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 AccessNon-invasive liver disease assessment to identify portal hypertension: A systematic review supporting the AASLD Practice Guideline.
HepatologyPortal hypertension is a serious complication of cirrhosis, which leads to life-threatening complications. Hepatic venous pressure gradient (HVPG), a surrogate of portal pressure, is the reference standard test to assess the severity of portal hypertension. However, since HVPG is limited by its invasiveness and by its availability, non-invasive liver disease assessments (NILDAs) to assess portal pressure, especially clinically significant portal hypertension (CSPH), are needed.
We conducted a systematic review of Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, and Daily, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus from each database's inception to April 22nd, 2022. We included only studies in English that examined ≥50 patients in single liver disease etiologies which compared non-invasive tests (blood, and/or imaging) to HVPG for predicting clinically significant portal hypertension (CSPH; defined as HVPG ≥10 mm Hg) in patients with chronic liver disease (this therefore limited the number of studies that could be included). Outcomes reported included measures of diagnostic test accuracy. Additionally, a narrative review of studies not eligible for the systematic review is also provided.
Nine studies with 2,492 patients met the inclusion criteria. There was substantial heterogeneity with regard to liver disease studied and cutoff values used to detect CSPH. Blood based tests, including aspartate to platelet ratio index (APRI) (56% sensitivity and 68% specificity) and fibrosis-4 (FIB-4) (54% sensitivity and 73% specificity) had low accuracy measures. Imaging based tests (transient elastography (TE) and shear wave elastography detection of liver stiffness (LSM)) had better accuracy, but also had substantial variation; at 15 kPa, TE sensitivity was 90%-96% and specificity was 48%-50% while at 25 kPa, its sensitivity and specificity were 57%-85% and 82%-93%, respectively. The narrative review suggested that imaging based tests are the best available NILDA to detect CSPH, CSPH is highly unlikely to be present at an LSM ≤15 kPa and likely to be present at an LSM ≥25 kPa.
While imaging-based NILDA appeared to have higher accuracy than blood-based tests to detect CSPH, only 9 studies fit the a priori established inclusion criteria for the SR. In addition, there was substantial study heterogeneity and variation in cutoffs for LSM to detect CSPH, limiting the ability to establish definitive cutoffs to detect CSPH.
Accuracy of blood-based biomarkers for staging liver fibrosis in chronic liver disease: A systematic review supporting the AASLD Practice Guideline.
HepatologyBlood-based biomarkers have been proposed as an alternative to liver biopsy for non-invasive liver disease assessment (NILDA) in chronic liver disease (CLD). Our aims for this systematic review were to evaluate the diagnostic utility of selected blood-based tests either alone, or in combination, for identifying significant fibrosis (F2-4), advanced fibrosis (F3-4) and cirrhosis (F4), as compared to biopsy in CLD.
We included a comprehensive search of databases including Ovid MEDLINE(R), EMBASE, Cochrane Database, and Scopus through to April 2022. Two independent reviewers selected 286 studies with 103,162 patients. The most frequently identified studies included the simple aminotransferase-to-platelet ratio index (APRI) and fibrosis (FIB)-4 markers (with low-to-moderate risk of bias) in hepatitis B virus (HBV) and C virus (HCV), HIV-HCV/HBV co-infection, and nonalcoholic fatty liver disease (NAFLD). Positive (LR+) and negative (LR) likelihood ratios across direct and indirect biomarker tests for HCV and HBV for F2-4, F3-4, or F4 were 1.66-6.25 and 0.23-0.80, 1.89-5.24 and 0.12-0.64, and 1.32-7.15 and 0.15-0.86 respectively; LR+ and LR for NAFLD F2-4, F3-4 and F4 were 2-65-3.37 and 0.37-0.39, 2.25-6.76 and 0.07-0.87, and 3.90 and 0.15 respectively. Overall, proportional odds ratio indicated FIB-4 <1.45 was better than APRI <0.5 for F2-4. FIB-4 >3.25 was also better than APRI >1.5 for F3-4 and F4. There was limited data for combined tests.
Blood-based biomarkers are associated with small-to-moderate change in pre-test probability for diagnosing F2-4, F3-4, and F4 in viral hepatitis, HIV-HCV co-infection, and NAFLD, with limited comparative or combination studies for other CLD.
Imaging-based non-invasive liver disease assessment for staging liver fibrosis in chronic liver disease: A systematic review supporting the AASLD Practice Guideline.
