Publications by authors named "Mohammed Eslam"

98 Publications

NR1H4 rs35724 G>C variant modulates liver damage in nonalcoholic fatty liver disease.

Liver Int 2021 Jul 16. Epub 2021 Jul 16.

Sezione di Gastroenterologia e Epatologia, Dipartimento di Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza "G. D'Alessandro", University of Palermo, Palermo, Italy.

Background And Aims: Farnesoid X receptor (FXR) plays a key role in bile acid and lipid homeostasis. Experimental evidence suggests that it can modulate liver damage related to nonalcoholic fatty liver disease (NAFLD). We examined the impact of the NR1H4 rs35724 G>C, encoding for FXR, on liver damage in a large cohort of patients at risk of steatohepatitis.

Methods: We considered 2,660 consecutive individuals at risk of steatohepatitis with liver histology. The rs35724 G>C polymorphisms were genotyped by TaqMan assays. Gene expression was evaluated by RNASeq in a subset of patients (n = 124).

Results: The NR1H4 rs35724 CC genotype, after adjusting for clinic-metabolic and genetic confounders and for enrolling centre, was protective against severity of steatosis (GG vs CC OR 0.77, 95% CI 0.62-0.95; P = .01), steatohepatitis (GG vs CC OR 0.62, 95% CI 0.47-0.83; P = .001) and severity of fibrosis (GG vs CC OR 0.83, 95% CI 0.67-0.98; P = .04). The C allele was associated with higher total circulating cholesterol (P = .01). Patients carrying the NR1H4 rs35724 C allele had significantly higher hepatic mRNA levels of FXR and were associated with higher hepatic FGFR4 and Cyp39A1 that are in turn involved in bile acid synthesis.

Conclusions: Increased hepatic FXR expression due to the NR1H4 rs35724 C allele is linked to higher serum cholesterol but protects against steatosis, steatohepatitis and liver fibrosis. The translational relevance of these results for patient risk stratification and FXR-targeted therapy warrants further investigation.
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http://dx.doi.org/10.1111/liv.15016DOI Listing
July 2021

Incorporating fatty liver disease in multidisciplinary care and novel clinical trial designs for patients with metabolic diseases.

Lancet Gastroenterol Hepatol 2021 Jul 12. Epub 2021 Jul 12.

Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia.

With the global epidemics of obesity and associated conditions, including type 2 diabetes, metabolic dysfunction-associated fatty liver disease, chronic kidney disease, hypertension, stroke, cardiovascular disease, osteoporosis, cancer, and cognitive changes, the prevalence of multimorbidity is rapidly increasing worldwide. In this Review, a panel of international experts from across the spectrum of metabolic diseases come together to identify the challenges and provide perspectives on building a framework for a virtual primary care-driven, patient-centred, multidisciplinary model to deliver holistic care for patients with metabolic dysfunction-associated fatty liver disease and associated metabolic diseases. We focus on clinical care and innovative trial design for metabolic dysfunction-associated fatty liver disease and associated metabolic diseases. This work represents a call to action to promote collaboration and partnerships between stakeholders for improving the lives of people with, or at risk of, metabolic dysfunction-associated fatty liver disease and associated metabolic diseases.
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http://dx.doi.org/10.1016/S2468-1253(21)00132-1DOI Listing
July 2021

Development of a simple dynamic algorithm for individualized hepatocellular carcinoma risk-based surveillance using pre- and post-treatment general evaluation score.

Liver Int 2021 Jun 26. Epub 2021 Jun 26.

Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia.

Background And Aims: With the growing number of treated hepatitis C patients, the current 'one-size-fits-all' hepatocellular carcinoma (HCC) surveillance strategies for patients with advanced fibrosis represents a great burden on healthcare systems. An individualized HCC risk strategy incorporates the dynamic changes of HCC risk are lacking.

