The latest medical research on Transplant Hepatology
The research magnet gathers the latest research from around the web, based on your specialty area. Below you will find a sample of some of the most recent articles from reputable medical journals about transplant hepatology gathered by our medical AI research bot.
The selection below is filtered by medical specialty. Registered users get access to the Plexa Intelligent Filtering System that personalises your dashboard to display only content that is relevant to you.
Want more personalised results?Request Access
Natural History of Liver Disease in a Large International Cohort of Children with Alagille syndrome: Results from The GALA Study.Hepatology
Alagille syndrome (ALGS) is a multisystem disorder, characterized by cholestasis. Existing outcome data are largely derived from tertiary centers and real-world data are lacking. This study aimed to elucidate the natural history of liver disease in a contemporary, international, cohort of children with ALGS.
Multicenter retrospective study of children with a clinically and/or genetically confirmed ALGS diagnosis, born Jan-1997 - Aug-2019. Native liver survival (NLS) and event-free survival rates were assessed. Cox models were constructed to identify early biochemical predictors of clinically evident portal hypertension (CEPH) and NLS.
1433 children (57% male) from 67 centers in 29 countries were included. 10 and 18-years NLS rates were 54.4% and 40.3%. By 10 and 18-years, 51.5% and 66.0% of ALGS children experienced ≥1 adverse liver-related event (CEPH, transplant or death). Children (>6 and ≤12 months) with median total bilirubin (TB) levels between ≥5.0 and <10.0 mg/dL had a 4.1-fold (95% CI 1.6 - 10.8) and those ≥10.0 mg/dL had an 8.0-fold (95% CI 3.4 - 18.4) increased risk of developing CEPH compared with those <5.0 mg/dL. Median TB levels between ≥5.0 and <10.0 mg/dL and >10.0 mg/dL were associated with a 4.8 (95% CI 2.4 - 9.7) and 15.6 (95% CI 8.7 - 28.2) increased risk of transplantation relative to <5.0 mg/dL. Median TB <5.0 mg/dL were associated with higher NLS rates relative to ≥5.0 mg/dL, with 79% reaching adulthood with native liver (p<0.001).
In this large international cohort of ALGS, only 40.3% of children reach adulthood with their native liver. A TB <5.0 mg/dL between 6-and-12-months of age is associated with better hepatic outcomes. These thresholds provide clinicians with an objective tool to assist with clinical decision-making and in the evaluation of novel therapies.
Rapid in vivo multiplexed editing (RIME) of the adult mouse liver.Hepatology
Assessing mammalian gene function in vivo has traditionally relied on manipulation of the mouse genome in embryonic stem cells or peri-zygotic embryos. These approaches are time consuming and require extensive breeding when simultaneous mutations in multiple genes is desired. The aim of this study is to introduce a Rapid In vivo Multiplexed Editing (RIME) method, and to provide proof-of-concept of this system.
RIME, a system wherein CRISPR/Cas9 technology, paired with adeno-associated viruses (AAVs), permits the inactivation of one or more genes in the adult mouse liver. The method is quick, requiring as little as 1 month from conceptualization to knockout (KO), and highly efficient, enabling editing in >95% of target cells. To highlight its utility, we used this system to inactivate, alone or in combination, genes with functions spanning metabolism, mitosis, mitochondrial maintenance, and cell proliferation.
RIME enables the rapid, efficient, and inexpensive analysis of multiple genes in the mouse liver in vivo.
RIPK3 dampens mitochondrial bioenergetics and lipid droplet dynamics in metabolic liver disease.Hepatology
Receptor-interacting protein kinase 3 (RIPK3) mediates non-alcoholic fatty liver disease (NAFLD) progression, but its metabolic function is unclear. Here, we aimed to investigate the role of RIPK3 in modulating mitochondria function, coupled with lipid droplet (LD) architecture in NAFLD.