HepatologyTransient elastography (TE), shear-wave elastography (SWE), and/or magnetic resonance elastography (MRE), each providing liver stiffness measurement (LSM), are the most studied imaging-based noninvasive liver disease assessment (NILDA) techniques. To support the American Association for the Study of Liver Diseases guidelines on NILDA, we summarized the evidence on the accuracy of these LSM methods to stage liver fibrosis (F).
A comprehensive search for studies assessing LSM by TE, SWE, or MRE for the identification of significant fibrosis (F2-4), advanced fibrosis (F3-4), or cirrhosis (F4), utilizing histopathology as standard of reference by liver disease etiology in adults or children from inception to April 2022 was performed. We excluded studies with <50 patients with a single disease entity and mixed liver disease etiologies (with the exception of HCV/HIV co-infection). Out of 9447 studies, 240 with 61,193 patients were included in this systematic review. In adults, sensitivities for the identification of F2-4 ranged from 51% to 95%, for F3-4 from 70% to 100%, and for F4 from 60% to 100% across all techniques/diseases, whereas specificities ranged from 36% to 100%, 74% to 100%, and 67% to 99%, respectively. The largest body of evidence available was for TE; MRE appeared to be the most accurate method. Imaging-based NILDA outperformed blood-based NILDA in most comparisons, particularly for the identification of F3-4/F4. In the pediatric population, imaging-based NILDA is likely as accurate as in adults.
LSM from TE, SWE, and MRE show acceptable to outstanding accuracy for the detection of liver fibrosis across various liver disease etiologies. Accuracy increased from F2-4 to F3-4 and was the highest for F4. Further research is needed to better standardize the use of imaging-based NILDA, particularly in pediatric liver diseases.
Feasibility of hepatitis C elimination by screening and treatment alone in high-income countries.
HepatologyDespite the availability of highly effective direct-acting antiviral therapy, chronic hepatitis C (CHC) continues to cause a major public health burden. In many high-income countries, treatment rates have been declining, which was exacerbated by the impact of the COVID-19 pandemic, threatening the ability to meet the World Health Organization (WHO)'s targets for eliminating hepatitis C virus (HCV) as a public health threat by 2030. We sought to model the impact of CHC in Canada, a resource-rich country with ongoing immigration from HCV-endemic regions; which relies exclusively on risk-based screening for case identification.
We developed an agent-based model to characterize the HCV epidemic in a high-income country with ongoing immigration. Combinations of prevention such as harm-reduction, screening, and treatment strategies were considered. Model parameters were estimated from the literature and calibrated against historical HCV data. Sensitivity analyses were performed to assess uncertainty. Under the current status quo of risk-based screening, we predict the incidence of CHC-induced decompensated cirrhosis, hepatocellular carcinoma, and liver-related deaths would decrease by 79.4%, 76.1%, and 62.1%, respectively, between 2015-2030, but CHC incidence would only decrease by 11.1%. Results were sensitive to HCV transmission rate and annual number of people initiating treatment.
Current risk-based screening, and subsequent treatment, will be inadequate to achieve WHO goals. With extensive scale-up in screening, and treatment, the mortality target may be achievable, but the target for preventing new CHC cases is unlikely reachable, highlighting the importance of developing enhanced harm-reduction strategies for HCV elimination.
Safety and efficacy of off-label bulevirtide monotherapy in HDV patients with decompensated Child-B cirrhosis - a real world case series.
HepatologyChronic hepatitis D is the most debilitating form of viral hepatitis frequently progressing to cirrhosis and subsequent decompensation. However, the HDV entry inhibitor bulevirtide is only approved for antiviral treatment of patients with compensated disease. We aimed for the analysis of real-world data on the off-label use of bulevirtide in the setting of decompensated liver cirrhosis.
We conducted a retrospective study in HDV-patients with decompensated liver disease at German, Austrian and Italian centers. We included 19 patients (47% male, mean age: 51 y) with liver cirrhosis Child-Pugh B. Median MELD score was 12 (range 9-17) at treatment initiation. Median observation period was 41 weeks. Virologic response was achieved in 74% and normal ALT was observed in 74%. Combined response was achieved by 42%. The most relevant adverse events included self-limited ALT flares, an asymptomatic increase in bile acids and need for liver transplantation. Despite bile acid increases adverse events were considered unrelated. Clinical and laboratory improvement from Child-Pugh B to A occurred in 47% (n=9/19). Improvements in the amount of ascites were observed in 58% of patients initially presenting with ascites (n=7/12).
