounced liver necro-inflammatory activity (p = 0.022). CONCLUSIONS: In symptomatic HEV gt3 infections, clade efg is associated with a more severe disease presentation, higher serum CXCL10 levels, and liver necro-inflammatory activity, irrespective of known host risk factors. CLINICAL TRIAL REGISTRATION: The protocol was submitted to clinicaltrials.gov (NCT04670419). IMPACT AND IMPLICATIONS: HEV genotype (gt) 3 infections display a wide spectrum of clinical presentations currently ascribed to host factors. Here we examined the role of viral factors on liver disease outcomes by combining viral phylogeny with clinical, biochemical, cytokine, and histological data from 274 Belgian adults infected with HEV presenting between 2010 and 2018. HEV gt 3 clade efg infections were associated with a more severe disease presentation, higher serum CXCL10 levels and liver necro-inflammatory activity, irrespective of known host risk factors. HEV gt3 clade-dependent clinical outcomes call for broad HEV gt3 subtyping in clinical practice and research to help identify those at higher risk for worse outcomes and to further unravel underlying virus-host interactions.

Experimental hepatic encephalopathy causes early but sustained glial transcriptional changes.

Hepatic encephalopathy (HE) is a common complication of liver cirrhosis, associated with high morbidity and mortality, for which no brain-targeted therapies exist at present. The interplay between hyperammonemia and inflammation is thought to drive HE development. As such, astrocytes, the most important ammonia-metabolizing cells in the brain, and microglia, the main immunomodulatory cells in the brain, have been heavily implicated in HE development. As insight into cellular perturbations driving brain pathology remains largely elusive, we aimed to investigate cell-type specific transcriptomic changes in the HE brain. In the recently established mouse bile duct ligation (BDL) model of HE, we performed RNA-Seq of sorted astrocytes and microglia at 14 and 28 days after induction. This revealed a marked transcriptional response in both cell types which was most pronounced in microglia. In both cell types, pathways related to inflammation and hypoxia, mechanisms commonly implicated in HE, were enriched. Additionally, astrocytes exhibited increased corticoid receptor and oxidative stress signaling, whereas microglial transcriptome changes were linked to immune cell attraction. Accordingly, both monocytes and neutrophils accumulated in the BDL mouse brain. Time-dependent changes were limited in both cell types, suggesting early establishment of a pathological phenotype. While HE is often considered a unique form of encephalopathy, astrocytic and microglial transcriptomes showed significant overlap with previously established gene expression signatures in other neuroinflammatory diseases like septic encephalopathy and stroke, suggesting common pathophysiological mechanisms. Our dataset identifies key molecular mechanisms involved in preclinical HE and provides a valuable resource for development of novel glial-directed therapeutic strategies.

Hepatic safety and efficacy of immunomodulatory drugs used in patients with autoimmune hepatitis.

BACKGROUND AND AIMS: There is little data on the hepatic efficacy and safety of immunomodulatory drugs used in patients with autoimmune hepatitis (AIH), despite their established use in dermatology, rheumatology and inflammatory bowel diseases (IBD). Our aim was to collect real-life data on the experience of expert centres in treating AIH patients with these drugs, considered unconventional for AIH management. METHODS: Online survey among hepatology centres being part of the European Reference Network on Hepatological Diseases (ERN RARE-LIVER). RESULTS: 25 AIH patients have been reported. Ten were female, median age at diagnosis was 28 years; median follow-up was 17 months. All had initially received AIH-standard treatment. AIH-unconventional treatment was initiated for concomitant autoimmune diseases in 15 cases: nine for IBD (five vedolizumab and four ustekinumab), and one each for following diseases: autoinflammatory syndrome (tocilizumab), chronic urticaria (omalizumab), rheumatoid arthritis (abatacept), psoriasis (guselkumab), psoriatric arthritis (secukinumab, followed by ustekinumab) and alopecia (ruxolitinib). Three patients were treated with immunomodulatory drugs for side effects of previous treatments, including two patients with IBD treated with vedolizumab and ustekinumab, respectively, and one treated with belimumab. At the end of follow-up, 13 patients were in complete biochemical response, the patient on omalizumab had a relapse, and four patients with concomitant IBD had insufficient response. Seven patients were treated for lack of biochemical remission, of whom six with belimumab, all initially reaching complete biochemical response, but five relapsing during follow-up; and one with secukinumab, having concomitant rheumatoid arthritis and ankylosing spondylitis, reaching complete biochemical response. Only the patient on abatacept received unconventional treatment as monotherapy. Side effects were reported in two patients on belimumab: one recurrent soft tissue infections, one fatigue and arthralgia. CONCLUSION: Among 25 AIH patients who were treated with immunomodulatory drugs for different reasons, the majority had a fovorable course, relapse was frequent in difficult-to-treat patients who received belimumab, and four with concomitant IBD had insufficient response.