Functional studies evaluating mitochondria and LD biology were performed in wild-type (WT) and Ripk3-/- mice fed a choline-deficient, amino acid-defined (CDAA) diet for 32 and 66 weeks and in CRISPR-Cas9 Ripk3-null fat-loaded immortalized hepatocytes. The association between hepatic perilipin (PLIN) 1 and 5, RIPK3 and disease severity was also addressed in a cohort of NAFLD patients and in PLIN1-associated familial partial lipodystrophy. Ripk3 deficiency rescued impairment in mitochondrial biogenesis, bioenergetics and function in CDAA diet-fed mice and fat-loaded hepatocytes. Ripk3 deficiency was accompanied by a strong upregulation of antioxidant systems, leading to diminished oxidative stress upon fat loading both in vivo and in vitro. Strikingly, Ripk3-/- hepatocytes displayed smaller size LD in higher numbers than WT cells after incubation with free fatty acids. Ripk3 deficiency upregulated adipocyte and hepatic levels of LD-associated proteins PLIN1 and PLIN5. PLIN1 upregulation controlled LD structure and diminished mitochondrial stress upon free fatty acid overload in Ripk3-/- hepatocytes and was associated with diminished human NAFLD severity. Conversely, a pathogenic PLIN1 frameshift variant was associated with NAFLD and fibrosis, as well as with increased hepatic RIPK3 levels in familial partial lipodystrophy.
Ripk3 deficiency restores mitochondria bioenergetics and impacts LD dynamics. RIPK3 inhibition is promising in ameliorating NAFLD.
AIF1+ CSF1R+ MSCs, induced by TNF-α, act to generate an inflammatory microenvironment and promote hepatocarcinogenesis.Hepatology
Increasing evidence suggests that mesenchymal stem cells (MSCs) home to injured local tissues and the tumor microenvironment in the liver. Chronic inflammation is regarded as the major trait of primary liver cancer. However, the characteristics of endogenous MSCs in the inflammatory environment and their role in the occurrence of liver cancer remain obscure.
Using single-cell RNA sequencing, we identified a distinct inflammation-associated subset of MSCs, namely AIF1+ CSF1R+ MSCs, which existed in the microenvironment before the occurrence of liver cancer. Further, we found that this MSC subgroup is likely to be induced by TNF-α stimulation through the TNFR1/SIRT1 pathway. In a rat primary liver cancer model, we showed that MSCs with high SIRT1 expression (Ad-Sirt1-MSCs) promoted macrophage recruitment and synergistically facilitated liver cancer occurrence by secreting CCL5. Interestingly, depletion of macrophages or knockdown of CCL5 expression in Ad-Sirt1-MSCs attenuated the promotive effect of Ad-Sirt1-MSCs on liver inflammation and hepatocarcinogenesis. Finally, we demonstrated that SIRT1 upregulated CCL5 expression via activation of the AKT/HIF1α signaling axis in MSCs.
Together, our results show that MSCs which are mobilized to the injured site can be educated by macrophages. In turn, the educated MSCs are involved in generating a chronic inflammatory microenvironment and promoting hepatocarcinogenesis.
Performance of AGA Clinical Care Pathway for the Risk Stratification of Patients with Nonalcoholic Fatty Liver Disease in the US population.Hepatology
The American Gastroenterological Association (AGA) recently launched the Clinical Care Pathway for the Risk Stratification and Management of Patients with NAFLD to identify adults with significant fibrosis. We aimed to examine this pathway's performance in the US population.
Using the 2017-2018 National Health and Nutrition Examination Survey (NHANES) data, we identified participants aged≥18 with available FIB-4 score and liver stiffness measurement (LSM) in the absence of other liver diseases. Based on the AGA clinical pathway, FIB-4<1.3 and LSM<8kPa by vibration-controlled transient elastography (VCTE) are associated with low-risk of significant fibrosis. Using these cutoffs, we examined the pathway performance using negative predictive value (NPV) and positive predictive value (PPV) and explored alternative risk stratification strategies. There were 2,322 participants with available data (projected to 94.2 million US adults). The NPV of LSM≥8kPa among those with FIB-4<1.3 was 90%, while the PPV among those with FIB-4 1.3-2.67 was 13%. As diabetes was a strong predictor of fibrosis, we propose a simple, alternative strategy to eliminate the indeterminate FIB-4 range and perform VCTE in those with FIB-4≥1.3 and diabetes. This strategy would decrease the number of VCTEs from 14.5 to 4.9 million and increase PPV from 13% to 33%, without compromising the NPV among those who did not undergo VCTE.
The implementation of the current AGA clinical pathway would lead to overutilization of VCTE. An alternative strategy using FIB-4≥1.3 and diabetes to select adults undergoing second-line testing will improve this pathway's performance and minimize unnecessary VCTEs.
The Liver Cancer Immune Microenvironment: Therapeutic Implications for Hepatocellular Carcinoma.Hepatology
The liver is the sixth most common site of primary cancer in humans, and the fourth leading cause of cancer-related death in the world. Hepatocellu...