Methods: This single-centre observational study included 3075 patients, with advanced fibrosis (≥F3) who achieved SVR following DAAs at Egyptian Liver research institute and hospital (ELRIAH) with follow-up period (range 6-72 months). The performance of a recently developed General Evaluation Score (GES) HCC risk stratification score was calculated pre- and post-treatment using Harrell's c statistic. Times to HCC and cumulative incidences were calculated with Kaplan-Meier method and compared using log-rank (Mantel-Cox) test.

Results: Pre-treatment GES score stratified patients into low (60.4%), intermediate (23.4%), and (16.2%) high-risk score where 5-year cumulative incidences of HCC were 1.66%, 4.45% and 7.64%, respectively. Harrell's c statistic was 0.801. Post-treatment GES score stratified patients into low (57.4%), intermediate (30.7%) and (11.9%) high-risk score where 5-year cumulative incidences of HCC were 1.35%, 3.49% and 11.09% respectively. The cumulative HCC incidence increased significantly with higher scores (P < .001). Harrell's c statistic was 0.818. Using pre- and post-treatment GES score, GES algorithm was developed with higher predictive value. The cumulative HCC incidence increased significantly with higher scores (P < .001). Harrell's c statistic was 0.832.

Conclusion: A dynamic algorithm incorporating both pre- and post-GES scores have better performance and predictive value compared with only pre-treatment assessments. The proposed algorithm would help to stratify those who need intensive or being excluded from screening.
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http://dx.doi.org/10.1111/liv.14995DOI Listing
June 2021

Mistranslation Drives Alterations in Protein Levels and the Effects of a Synonymous Variant at the Fibroblast Growth Factor 21 Locus.

Adv Sci (Weinh) 2021 06 1;8(11):2004168. Epub 2021 May 1.

Storr Liver Centre Westmead Institute for Medical Research Westmead Hospital and University of Sydney Westmead NSW 2145 Australia.

Fibroblast growth factor 21 (FGF21) is a liver-derived hormone with pleiotropic beneficial effects on metabolism. Paradoxically, FGF21 levels are elevated in metabolic diseases. Interventions that restore metabolic homeostasis reduce FGF21. Whether abnormalities in FGF21 secretion or resistance in peripheral tissues is the initiating factor in altering FGF21 levels and function in humans is unknown. A genetic approach is used to help resolve this paradox. The authors demonstrate that the primary event in dysmetabolic phenotypes is the elevation of FGF21 secretion. The latter is regulated by translational reprogramming in a genotype- and context-dependent manner. To relate the findings to tissues outcomes, the minor (A) allele of rs838133 is shown to be associated with increased hepatic inflammation in patients with metabolic associated fatty liver disease. The results here highlight a dominant role for translation of the FGF21 protein to explain variations in blood levels that is at least partially inherited. These results provide a framework for translational reprogramming of FGF21 to treat metabolic diseases.
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http://dx.doi.org/10.1002/advs.202004168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188187PMC
June 2021

MAFLD better predicts the progression of atherosclerotic cardiovascular risk than NAFLD: Generalized estimating equation approach.

Hepatol Res 2021 Jun 15. Epub 2021 Jun 15.

Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.

Aim: Metabolic associated fatty liver disease (MAFLD) partly overlaps with non-alcoholic fatty liver disease (NAFLD). Thus, using a generalized estimating equation (GEE) approach, we aimed to investigate the difference in worsening of atherosclerotic cardiovascular disease (ASCVD) risk between patients with MAFLD and NAFLD. We also investigated factors related to the difference between the two groups.

Methods: We enrolled 2306 subjects with fatty liver (MAFLD 80.7%, NAFLD 63.4%). Subjects with MAFLD/NAFLD were sub-classified into three groups: NAFLD with no metabolic dysfunction (non-Met NAFLD), overlapping, and MAFLD with moderate alcohol consumption (mod-Alc MAFLD). ASCVD risk was estimated by non-invasive tests, including the Suita score. An event was defined as worsening of these scores from the low-risk to the high-risk group. Independent factors for the event were analyzed by Cox regression analysis with the GEE.