This report on off-label bulevirtide treatment in patients with decompensated HDV cirrhosis shows similar virologic and biochemical response rates as observed in compensated liver disease. Significant improvements were observed on surrogates of hepatic function and portal hypertension. However, this improvement was not seen in all patients. Controlled trials are needed to confirm safety and efficacy of bulevirtide in decompensated HDV-cirrhosis.
Impact of clonal hematopoiesis of indeterminate potential on hepatocellular carcinoma in individuals with steatotic liver disease.
HepatologyMetabolic dysfunction associated steatotic liver disease (MASLD) is a global epidemic and is the most rapidly rising cause of hepatocellular carcinoma (HCC). Clonal hematopoiesis of indeterminate potential (CHIP) contributes to neoplastic and cardiometabolic disorders and is considered a harbinger of tissue inflammation. CHIP was recently associated with increased risk of liver disease. The aim of this study was to examine whether CHIP is associated with HCC development in patients with SLD.
We considered individuals with MASLD-HCC (n=208) and controls with (n=414) and without (n=259) advanced fibrosis who underwent whole exome sequencing. CHIP was diagnosed when ≥2 variant callers identified a known myeloid mutation with VAF ≥2%.
CHIP was observed in 116 participants (13.1%), most frequently in DNMT3A, TET2, TP53 and ASXL1, and correlated with age (p<0.0001) and advanced liver fibrosis (p=0.001). Higher AST levels predicted non-DNMT3A-CHIP, in particular with variant allele frequency (VAF)≥10% (OR 1.14, 1.03-1.28 and OR 1.30, 1.12-1.49, respectively, p<0.05). After adjustment for sex, diabetes and a polygenic risk score of inherited MASLD predisposition CHIP was associated with cirrhosis (2.00, 1.30-3.15, p=0.02), and with HCC even after further adjustment for cirrhosis (OR 1.81, 1.11-2.00, 1.30-3.15, p=0.002). Despite the strong collinearity among aging and development of CHIP and HCC, non-DNTM3A-CHIP and TET2 lesions remained associated with HCC after full correction for clinical/genetics covariates and age (OR 2.45, 1.35-4.53; OR 4.8, 1.60-17.0, p=0.02).
We observed an independent association between CHIP, particularly related to non-DNTM3A and TET2 genetic lesions, and MASLD-HCC.
Intrahepatic immunoglobulin a complex induces polarization of cancer-associated fibroblasts to matrix phenotypes in the tumor microenvironment of hepatocellular carcinoma.
HepatologyCancer-associated fibroblasts (CAFs) play key roles in the tumor microenvironment (TME). Immunoglobulin A (IgA) contributes to inflammation and dismantling anti-tumor immunity in the human liver. In this study, we aimed to elucidate the effects of the IgA complex on CAFs in the TME of hepatocellular carcinoma (HCC).
CAF dynamics in HCC TME were analyzed via single-cell RNA sequencing of HCC samples. CAFs isolated from 50 HCC samples were treated with mock or serum-derived IgA dimers in vitro. Progression-free survival of advanced HCC patients treated with atezolizumab and bevacizumab was significantly longer in those with low serum IgA levels (p<0.05). Single-cell analysis showed that sub-cluster proportions in the CAF-fibroblast activation protein-α (FAP) matrix were significantly increased in patients with high serum IgA levels. Flow cytometry revealed a significant increase in the mean fluorescence intensity of FAP in the CD68+ cells from patients with high serum IgA levels (p<0.001). We confirmed CD71 (IgA receptor) expression in CAFs, and IgA-treated CAFs exhibited higher programmed death-ligand 1 (PD-L1) expression levels than those in mock-treated CAFs (p<0.05). Co-culture with CAFs attenuated cytotoxic function of activated CD8+ T cells. Interestingly, activated CD8+ T cells co-cultured with IgA-treated CAFs exhibited increased programmed death-1 (PD-1) expression levels than those co-cultured with mock-treated CAFs (p<0.05).
Intrahepatic IgA induced polarization of HCC-CAFs into more malignant matrix phenotypes and attenuates cytotoxic T cell function. Our study highlighted their potential roles in tumor progression and immune suppression.
Inhibition of sodium-glucose cotransporter-2 and liver-related complications in individuals with diabetes: A mendelian randomization and population-based cohort study.