Patients hospitalized with alcohol-related liver disease and prior bariatric surgery are more prone to develop acute-on-chronic liver failure.

BACKGROUND & AIMS: Patients with a history of bariatric surgery (BS) are susceptible to developing alcohol use disorder. We and others have previously shown that these patients can develop severe alcohol-related liver disease (ARLD). Our aim was to describe the demographics, co-morbidities and mortality of a hospitalized population diagnosed with alcohol-related liver disease, in relation to BS. METHODS: We included 299 patients hospitalized with ARLD at the Ghent University Hospital between 1 January 2018 and 31 December 2022. Clinical, biochemical and outcome data were retrospectively retrieved from the most recent hospitalization. Statistical analysis was performed using the t test, Mann-Whitney U and χ2 tests. RESULTS: Thirteen per cent (39/299) of patients admitted with ARLD had a history of bariatric surgery, of whom 25 (64.1%) had undergone Roux-en-Y gastric bypass. Patients with a history of BS were predominantly female (76.9%), in contrast to the non-BS population (29.2%) (p < .0001), and despite being significantly younger (p < .0001) and had a similar survival (61.5% vs. 58.1%). Bariatric surgery and older age at diagnosis were both significantly associated with poorer transplant-free survival. The cause of death was acute-on-chronic liver failure in 73.3% of BS patients, compared to only 19.2% of those without a history of BS (p < .0001). The weekly amount of alcohol consumed (p = .012) and duration of use (p < .0001) were significantly lower/shorter in the BS population. CONCLUSIONS: BS patients hospitalized with ARLD are predominantly younger women with a lower cumulative alcohol consumption compared to those without prior BS. BS impacted transplant-free survival, with ACLF as the predominant cause of death in these patients.

Etiology and Outcome of Adult and Pediatric Acute Liver Failure in Europe.

Acute liver failure (ALF) is rare but life-threatening. Common causes include intoxications, infections, and metabolic disorders. Indeterminate etiology is still frequent. No systematic data on incidence, causes, and outcome of ALF across Europe are available. Via an online survey we reached out to European Reference Network Centers on rare liver diseases. Numbers and etiology of ALF cases during 2020 were retrieved and diagnostic and treatment availabilities assessed. In total, 455 cases (306 adult, 149 pediatric) were reported from 36 centers from 20 countries. Intoxication was the most common cause in adult and pediatric care. The number of cases with indeterminate etiology is low. Diagnostic tools and specific treatment options are broadly available within this network. This is the first approach to report on etiology and outcome of ALF in the pediatric and adult population in Europe. High diagnostic yield and standard of care reflects the expert status of involved centers.

Improving quality of life in patients with rare autoimmune liver diseases by structured peer-delivered support (Q.RARE.LI): study protocol for a transnational effectiveness-implementation hybrid trial.