Results: In Cox regression analysis, MAFLD (HR 1.08, 95% CI 1.02-1.15, p = 0.014) and alcohol consumption (20-39 g/day; HR 1.73, 95% CI 1.26-2.36, p = 0.001) were independently associated with worsening of the Suita score. In a subanalysis, the incidence of the event was significantly lower in non-Met NAFLD than in the overlapping group (HR 0.70, 95% CI 0.50-0.98, p = 0.042). However, no significant difference was observed in the incidence between the overlapping and mod-Alc MAFLD group (HR 1.19, 95% CI 0.89-1.58, p = 0.235).

Conclusions: The GEE approach demonstrates that MAFLD better identifies patients with worsening of ASCVD risk than NAFLD. Moreover, the superiority of MAFLD over NAFLD was due to the presence of metabolic dysfunction rather than moderate alcohol consumption.
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http://dx.doi.org/10.1111/hepr.13685DOI Listing
June 2021

Endotrophin, a pro-peptide of Type VI collagen, is a biomarker of survival in cirrhotic patients with hepatocellular carcinoma.

Hepat Oncol 2020 Dec 18;8(2):HEP32. Epub 2020 Dec 18.

Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital & University of Sydney, NSW, Australia.

Aim: Type VI collagen, is emerging as a signaling collagen originating from different types of fibroblasts. A specific fragment of Type VI collagen, the pro-peptide, is also known as the hormone endotrophin. We hypothesized that this fibroblast hormone would be of particular relevance in cancer types with a high amount of fibrosis activity, namely for outcome in hepatocellular carcinoma (HCC) cirrhotic patients.

Patients & Methods: Plasma C6M, PRO-C6 and alphafeto-protein (AFP) were assessed in 309 patients with mixed etiologies (hepatitis C, hepatitis B, alcohol and nonalcoholic fatty liver) diagnosed as cirrhotics, cirrhotics with HCC, noncirrhotics and healthy controls. Progression-free survival and overall survival (OS) data were collected up to 6120 days after diagnosis. The ability of each marker to predict survival was investigated.

Results & Conclusion: The level of endotrophin assessed by PRO-C6 was able to separate healthy controls, noncirrhotics and cirrhotics from HCC (p < 0.05-0.0001). Both endotrophin and C6M provided value in the prediction of OS in cirrhotic patients with HCC. In the multivariate analysis for identifying HCC, in patients with high endotrophin (highest quartile) and that were positive for AFP (≥20 IU/ml), the hazard ratio for predicting OS was increased from 3.7 (p = 0.0006) to 14.4 (p = 0.0001) when comparing with AFP positive as a stand-alone marker. In conclusion, plasma levels for markers of Type VI collagen remodeling were associated with survival in cirrhotic patients with HCC. A combination of AFP with endotrophin improved the prognostic value compared with AFP alone for predicting OS in cirrhotic patients with HCC.
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http://dx.doi.org/10.2217/hep-2020-0030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162185PMC
December 2020

Non-Obese MAFLD Is Associated with Colorectal Adenoma in Health Check Examinees: A Multicenter Retrospective Study.

Int J Mol Sci 2021 May 22;22(11). Epub 2021 May 22.

Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan.

