Global prevalence of MAFLD-related hepatocellular carcinoma: A systematic review and meta-analysis.

BACKGROUND & AIMS: The global proportion of hepatocellular carcinoma (HCC) attributable to metabolic dysfunction-associated fatty liver disease (MAFLD) is unclear. The MAFLD diagnostic criteria allows objective diagnosis in the presence of steatosis plus defined markers of metabolic dysfunction, irrespective of concurrent liver disease. We aimed to determine the total global prevalence of MAFLD in HCC cohorts (total-MAFLD), including the proportion with MAFLD as their sole liver disease (single-MAFLD), and the proportion of those with concurrent liver disease where MAFLD was a contributary factor (mixed-MAFLD). METHODS: This systematic review and meta-analysis included studies systematically ascertaining MAFLD in HCC cohorts, defined using international expert panel criteria including ethnicity specific BMI cut-offs. A comparison of clinical and tumour characteristics was performed between single-MAFLD, mixed-MAFLD and non-MAFLD HCC. RESULTS: 22 studies (56,565 individuals with HCC) were included. Total and single-MAFLD HCC prevalence was 48.7% (95% CI; 34.5% - 63.0%) and 12.4% (95% CI; 8.3% - 17.3%), respectively. In HCC due to chronic hepatitis B, C and alcohol-related liver disease, mixed-MAFLD prevalence was 40.0% (95% CI; 30.2% - 50.3%), 54.1% (95% CI; 40.4% - 67.6%) and 64.3% (95% CI; 52.7% - 75.0%), respectively. Mixed-MAFLD HCC had significantly higher likelihood of cirrhosis and lower likelihood of metastatic spread compared to single-MAFLD HCC, and a higher platelet count and lower likelihood of macrovascular invasion compared to non-MAFLD HCC. CONCLUSION: MAFLD is common as a sole aetiology, but more so and as a co-factor in mixed-aetiology HCC, supporting the use of a positive diagnostic criteria.

Inhibition of MERTK reduces organ fibrosis in mouse models of fibrotic disease.

Transforming growth factor-ß (TGFß) drives fibrosis and disease progression in a number of chronic disorders, but targeting this ubiquitously expressed cytokine may not yield a viable and safe antifibrotic therapy. Here, we sought to identify alternative ways to inhibit TGFß signaling using human hepatic stellate cells and macrophages from humans and mice in vitro, as well as mouse models of liver, kidney, and lung fibrosis. We identified Mer tyrosine kinase (MERTK) as a TGFß-inducible effector of fibrosis that was up-regulated during fibrosis in multiple organs in three mouse models. We confirmed these findings in liver biopsy samples from patients with metabolic dysfunction-associated fatty liver disease (MAFLD). MERTK also induced TGFß expression and drove TGFß signaling resulting in a positive feedback loop that promoted fibrosis in cultured cells. MERTK regulated both canonical and noncanonical TGFß signaling in both mouse and human cells in vitro. MERTK increased transcription of genes regulating fibrosis by modulating chromatin accessibility and RNA polymerase II activity. In each of the three mouse models, disrupting the fibrosis-promoting signaling loop by reducing MERTK expression reduced organ fibrosis. Pharmacological inhibition of MERTK reduced fibrosis in these mouse models either when initiated immediately after injury or when initiated after fibrosis was established. Together, these data suggest that MERTK plays a role in modulating organ fibrosis and may be a potential target for treating fibrotic diseases.

Efficacy of Trimetazidine in the Prevention of Contrast-Induced Nephropathy in Patients Undergoing Contrast Coronary Intervention: A Systematic Review and Meta-Analysis (PRISMA).