BACKGROUND: Psychosocial support is a crucial component of adequate rare disease care, but to date psychosocial support needs of this patient population are insufficiently met. Within Q.RARE.LI, we strive to evaluate the effectiveness of a structured, transdiagnostic, and location-independent psychosocial support intervention in routine care of patients with rare autoimmune liver diseases in five countries and prepare its implementation. METHODS: Within an effectiveness-implementation hybrid trial, we aim to a) investigate the effectiveness of the intervention in routine care in five diverse healthcare systems and b) assess implementation outcomes, examine and prepare the implementation context, and develop country-specific implementation strategies. To assess effectiveness, we will include N = 240 patients with rare autoimmune liver diseases. Within a two-armed randomized controlled trial (allocation ratio 1:1), we will compare structured and peer-delivered psychosocial support in addition to care-as-usual (CAU) with CAU alone. Outcomes will be assessed via electronic database entry prior to intervention, directly after, and at a three-month follow-up. Our primary effectiveness outcome will be mental health-related quality of life at post-assessment. Secondary outcomes include depression and anxiety severity, perceived social support, helplessness, and disease acceptance. Implementation outcomes will be assessed within a mixed-methods process evaluation. In a quantitative cross-sectional survey, we will examine perceived acceptability and feasibility in patients, peer-counselors, and healthcare providers involved in delivery of the intervention. In qualitative focus groups, we will analyze the implementation context and determine barriers and facilitators for implementation with different stakeholders (patients and/or representatives, peer-counselors, healthcare providers, health insurers). Based on these results, we will derive country-specific implementation strategies and develop a concrete implementation plan for each country. DISCUSSION: The intervention is expected to help patients adjust to their disease and improve their mental quality of life. The transdiagnostic and location-independent program has the potential to reach patients for psychosocial support who are usually hard to reach. By preparing the implementation in five countries, the project can help to make low-threshold psychosocial support available to many patients with rare diseases and improve comprehensive healthcare for an often neglected group. TRIAL REGISTRATION: ISRCTN15030282.

Maternal and Perinatal Risk Factors for Pediatric Nonalcoholic Fatty Liver Disease: A Systematic Review.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) has become the most common pediatric liver disease. The intrauterine and early life environment can have an important impact on long-term metabolic health. We investigated the impact of maternal prepregnancy obesity, (pre)gestational diabetes, breastfeeding, and birth anthropometrics/preterm birth on the development of NAFLD in children and adolescents. METHODS: A comprehensive search was performed in MEDLINE, PubMed Central, EMBASE, and grey literature databases through August 2020. The primary outcome was the prevalence of pediatric NAFLD, whereas the histologic severity of steatohepatitis and/or fibrosis were secondary outcomes. Study selection, data extraction, and quality assessment were performed by 2 independent reviewers. RESULTS: Our systematic review included 33 articles. Study heterogeneity regarding patient populations, diagnostic tools, and overall quality was considerable. Eight studies determined the impact of maternal prepregnancy overweight/obesity and identified this as a possible modifiable risk factor for pediatric NAFLD. Conversely, 8 studies investigated (pre)gestational diabetes, yet the evidence on its impact is conflicting. Breastfeeding was associated with a reduced risk for NAFLD, steatohepatitis, and fibrosis, especially in studies that evaluated longer periods of breastfeeding. Being born preterm or small for gestational age has an unclear impact on the development of NAFLD, although an early catch-up growth might drive NAFLD. CONCLUSIONS: In a systematic review, we found that maternal prepregnancy overweight and obesity were associated with an increased risk of pediatric NAFLD. Breastfeeding might be protective against the development of NAFLD when the duration of breastfeeding is sufficiently long (≥6 months).