Genetic predisposition to porto-sinusoidal vascular disorder: a functional genomic-based, multi-generational family study.Hepatology
Porto-sinusoidal vascular disorder (PSVD) is a group of liver vascular diseases featuring lesions encompassing the portal venules and sinusoids unaccompanied by cirrhosis, irrespective of the presence/absence of portal hypertension. It can occur secondary to coagulation disorders or insult by toxic agents. However, the cause of PSVD remains unknown in most cases. Hereditary cases of PSVD are exceptionally rare, but they are of particular interest and may unveil genetic alterations and molecular mechanisms associated with the disease.
We performed genome sequencing of four patients and two healthy individuals of a large multi-generational Lebanese family with PSVD and identified a heterozygous deleterious variant (c.547C>T, p.R183W) of FCHSD1, an uncharacterised gene, in patients. This variant segregated with the disease, and its pattern of inheritance was suggestive of autosomal dominant with variable expressivity. RNA structural modelling of human FCHSD1 suggests that the C-to-T substitution at position 547, corresponding to FCHSD1R183W , may increase both mRNA and protein stability and its interaction with mLST8, a key protein of the mTOR pathway. These predictions were substantiated by biochemical analyses, which showed that FCHSD1R183W induced high FCHSD1 mRNA stability, overexpression of FCHSD1 protein, and an increase in mTORC1 activation. This human FCHSD1 variant was introduced into mice through CRISPR/Cas9 genome editing. Nine out of the fifteen mice carrying the human FCHSD1R183W variant mimicked the phenotype of human PSVD, including splenomegaly and enlarged portal vein.
Aberrant FCHSD1 structure and function leads to mTOR pathway overactivation and may cause PSVD.
FGFR1/Klothoβ agonist BFKB8488A improves lipids and liver health markers in patients with diabetes or NAFLD: a phase 1b randomized trial.Hepatology
BFKB8488A is a bispecific antibody targeting fibroblast growth factor receptor 1c and Klothoβ. This phase 1b study assessed safety, tolerability, pharmacokinetics, immunogenicity, and pharmacodynamics of BFKB8488A in patients with type 2 diabetes mellitus (T2DM) or NAFLD.
Patients were randomized to receive multiple doses of BFKB8488A at various dose levels and dosing intervals (QW, Q2W, or Q4W) or placebo for 12 weeks. The primary outcome was the safety of BFKB8488A. Overall, 153 patients (T2DM: 91; NAFLD: 62) were enrolled and received at least 1 dose of treatment. Of these, 102 patients (62.7%) reported at least 1 adverse event (BFKB8488A: 83 [68.6%]; placebo: 19 [59.4%]). BFKB8488A exhibited nonlinear pharmacokinetics, with greater than dose-proportional increases in exposure. The treatment-emergent ADA incidence was 22.7%. Overall, trends in exposure-dependent increases in HDL and decreases in triglyceride levels were observed. Decreases in ALT and AST were 0.7% and 9.2% for medium-exposure and 7.3% and 11.2% for high-exposure tertiles, compared with increases of 7.5% and 17% in the placebo group, respectively, at Day 85. In NAFLD patients, the mean decrease from baseline liver fat was 13.0%, 34.5%, and 49.0% in the low-, medium-, and high-exposure tertiles, respectively, compared to 0.1% with placebo at Day 85.
BFKB8488A was adequately tolerated in patients with T2DM or NAFLD, leading to triglyceride reduction, HDL improvements, and trends in improvement in markers of liver health for both populations, and marked liver fat reduction in patients with NAFLD. (ClinicalTrials.gov:NCT03060538).
Health Disparities in Chronic Liver Disease.Hepatology
The syndemic of hazardous alcohol consumption, opioid use, and obesity have led to important changes in liver disease epidemiology that have exacer...
Janus Kinase 2 inhibition by pacritinib as potential therapeutic target for liver fibrosis.Hepatology
Janus-kinase-2 (JAK2) signaling is increased in human and experimental liver fibrosis with portal hypertension. JAK2 inhibitors, such as pacritinib., are already in advanced clinical development for other indications and might also be effective in liver fibrosis. Here, we investigated the anti-fibrotic role of the JAK2-inhibitor pacritinib on activated hepatic stellate cells (HSC) in vitro and in two animal models of liver fibrosis in vivo.