Objective: The present systematic review assessed the efficacy of peri-procedurally administered trimetazidine in the prevention of contrast-induced nephropathy (CIN) in patients undergoing coronary interventions with contrast agents. Methods: We performed a systematic literature review of articles published in PubMed and Google Scholar by 7 December 2023 and included articles from the last 15 years that evaluated the efficacy of trimetazidine in preventing CIN in cardiac patients undergoing coronary intervention. Results: After title/abstract and full-text screening, this systematic review included 9 randomized controlled trials (N = 2158 patients) with two groups: Trimetazidine (60-70 mg/day 24 to 48 h before and up to 72 h after the procedure) with hydration and the control group with only hydration. A total of 234/2158 patients developed CIN (Incidence rate [IR], 10.8%) as per the CIN definition of the Contrast Media Safety Committee of the European Society of Urogenital Radiology. The incidence of CIN in the trimetazidine vs. control group was 6.4% (69/1083) vs. 15.4% (165/1075), and the odds ratio (95% CI) was 0.3753 (0.279-0.504). Conclusions: In conclusion, the trimetazidine group had a lower incidence of CIN. Trimetazidine offers a reno-protective effect and helps in reducing the CIN incidence in patients undergoing cardiac intervention. Peri-procedure administration of trimetazidine significantly decreases the risk of CIN in patients despite comorbidities.

Hepatitis B virus and hepatitis C virus affect mitochondrial function through different metabolic pathways, explaining virus-specific clinical features of chronic hepatitis.

BACKGROUND: Hepatitis C virus (HCV) and hepatitis B virus (HBV) cause chronic hepatitis with important clinical differences. HCV causes hepatic steatosis and insulin resistance, while HBV confers increased risk of liver cancer. We hypothesised these differences may be due to virus-specific effects on mitochondrial function. METHODS: Seahorse technology was utilised to investigate effects of virus infection on mitochondrial function. Cell based assays were used to measure mitochondrial membrane potential and quantify pyruvate and lactate. Mass spectrometry was performed on mitochondria isolated from HBV expressing, HCV infected and control cells cultured with isotope-labelled amino acids, to identify proteins with different abundance. Altered expression of key mitochondrial proteins was confirmed by real time PCR and western blot. RESULTS: Reduced mitochondrial function and ATP production were observed with HCV infection and HBV expression. HCV impairs glycolysis and reduces expression of genes regulating fatty acid oxidation, promoting lipid accumulation. HBV causes lactate accumulation by increasing expression of lactate dehydrogenase A, which converts pyruvate to lactate. In HBV expressing cells there was marked enrichment of pyruvate dehydrogenase kinase, inhibiting conversion of pyruvate to acetyl-CoA and thereby reducing its availability for mitochondrial oxidative phosphorylation. CONCLUSIONS: HCV and HBV impair mitochondrial function and reduce ATP production. HCV reduces acetyl-CoA availability for energy production by impairing fatty acid oxidation, causing lipid accumulation and hepatic steatosis. HBV has no effect on fatty oxidation but reduces acetyl-CoA availability by disrupting pyruvate metabolism. This promotes lactic acidosis and oxidative stress, increasing the risk of disease progression and liver cancer.

Hepatitis C Virus Antiviral Drug Resistance and Salvage Therapy Outcomes Across Australia.

Background: Hepatitis C virus (HCV) infection can now be cured with well-tolerated direct-acting antiviral (DAA) therapy. However, a potential barrier to HCV elimination is the emergence of resistance-associated substitutions (RASs) that reduce the efficacy of antiviral drugs, but real-world studies assessing the clinical impact of RASs are limited. Here, an analysis of the impact of RASs on retreatment outcomes for different salvage regimens in patients nationally who failed first-line DAA therapy is reported. Methods: We collected data from 363 Australian patients who failed first-line DAA therapy, including: age, sex, fibrosis stage, HCV genotype, NS3/NS5A/NS5B RASs, details of failed first-line regimen, subsequent salvage regimens, and treatment outcome. Results: Of 240 patients who were initially retreated as per protocol, 210 (87.5%) achieved sustained virologic response (SVR) and 30 (12.5%) relapsed or did not respond. The SVR rate for salvage regimens that included sofosbuvir/velpatasvir/voxilaprevir was 94.3% (n = 140), sofosbuvir/velpatasvir 75.0% (n = 52), elbasvir/grazoprevir 81.6% (n = 38), and glecaprevir/pibrentasvir 84.6% (n = 13). NS5A RASs were present in 71.0% (n = 210) of patients who achieved SVR and in 66.7% (n = 30) of patients who subsequently relapsed. NS3 RASs were detected in 20 patients (20%) in the SVR group and 1 patient in the relapse group. NS5B RASs were observed in only 3 patients. Cirrhosis was a predictor of relapse after retreatment, as was previous treatment with sofosbuvir/velpatasvir. Conclusions: In our cohort, the SVR rate for sofosbuvir/velpatasvir/voxilaprevir was higher than with other salvage regimens. The presence of NS5A, NS5B, or NS3 RASs did not appear to negatively influence retreatment outcomes.