Intensive Lifestyle Management Improves Steatosis and Fibrosis in Pediatric Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: Childhood obesity, with associated comorbidities such as nonalcoholic fatty liver disease (NAFLD), is an increasing global health problem. Although lifestyle management is the mainstay of treatment, its efficacy on liver fibrosis has not yet been established. METHODS: Children and adolescents admitted for severe obesity at a tertiary center (Zeepreventorium, De Haan, Belgium) were enrolled in this prospective study. Intensive lifestyle therapy encompassed caloric restriction, physical activity, education on a healthy lifestyle, and psychosocial support. At baseline, 6 months, and 12 months, liver ultrasound and transient elastography with controlled attenuation parameter were performed to assess liver steatosis and fibrosis. RESULTS: A total of 204 patients (median age, 14.0 y; body mass index Z-score, +2.8) were evaluated at admission. NAFLD on ultrasound was present in 71.1%, whereas 68.6% had controlled attenuation parameter values of 248 dB/m or greater. A total of 32.8% of patients had at least F2 fibrosis, including 10.3% with transient elastography of 9 kPa or greater. After 6 months, the median body weight loss was 16.0% in the 167 patients evaluated. Fibrosis improved in 75.0% (P < .001). Baseline severity of liver fibrosis and steatosis were predictors of fibrosis resolution. Seventy-nine patients had reached the 1-year time point. The improvements were sustained because fibrosis regressed at least 1 stage in all patients with baseline fibrosis. Fasting serum alanine aminotransferase and homeostasis model assessment of insulin resistance decreased significantly over the 1-year period (P < .001). CONCLUSIONS: NAFLD and associated fibrosis are highly prevalent in children and adolescents with severe obesity. An intensive multidisciplinary lifestyle management program that causes significant weight loss not only improves liver steatosis, but also fibrosis.

90Y Radioembolization versus Drug-eluting Bead Chemoembolization for Unresectable Hepatocellular Carcinoma: Results from the TRACE Phase II Randomized Controlled Trial.

Background Transarterial chemoembolization (TACE) is the recommended treatment for intermediate hepatocellular carcinoma (HCC) according to the Barcelona Clinic Liver Cancer guidelines. Prospective uncontrolled studies suggest that yttrium 90 (90Y) transarterial radioembolization (TARE) is a safe and effective alternative. Purpose To compare the efficacy and safety of TARE with TACE for unresectable HCC. Materials and Methods In this single-center prospective randomized controlled trial (TRACE), 90Y glass TARE was compared with doxorubicin drug-eluting bead (DEB) TACE in participants with intermediate-stage HCC, extended to Eastern Cooperative Oncology Group performance status 1 and those with early-stage HCC not eligible for surgery or thermoablation. Participants were recruited between September 2011 and March 2018. The primary end point was time to overall tumor progression (TTP) (Kaplan-Meier analysis) in the intention-to-treat (ITT) and per-protocol (PP) groups. Results At interim analysis, 38 participants (median age, 67 years; IQR, 63-72 years; 33 men) were randomized to the TARE arm and 34 (median age, 68 years; IQR, 61-71 years; 30 men) to the DEB-TACE arm (ITT group). Median TTP was 17.1 months in the TARE arm versus 9.5 months in the DEB-TACE arm (ITT group hazard ratio [HR], 0.36; 95% CI: 0.18, 0.70; P = .002) (PP group, 32 and 34 participants, respectively, in each arm; HR, 0.29; 95% CI: 0.14, 0.60; P < .001). Median overall survival was 30.2 months after TARE and 15.6 months after DEB-TACE (ITT group HR, 0.48; 95% CI: 0.28, 0.82; P = .006). Serious adverse events grade 3 or higher (13 of 33 participants [39%] vs 19 of 36 [53%] after TARE and DEB-TACE, respectively; P = .47) and 30-day mortality (0 of 33 participants [0%] vs three of 36 [8.3%]; P = .24) were similar in the safety groups. At the interim, the HR for the primary end point, TTP, was less than 0.39, meeting the criteria to halt the study. Conclusion With similar safety profile, yttrium 90 radioembolization conferred superior tumor control and survival compared with chemoembolization using drug-eluting beads in selected participants with early or intermediate hepatocellular carcinoma. Clinical trial registration no. NCT01381211 © RSNA, 2022 Online supplemental material is available for this article.