HepatologyNo medication has been found to reduce the liver-related events. We evaluated the effect of sodium-glucose cotransporter-2 inhibitor (SGLT2i) on liver-related outcomes.
Single nucleotide polymorphisms (SNPs) associated with SGLT2 inhibition were identified, and a genetic risk score (GRS) was computed using the UK Biobank (UKB) data (n=337,138). Two-sample Mendelian randomization (MR) was conducted using the FinnGen (n=218,792) database and UKB data. In parallel, a nationwide population-based study using the Korean National Health Insurance Service (NHIS) database was conducted. The development of liver-related complications (i.e., hepatic decompensation, hepatocellular carcinoma, liver transplantation, and death) was compared between individuals with type 2 diabetes mellitus and steatotic liver diseases treated with SGLT2i (n=13,208) and propensity score-matched individuals treated with dipeptidyl peptidase-4 inhibitor (DPP4i) (n=70,342). After computing GRS with six SNPs (rs4488457, rs80577326, rs11865835, rs9930811, rs34497199, and rs35445454), GRS-based MR showed that SGLT2 inhibition (per 1 SD increase of GRS, 0.1% lowering of HbA1c) was negatively associated with cirrhosis development (adjusted odds ratio=0.83, 95% confidence interval [CI]=0.70-0.98, p=0.03) and this was consistent in two-sample MR (odds ratio=0.73, 95% CI=0.60-0.90, p=0.003). In the Korean NHIS database, the risk of liver-related complications was significantly lower in the SGLT2i group than in the DPP4i group (adjusted hazard ratio [aHR]=0.88, 95% CI=0.79-0.97, p=0.01), and this difference remained significant (aHR=0.72-0.89, all p<0.05) across various sensitivity analyses.
Both Mendelian randomizations using two European cohorts and a Korean nationwide population-based cohort study suggest that SGLT2 inhibition is associated with a lower risk of liver-related events.
Early onset of pathological polyploidization and cellular senescence in hepatocytes lacking RAD51 creates a pro-fibrotic and pro-tumorigenic inflammatory microenvironment.
HepatologyRAD51 is a highly conserved DNA repair protein and is indispensable for embryonic viability. As a result, the role of RAD51 in liver development and function is unknown. Our aim was to characterize the function of RAD51 in postnatal liver development.
RAD51 is highly expressed during liver development and during regeneration following hepatectomy and hepatic injury, and is also elevated in chronic liver diseases. We generated hepatocyte-specific Rad51 deletion mouse model using Alb-Cre (Rad51-CKO) and AAV8-TBG-Cre to evaluate the function of RAD51 in liver development and regeneration. The phenotype in Rad51-CKO mice is dependent on Cre recombinase dosage, with Rad51fl/fl; Alb-Cre+/+ manifesting a more severe phenotype than the Rad51fl/fl; Alb-Cre+/- mice. RAD51 deletion in postnatal hepatocytes results in aborted mitosis and early onset of pathological polyploidization that is associated with oxidative stress and cellular senescence. Remarkable liver fibrosis occurs spontaneously as early as in 3-month-old Rad51fl/fl; Alb-Cre+/+ mice. While liver regeneration is compromised in Rad51-CKO mice, they are more tolerant of carbon tetrachloride (CCl4)-induced hepatic injury and resistant to DEN/CCl4-induced hepatocellular carcinoma (HCC). A chronic inflammatory microenvironment created by the senescent hepatocytes appears to activate ductular reaction and consequently a transdifferentiation of cholangiocytes to hepatocytes. The newly-derived RAD51 functional immature hepatocytes proliferate vigorously, acquire increased malignancy, and eventually give rise to HCC.
Our results demonstrate a novel function of RAD51 in liver development, homeostasis and tumorigenesis. The Rad51-CKO mice represent a unique genetic model for premature liver senescence, fibrosis and hepatocellular carcinogenesis.
Restoring SRSF3 in Kupffer cells attenuates obesity-related insulin resistance.
HepatologyIn obesity, depletion of Kupffer cells (KCs) expressing CRIg (complement receptor of the immunoglobulin superfamily) leads to microbial DNA accumulation, which subsequently triggers tissue inflammation and insulin resistance. However, the mechanism underlying obesity-mediated changes in KC complement immune functions is largely unknown.