Heterogeneity of hepatocellular carcinoma: from mechanisms to clinical implications.

Hepatocellular Carcinoma (HCC) is one of the most common types of primary liver cancer. Current treatment options have limited efficacy against this malignancy, primarily owing to difficulties in early detection and the inherent resistance to existing drugs. Tumor heterogeneity is a pivotal factor contributing significantly to treatment resistance and recurrent manifestations of HCC. Intratumoral heterogeneity is an important aspect of the spectrum of complex tumor heterogeneity and contributes to late diagnosis and treatment failure. Therefore, it is crucial to thoroughly understand the molecular mechanisms of how tumor heterogeneity develops. This review aims to summarize the possible molecular dimensions of tumor heterogeneity with an emphasis on intratumoral heterogeneity, evaluate its profound impact on the diagnosis and therapeutic strategies for HCC, and explore the suitability of appropriate pre-clinical models that can be used to best study tumor heterogeneity; thus, opening new avenues for cancer treatment.

Attitudes towards transjugular intrahepatic portosystemic shunt (TIPS) in Australia: a national survey of TIPS centres.

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) is a minimally invasive therapeutic option to treat the sequelae of portal hypertension. It is unclear whether current international recommendations are reflected in current clinical practice across Australia and the extent of variations in care. This study aimed to address this gap in knowledge and benchmark the current landscape of TIPS services in Australia against international guidelines. METHODS: We designed a 42-item questionnaire according to practice-based recommendations and standards of international guidelines to investigate current landscape of TIPS service across four key domains: (1) service provision, (2) patient selection and indications, (3) best procedure practice, and (4) postoperative care. RESULTS: Gastroenterologist/hepatologists from 23 major liver centres (67.6%) across Australia currently performing TIPS completed the questionnaire. Between 2017 and 2020, there were 456 elective TIPS insertions. Units offering TIPS service had a low median number of TIPS insertions (n=7 per annum). More than half of respondents (56.5%) did not have institutional clinical practice protocols. There was marked variation in practices across institutions in terms of TIPS indications and patient selection. Despite variations, the success rate of elective TIPS was high at 91.7% (79-100%), with 86.6% (29-100%) for rescue TIPS. There was significant variation in postoperative follow-up and care. CONCLUSION: Current TIPS practice in Australia varies significantly across institutions. There is a need for a national consensus clinical practice guidelines to improve access and minimise unwarranted variation. A national registry for TIPS could measure, monitor, and report on quality of clinical care and patient outcomes.

Serum PRO-C3 is useful for risk prediction and fibrosis assessment in MAFLD with chronic kidney disease in an Asian cohort.

BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) is an emerging risk factor for chronic kidney disease (CKD). N-terminal propeptide of collagen type 3 (PRO-C3) is a biomarker of advanced fibrosis in MAFLD and PRO-C3 may be involved in renal fibrosis. We aimed to use PRO-C3 measurements to generate a new algorithmic score to test the prediction of MAFLD with chronic kidney disease (MAFLD-CKD). METHODS: A derivation and independent validation cohort of 750 and 129 Asian patients with biopsy-confirmed MAFLD were included. Serum PRO-C3 concentration was measured and regression analyses were performed to examine associations with MAFLD-CKD. A derivative algorithm for MAFLD-CKD risk prediction was evaluated with receiver operator characteristic (ROC) curve analysis. RESULTS: The study included two Asian cohorts (n = 180 with MAFLD-CKD; mean-eGFR: 94.93 mL/min/1.73 m2; median-urinary albumin-to-creatinine ratio: 6.58 mg/mmol). PRO-C3 was associated with the severity of MAFLD-CKD and independently associated with MAFLD-CKD (adjusted odds ratio = 1.16, 95% confidence interval [CI]: 1.08-1.23, p < .001). A new non-invasive score (termed PERIOD) including PRO-C3 efficiently predicted MAFLD-CKD (AUROC = .842, 95% CI: .805-.875). Accuracy, specificity and negative predictive values were 80.2%, 85.1% and 88.4%, respectively. In the validation cohort, the PERIOD score had good diagnostic performance (AUROC = .807, 95% CI: .691-.893) with similar results in all patient subgroups. In the MAFLD-CKD subgroup, the accuracy for identifying advanced fibrosis was further improved by combining the PRO-C3-based ADAPT with the Agile 3+ scores (AUROC = .90, 95% CI: .836-.964). CONCLUSIONS: The PERIOD score is helpful for accurately predicting the risk of MAFLD-CKD. PRO-C3 can also be used to assess liver fibrosis in people with MAFLD-CKD.

Using a human colonoid-derived monolayer to study bacteriophage translocation.

Bacteriophages (phages) are estimated to be the most abundant microorganisms on Earth. Their presence in human blood suggests that they can translocate from non-sterile sites such as the gastrointestinal tract where they are concentrated. To examine phage translocation ex vivo, we adapted a primary colonoid monolayer model possessing cell diversity and architecture, and a thick layer of mucus akin to the colonic environment in vivo. We show that the colonoid monolayer is superior to the Caco-2 cell-line model, possessing intact and organized tight junctions and generating a physiologically relevant mucus layer. We showed, using two different phages, that translocation across the colonoid monolayer was largely absent in differentiated monolayers that express mucus, unlike Caco-2 cultures that expressed little to no mucus. By stimulating mucus production or removing mucus, we further demonstrated the importance of colonic mucus in preventing phage translocation. Finally, we used etiological drivers of gut permeability (alcohol, fat, and inflammatory cytokines) to measure their effects on phage translocation, demonstrating that all three stimuli have the capacity to amplify phage translocation. These findings suggest that phage translocation does occur in vivo but may be largely dependent on colonic mucus, an important insight to consider in future phage applications.

Corrigendum to "Trends in decompensated cirrhosis and hepatocellular carcinoma among people with a hepatitis B notification in New South Wales" [JHEP Reports 4 (2022)].

[This corrects the article DOI: 10.1016/j.jhepr.2022.100552.].

Inhibition of cellular factor TM6SF2 suppresses secretion pathways of Hepatitis B, Hepatitis C and Hepatitis D viruses.

Chronic viral hepatitis is caused by hepatitis B virus, hepatitis C virus or hepatitis D virus (HBV, HCV, and HDV). Despite different replication strategies, all these viruses rely on secretion through the host endoplasmic reticulum-Golgi pathway, providing potential host targets for antiviral therapy. Knockdown of transmembrane 6 superfamily member 2 (TM6SF2) in virus cell culture models reduced secretion of infectious HCV virions, HDV virions and HBV subviral particles. Moreover, in a cohort of people with hepatitis B a TM6SF2 polymorphism (rs58542926 CT/TT, which causes protein misfolding and reduced TM6SF2 in the liver) correlated with lower concentrations of subviral particles in blood, complementing our previous work showing decreased HCV viral load in people with this polymorphism. In conclusion, the host protein TM6SF2 plays a key role in secretion of HBV, HCV and HDV, providing the potential for novel pan-viral agents to treat people with chronic viral hepatitis.

Asian Pacific Association for the Study of the Liver clinical practice guidelines on liver transplantation.