Combined Therapy with a CCR2/CCR5 Antagonist and FGF21 Analogue Synergizes in Ameliorating Steatohepatitis and Fibrosis.

(1) Background: With new potential drug targets emerging, combination therapies appear attractive to treat non-alcoholic steatohepatitis (NASH) and fibrosis. Chemokine receptor CCR2/5 antagonists can improve fibrosis by reducing monocyte infiltration and altering hepatic macrophage subsets. Fibroblast growth factor 21 (FGF21) may improve NASH by modulating lipid and glucose metabolism. We compared effects of single drug to combination treatment as therapeutic strategies against NASH. (2) Methods: We analyzed serum samples and liver biopsies from 85 nonalcoholic fatty liver disease (NAFLD) patients. A CCR2/5 inhibitor (BMS-687681-02-020) and a pegylated FGF21 agonist (BMS-986171) were tested in male C57BL/6J mice subjected to dietary models of NASH and fibrosis (choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) up to 12 weeks; short- (2w) or long-term (6w) treatment). (3) Results: In NAFLD patients, chemokine CCL2 and FGF21 serum levels correlated with inflammatory serum markers, only CCL2 was significantly associated with advanced liver fibrosis. In rodent NASH, CCR2/5 inhibition significantly reduced circulating Ly6C+ monocytes and hepatic monocyte-derived macrophages, alongside reduced hepatic inflammation and fibrosis. FGF21 agonism decreased body weight, liver triglycerides and histological NASH activity. Combination treatment reflected aspects of both compounds upon short- and long-term application, thereby amplifying beneficial effects on all aspects of steatohepatitis and fibrosis. (4) Conclusions: CCR2/5 inhibition blocks hepatic infiltration of inflammatory monocytes, FGF21 agonism improves obesity-related metabolic disorders. Combined therapy ameliorates steatohepatitis and fibrosis more potently than single drug treatment in rodent NASH, corroborating the therapeutic potential of combining these two approaches in NASH patients.

Vasomodulators and Liver Transplantation for Portopulmonary Hypertension: Evidence From a Systematic Review and Meta-Analysis.

BACKGROUND AND AIMS: Untreated portopulmonary hypertension (PoPH) carries a poor prognosis. Previous reports have described vasomodulator (VM) therapy and liver transplantation (LT) as treatment options. We aimed to provide summary estimates on the endpoints of pulmonary hemodynamics and survival in patients with PoPH, treated with different modalities. APPROACH AND RESULTS: We performed a systematic review with meta-analysis of mainly observational and case-control studies describing no treatment, VM, LT, or VM + LT in patients with PoPH. Twenty-six studies (1,019 patients) were included. Both VM and VM + LT improve pulmonary hemodynamics. A substantial proportion of patients treated with VM become eligible for LT (44%; 95% confidence interval [CI], 31-58). Pooled estimates for 1-, and 3-year postdiagnosis survival in patients treated with VM were 86% (95% CI, 81-90) and 69% (95% CI, 50-84) versus 82% (95% CI, 52-95) and 67% (95% CI, 53-78) in patients treated with VM + LT. Of note, studies reporting on the effect of VM mainly included Child-Pugh A/B patients, whereas studies reporting on VM + LT mainly included Child-Pugh B/C. Seven studies (238 patients) included both patients who received VM only and patients who received VM + LT. Risk of death in VM-only-treated patients was significantly higher than in patients who could be transplanted as well (odds ratio, 3.5; 95% CI, 1.4-8.8); however, importantly, patients who proceeded to transplant had been selected very strictly. In 50% of patients, VM can be discontinued post-LT (95% CI, 38-62). CONCLUSIONS: VM and VM + LT both improve pulmonary hemodynamics and prognosis in PoPH. In a strictly selected subpopulation of cases where LT is indicated based on severe liver disease and where LT is considered safe and feasible, treatment with VM + LT confers a better prognosis. Considering successful VM, 44% can proceed to LT, with half being able to postoperatively stop medication.