Using KC-specific deactivated Cas9 (dCas9) transgenic mice treated with guide RNA, we assessed the effects of restoring CRIg or the serine/arginine-rich splicing factor 3 (SRSF3) abundance on KC functions and metabolic phenotypes in obese mice. The impacts of weight loss on KC responses were evaluated in a diet switch mouse model. The role of SRSF3 in regulating KC functions was also evaluated using KC-specific SRSF3 knockout mice. Here, we report that overexpression of CRIg in KCs of obese mice protects against bacterial DNA accumulation in metabolic tissues. Mechanistically, SRSF3 regulates CRIg expression, which is essential for maintaining the CRIg+ KC population. During obesity, SRSF3 expression decreases, but it is restored with weight loss through a diet switch, normalizing CRIg+ KCs. KC SRSF3 is also repressed in obese human livers. Lack of SRSF3 in KCs in lean and obese mice decreases their CRIg+ population, impairing metabolic parameters. During the diet switch, the benefits of weight loss are compromised due to SRSF3 deficiency. Conversely, SRSF3 overexpression in obese mice preserves CRIg+ KCs and improves metabolic responses.
Restoring SRSF3 abundance in KCs offers a strategy against obesity-associated tissue inflammation and insulin resistance by preventing bacterial DNA accumulation.
Reversing malnutrition and low muscle strength with targeted enteral feeding in patients awaiting liver transplant: A randomized controlled trial.
HepatologyMost patients with decompensated cirrhosis fail to meet their nutrition targets. The impact of nasogastric feeding (NGF) on malnutrition in cirrhosis remains unknown. This study aims to assess the impact of pre-transplant NGF on pre- and post-liver transplant outcomes.
This single-centre, prospective randomized controlled trial of 55 patients with severe malnutrition and low handgrip strength (HGS) compared standard high-energy high-protein diet to diet plus supplemental nocturnal NGF whilst awaiting transplant. The primary outcome was change in HGS. Median age was 58.5 years (IQR 51.1-64), median MELD 24 (20-28.5), and 32 (58%) were male. Median duration of NGF was 63.0 days (34.5-127), following which time the median between group difference in HGS was 3.6 kg (95% CI: 1.7-5.2, p<0.001); an increase of 20% from baseline. Mid upper-arm circumference, triceps skinfold and immune function all increased significantly with NGF. Muscle and nutritional parameters continued to improve with increasing duration of feeding. NGF significantly increased daily energy intake between groups by 1285 kcal (95% CI: 860-1677) and protein intake by 51 g (95% CI: 32-71) (both p<0.001). All NGF patients met >100% of their measured nutritional requirements. Post-transplant clinical outcomes were similar between groups.
Targeted enteral feeding before LT improves HGS, anthropometry and immune function in severely malnourished cirrhotic patients. These findings provide a strong rationale for early consideration of NGF to reverse malnutrition and improve muscle strength. Appropriately powered studies should explore whether NGF can also impact clinically relevant outcomes including pre- and post-transplant mortality.
Development of a liver disease-Specific large language model chat Interface using retrieval augmented generation.
HepatologyLarge language models (LLMs) have significant capabilities in clinical information processing tasks. Commercially available LLMs, however, are not optimized for clinical uses and are prone to generating hallucinatory information. Retrieval-augmented generation (RAG) is an enterprise architecture that allows embedding of customized data into LLMs. This approach "specializes" the LLMs and is thought to reduce hallucinations.
We developed "LiVersa," a liver disease-specific LLM, by using our institution's protected health information (PHI)-complaint text embedding and LLM platform, "Versa." We conducted RAG on 30 publicly available American Association for the Study of Liver Diseases guidance documents to be incorporated into LiVersa.
We evaluated LiVersa's performance by conducting two rounds of testing. First, we compared LiVersa's outputs versus those of trainees from a previously published knowledge assessment. LiVersa answered all 10 questions correctly. Second, we asked 15 hepatologists to evaluate the outputs to ten hepatology topic questions generated by LiVersa, OpenAI's ChatGPT 4, and Meta's LLaMA 2. LiVersa's outputs were more accurate but were rated less comprehensive and safe compared to those of ChatGPT 4.
In this demonstration, we built a disease-specific and PHI-compliant LLMs using RAG. While LiVersa demonstrated higher accuracy in answering questions related to hepatology - there were some deficiencies due to limitations set by the number of documents used for RAG. LiVersa will likely require further refinement before potential live deployment. The LiVersa prototype, however, is a proof of concept for utilizing RAG to customize LLMs for clinical use cases.