Liver transplantation is a highly complex and challenging field of clinical practice. Although it was originally developed in western countries, it has been further advanced in Asian countries through the use of living donor liver transplantation. This method of transplantation is the only available option in many countries in the Asia-Pacific region due to the lack of deceased organ donation. As a result of this clinical situation, there is a growing need for guidelines that are specific to the Asia-Pacific region. These guidelines provide comprehensive recommendations for evidence-based management throughout the entire process of liver transplantation, covering both deceased and living donor liver transplantation. In addition, the development of these guidelines has been a collaborative effort between medical professionals from various countries in the region. This has allowed for the inclusion of diverse perspectives and experiences, leading to a more comprehensive and effective set of guidelines.

Drug-induced liver injury from selective androgen receptor modulators, anabolic-androgenic steroids and bodybuilding supplements in Australia.

BACKGROUND: Reports of DILI due to herbal and dietary supplements have been increasing over time. AIMS: To characterise clinical, laboratory and histopathological phenotypes and outcomes of drug-induced liver injury (DILI) due to anabolic-androgenic steroids (AAS), selective androgen receptor modulators (SARMs), and bodybuilding supplements (BBS) in Australia. METHODS: Retrospective case series. Patients presented to nine Australian tertiary hospitals, 2017-2023. DILI was defined biochemically and patients were included if their treating physician attributed DILI to preceding use of AAS, SARMs or BBS. Primary endpoint was time to normalisation of liver biochemistry. Secondary endpoints were hospitalisation for investigation or management of DILI, death attributable to liver injury, and liver transplantation. RESULTS: Twenty-three cases of DILI were identified, involving 40 drugs: 18 AAS, 14 SARMs and eight BBS. Patients were predominantly male (22/23), with median age 30 years (IQR 26-42). Most were symptomatic (21/23). Median latency of onset was 58 days (IQR 28-112 days) from drug commencement. Most patients (17/23) were admitted to hospital. Based on updated Roussel Uclaf Causality Assessment Method, DILI was possible in 17/23, probable in 2/23 and unlikely in 4/23. Median time to normalisation of liver biochemistry was 175 days (IQR 70-292 days) from presentation. Three (3/23) were treated with corticosteroids, 14/23 were treated for itch, and one (1/23) underwent liver transplantation. There were no deaths. CONCLUSIONS: The prognosis of DILI from AAS, SARMs and BBS is good although liver transplantation may rarely be required. A detailed drug history is important in uncovering DILI due to these supplements.

Geographic disparities in access to liver transplant for advanced cirrhosis: Time to ring the alarm!

Decompensated cirrhosis and hepatocellular cancer are major risk factors for mortality worldwide. Liver transplantation (LT), both live-donor LT or deceased-donor LT, are lifesaving, but there are several barriers toward equitable access. These barriers are exacerbated in the setting of critical illness or acute-on-chronic liver failure. Rates of LT vary widely worldwide but are lowest in lower-income countries owing to lack of resources, infrastructure, late disease presentation, and limited donor awareness. A recent experience by the Chronic Liver Disease Evolution and Registry for Events and Decompensation consortium defined these barriers toward LT as critical in determining overall survival in hospitalized cirrhosis patients. A major focus should be on appropriate, affordable, and early cirrhosis and hepatocellular cancer care to prevent the need for LT. Live-donor LT is predominant across Asian countries, whereas deceased-donor LT is more common in Western countries; both approaches have unique challenges that add to the access disparities. There are many challenges toward equitable access but uniform definitions of acute-on-chronic liver failure, improving transplant expertise, enhancing availability of resources and encouraging knowledge between centers, and preventing disease progression are critical to reduce LT disparities.

Thyroid function, adipokines and mitokines in metabolic dysfunction-associated steatohepatitis: A multi-centre biopsy-based observational study.