The utility of biomarkers in prognosis assessment of patients with acute liver failure.

BACKGROUND: Acute liver failure (ALF) is a rare but potential lethal condition characterized by the sudden development of jaundice, coagulopathy and hepatic encephalopathy in patients without underlying liver disease. In selected patients, emergency liver transplantation is required. Selection of these patients is based on clinical criteria such as the Kings College Criteria (KCC) or the Clichy criteria. AIMS: The aim of this work is to provide an overview of potential biomarkers that could improve the prognostic value of KCC. RESULTS: Several promising biomarkers involved in related pathophysiological processes have been identified. Some could be as stand-alone biomarkers; however, the best prognostic values have been observed in the combination of biomarkers with current models. Among these, the ALFSG Index that combines clinical parameters and circulating blood levels of CK18 claims a higher prognostic value than KCC. CONCLUSIONS: In this review, all potential biomarkers for ALF have been summarized to give an overview of the work performed over the last years, and a glimpse of what to expect in this field in the coming years.

Differential effects of selective- and pan-PPAR agonists on experimental steatohepatitis and hepatic macrophages☆.

BACKGROUND & AIMS: Peroxisome proliferator-activated receptors (PPARs) are essential regulators of whole-body metabolism, but also modulate inflammation in immune cells, notably macrophages. We compared the effects of selective PPAR agonists to those of the pan-PPAR agonist lanifibranor in non-alcoholic fatty liver disease (NAFLD), and studied isoform-specific effects on hepatic macrophage biology. METHODS: Lanifibranor or selective PPARα (fenofibrate), PPARγ (pioglitazone) and PPARδ (GW501516) agonists were therapeutically administered in choline-deficient, amino acid-defined high-fat diet (CDAA-HFD)- and Western diet (WD)-fed mouse models of NAFLD. Acute liver injury was induced by carbon tetrachloride (CCl4). The role of PPARs on macrophage functionality was studied in isolated hepatic macrophages, bone marrow-derived macrophages stimulated with palmitic acid, and circulating monocytes from patients with NAFLD. RESULTS: Lanifibranor improved all histological features of steatohepatitis in CDAA-HFD-fed mice, including liver fibrosis, thereby combining and exceeding specific effects of the single PPAR agonists. Its potent anti-steatotic efficacy was confirmed in a 3D liver biochip model with primary cells. Infiltrating hepatic monocyte-derived macrophages were reduced following PPAR agonist administration, especially with lanifibranor, even after short-term treatment, paralleling improved steatosis and hepatitis. Lanifibranor similarly decreased steatosis, liver injury and monocyte infiltration in the WD model. In the acute CCl4 model, neither single nor pan-PPAR agonists directly affected monocyte recruitment. Hepatic macrophages isolated from WD-fed mice displayed a metabolically activated phenotype. Lanifibranor attenuated the accompanying inflammatory activation in both murine palmitic acid-stimulated bone marrow-derived macrophages, as well as patient-derived circulating monocytes, in a PPARδ-dependent fashion. CONCLUSION: Pan-PPAR agonists combine the beneficial effects of selective PPAR agonists and may counteract inflammation and disease progression more potently. PPARδ agonism and lanifibranor directly modulate macrophage activation, but not infiltration, thereby synergizing with beneficial metabolic effects of PPARα/γ agonists. LAY SUMMARY: Peroxisome proliferated-activated receptors (PPARs) are essential regulators of metabolism and inflammation. We demonstrated that the pan-PPAR agonist lanifibranor ameliorated all aspects of non-alcoholic fatty liver disease in independent experimental mouse models. Non-alcoholic fatty liver disease and fatty acids induce a specific polarization status in macrophages, which was altered by lanifibranor to increase expression of lipid handling genes, thereby decreasing inflammation. PPAR isoforms have differential therapeutic effects on fat-laden hepatocytes, activated hepatic stellate cells and inflammatory macrophages, supporting the clinical development of pan-PPAR agonists.