Transcriptome analyses of JAK2 in human livers and other targets of pacritinib have been shown to correlate with profibrotic factors. While transcription of JAK2 correlated significantly with type I collagen (Col1a1) expression and other profibrotic genes, no correlation was observed for IRAK1 and CSF1R. Pacritinib decreased gene expression of fibrosis markers in mouse primary and human-derived HSC in vitro. Moreover, pacritinib decreased the proliferation, contraction and migration of HSC. C57 BL/6J mice received ethanol in drinking water (16%) or Western diet (WD) in combination with CCl4 intoxication for seven weeks to induce alcoholic or non-alcoholic fatty liver disease. Pacritinib significantly reduced liver fibrosis assessed by gene expression and Sirius red staining, as well as HSC activation assessed by alpha-smooth muscle actin (α-SMA) immunostaining in fibrotic mice. Furthermore, pacritinib decreased the gene expression of hepatic steatosis markers in experimental alcoholic liver disease. Additionally, pacritinib protected against liver injury as assessed by aminotransferase levels.
This study demonstrates that the JAK2 inhibitor pacritinib may be promising for the treatment of alcoholic and non-alcoholic liver fibrosis, and may be therefore relevant for human pathology.
Non-selective Beta Blockers, Hepatic Decompensation and Mortality in Cirrhosis: A National Cohort Study.Hepatology
Little is known about the effectiveness of nonselective beta blockers (NSBBs) in preventing hepatic decompensation in routine clinical settings. We investigated whether NSBBs are associated hepatic decompensation or liver-related mortality in a national cohort of Veterans with Child-Turcotte-Pugh (CTP) A-cirrhosis with no prior decompensations.
In an active comparator, new user design, we created a cohort of new users of carvedilol (n=123) vs. new users of selective beta blockers (SBBs) (n=561) and followed patients for up to 3 years. An inverse probability treatment weighting (IPTW) approach balanced demographic and clinical confounders. The primary analysis simulated intention-to-treat ("pseudo-ITT") with IPTW-adjusted Cox models; secondary analyses were pseudo-as-treated - both were adjusted for baseline and time-updating drug confounders. Subgroup analyses evaluated NSBB effects by hepatitis C (HCV) viremia status, CTP class, platelet count, alcohol-associated liver disease (ALD) etiology, and age. In pseudo-ITT analyses of carvedilol vs. SBBs, carvedilol was associated with a lower hazard of any hepatic decompensation (HR 0.59, 95% CI 0.42-0.83) and the composite outcome of hepatic decompensation/liver-related mortality (HR 0.56, 95% CI 0.41-0.76). Results were similar in pseudo-as-treated analyses (hepatic decompensation: HR 0.55, 95% CI 0.33-0.94; composite outcome: HR 0.62, 95% 0.38-1.01). In subgroup analyses, carvedilol was associated with lower hazard of primary outcomes in the absence of HCV viremia, higher CTP class and platelet count, younger age, and ALD etiology.
There is an ongoing need to noninvasively identify patients who may benefit from NSBBs for the prevention of hepatic decompensation.
Body weight changes and duration of estrogen exposure modulate the evolution of hepatocellular adenomas after contraception discontinuation.Hepatology
The natural history of hepatocellular adenomas (HCA) remains to be better described, especially in non-resected patients. We aim to identify the predictive factors of HCA evolution after estrogen-based contraception discontinuation.
We retrospectively included patients with a histological diagnosis of HCA from three centers. Clinical, radiological, and pathological data were collected to identify predictive factors of radiological evolution as per RECIST 1.1 and occurrence of complications (bleeding, malignant transformation). We built a score using variables modulating estrogen levels: body mass index and duration of estrogen-based contraception. An external cohort was used to validate this score.
183 patients were included; 161 women including 89% under estrogen-based contraception for a median of 12 years. Thirty percents of patients had at least one HNF1A-inactivated HCA, 45.5% at least one inflammatory HCA, and 11% at least one HCA with activation of B-catenin (bHCA/bIHCA). Twenty-one symptomatic bleedings (11%) and 11 malignant transformations (6%) occurred. Age<37 years old (p=0.004) and HCA>5cm at imaging were independently associated with symptomatic bleeding (p=0.003), while bHCA was independently associated with malignant transformation (P<0.001). After a median follow-up of 5 years, radiological regression was observed in 31%, stabilization in 47%, and progression in 22% of patients. Weight loss was associated with regression (p<0.0001) and weight gain with progression (p=0.02). The estrogen exposure score predicted radiological regression (OR=2.33, CI95%=1.29-4.19, p=0.005) with a linear relationship between the rate of estrogen exposure and the probability of regression. This result was confirmed in an external cohort of 72 female patients (p=0.003).
Weight variation is strongly associated with radiological evolution after oral contraception discontinuation. A score of estrogen exposure, easily assessable in clinical practice at diagnosis, predicts regression of HCA.