BACKGROUND AND AIMS: Thyroid axis is currently under investigation as a therapeutic target in metabolic dysfunction-associated steatotic liver disease (MASLD). Thyroid function was examined herein in the full spectrum of disease. METHODS: Subjects were recruited and had liver biopsies in two Gastroenterology-Hepatology Clinics (Greece and Australia) and one Bariatric-Metabolic Surgery Clinic (Italy). The main working sample was n = 677 subjects with MASLD after excluding subjects with abnormal free thyroxine levels. Participants were classified according to thyroid-stimulating hormone (TSH) standard criteria: Subclinical hyperthyroidism (<0.4 uIU/mL); Euthyroidism with relatively low (0.4 to <2.5 uIU/mL); euthyroidism with relatively high (2.5-4.0 uIU/mL); subclinical hypothyroidism (>4 uIU/mL). RESULTS: TSH as a continuous variable was positively associated with significant fibrosis (F ≥ 2), metabolic dysfunction-associated steatohepatitis (MASH) and at-risk MASH. Subclinical hypothyroidism was associated with fibrosis F ≥ 2 (odds ratio [OR] = 3.47, 95% confident interval [CI] [1.50, 8.05], p = .02), MASH (OR = 3.44, 95% CI [1.48, 7.98] p = .001) and at-risk MASH (OR = 3.88, 95% CI [1.76, 8.55], p = .001), before and after controlling for adiposity, central obesity, and insulin resistance. When leptin, adiponectin, or growth differentiation factor-15 were examined as moderators, significance was lost. Sex-specific analysis revealed a strong association between TSH and the presence of significant fibrosis among women, eliminated only when adipokines/mitokines were adjusted for. Restricted cubic spline analysis revealed associations between TSH and liver outcomes (p-values < .01) with inflection points for fibrosis F ≥ 2 being 2.49, for MASH being 2.67 and for at-risk MASH being 6.96. CONCLUSIONS: These observations provide support for studies on the administration of thyroid hormone in MASLD therapeutics for subclinical hypothyroidism and liver-specific thyroid receptor agonists for subjects across the TSH continuum.

Adult hypertension referral pathway and therapeutic management: British and Irish Hypertension Society position statement.

In the UK, most adults with hypertension are managed in Primary Care. Referrals to Secondary Care Hypertension Specialists are targeted to patients in whom further investigations are likely to change management decisions. In this position statement the British and Irish Hypertension Society provide clinicians with a framework for referring patients to Hypertension Specialists. Additional therapeutic advice is provided to optimise patient management whilst awaiting specialist review. Our aim is to ensure that referral criteria to Hypertension Specialists are consistent across the UK and Ireland to ensure equitable access for all patients.

Serum ferritin levels can predict long-term outcomes in patients with metabolic dysfunction-associated steatotic liver disease.

OBJECTIVE: Hyperferritinaemia is associated with liver fibrosis severity in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), but the longitudinal implications have not been thoroughly investigated. We assessed the role of serum ferritin in predicting long-term outcomes or death. DESIGN: We evaluated the relationship between baseline serum ferritin and longitudinal events in a multicentre cohort of 1342 patients. Four survival models considering ferritin with confounders or non-invasive scoring systems were applied with repeated five-fold cross-validation schema. Prediction performance was evaluated in terms of Harrell's C-index and its improvement by including ferritin as a covariate. RESULTS: Median follow-up time was 96 months. Liver-related events occurred in 7.7%, hepatocellular carcinoma in 1.9%, cardiovascular events in 10.9%, extrahepatic cancers in 8.3% and all-cause mortality in 5.8%. Hyperferritinaemia was associated with a 50% increased risk of liver-related events and 27% of all-cause mortality. A stepwise increase in baseline ferritin thresholds was associated with a statistical increase in C-index, ranging between 0.02 (lasso-penalised Cox regression) and 0.03 (ridge-penalised Cox regression); the risk of developing liver-related events mainly increased from threshold 215.5 µg/L (median HR=1.71 and C-index=0.71) and the risk of overall mortality from threshold 272 µg/L (median HR=1.49 and C-index=0.70). The inclusion of serum ferritin thresholds (215.5 µg/L and 272 µg/L) in predictive models increased the performance of Fibrosis-4 and Non-Alcoholic Fatty Liver Disease Fibrosis Score in the longitudinal risk assessment of liver-related events (C-indices>0.71) and overall mortality (C-indices>0.65). CONCLUSIONS: This study supports the potential use of serum ferritin values for predicting the long-term prognosis of patients with MASLD.