Colorectal adenoma is linked to metabolic dysfunction. Metabolic dysfunction-associated fatty liver disease (MAFLD) has a precise definition and three subtypes, including non-obese MAFLD. We aimed to investigate the impact of MAFLD on the prevalence of colorectal adenoma by comparing it to non-alcoholic fatty liver disease (NAFLD) in health check-up examinees. This is a multicenter retrospective study. We enrolled 124 consecutive health check-up examinees who underwent colonoscopy. NAFLD and MAFLD were present in 58 and 63 examinees, respectively. Colorectal adenoma was diagnosed by biopsy. The impact of the MAFLD definition on the prevalence of colorectal adenoma was investigated by logistic regression, decision-tree, and random forest analyses. In logistic regression analysis, MAFLD was identified as the only independent factor associated with the presence of colorectal adenoma (OR 3.191; 95% CI 1.494-7.070; = 0.003). MAFLD was also identified as the most important classifier for the presence of colorectal adenoma in decision-tree and random forest analyses (29 variable importance value). Among the three subtypes of MAFLD, non-obese MAFLD was the sole independent factor associated with the presence of colorectal adenoma (OR 3.351; 95% CI 1.589-7.262; ≤ 0.001). Non-obese MAFLD was also the most important classifier for the presence of colorectal adenoma in decision-tree and random forest analyses (31 variable importance value). MAFLD, particularly non-obese MAFLD, is the most important factor associated with the presence of colorectal adenoma rather than NAFLD. Colonoscopy examination should be considered in patients with MAFLD, especially those who are non-obese.
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http://dx.doi.org/10.3390/ijms22115462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196881PMC
May 2021

Associations of Hydroxysteroid 17-beta Dehydrogenase 13 Variants with Liver Histology in Chinese Patients with Metabolic-associated Fatty Liver Disease.

J Clin Transl Hepatol 2021 Apr 22;9(2):194-202. Epub 2021 Feb 22.

NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.

Background And Aims: In Europeans, variants in the () gene impact liver histology in metabolic-associated fatty liver disease (MAFLD). The impact of these variants in ethnic Chinese is unknown. The aim of this study was to investigate the potential associations in Chinese patients.

Methods: In total, 427 Han Chinese with biopsy-confirmed MAFLD were enrolled. Two single nucleotide polymorphisms in were genotyped: rs72613567 and rs6531975. Logistic regression was used to test the association between the single nucleotide polymorphisms and liver histology.

Results: In our cohort, the minor allele TA of the rs72613567 variant was related to an increased risk of fibrosis [odds ratio (OR): 2.93 (1.20-7.17), =0.019 for the additive model; OR: 3.32 (1.39-7.91), =0.007 for the recessive model], representing an inverse association as compared to the results from European cohorts. In contrast, we observed a protective effect on fibrosis for the minor A allele carriers of the rs6531975 variant [OR: 0.48 (0.24-0.98), =0.043 for the additive model; OR: 0.62 (0.40-0.94), =0.025 for the dominant model]. variants were only associated with fibrosis but no other histological features. Furthermore, rs6531975 modulated the effect of rs738409 on hepatic steatosis.

Conclusions: rs72613567 is a risk variant for fibrosis in a Han Chinese MAFLD population but with a different direction for allelic association to that seen in Europeans. These data exemplify the need for studying diverse populations in genetic studies in order to fine map genome-wide association studies signals.
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http://dx.doi.org/10.14218/JCTH.2020.00151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111109PMC
April 2021

Hepatic Dendritic Cells in the Development and Progression of Metabolic Steatohepatitis.

Front Immunol 2021 23;12:641240. Epub 2021 Mar 23.

Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia.

Metabolic Associated Fatty liver disease (MAFLD) is a global health problem and represents the most common cause of chronic liver disease in the world. MAFLD spectrum goes from simple steatosis to cirrhosis, in between metabolic steatohepatitis with progressive fibrosis, which pathogenesis is not completely understood. Hence, the role of the immune system has become an important fact in the trigger of inflammatory cascades in metabolic steatohepatitis and in the activation of hepatic stellate cells (HSCs). Among, the more studied immune cells in the pathogenesis of MAFLD are macrophages, T cells, natural killer and dendritic cells. In particular, hepatic dendritic cells had recently attracted a special attention, with a dual role in the pathogenesis of MAFLD. These cells have the capacity to switch from a tolerant state to active state inducing an inflammatory cascade. Furthermore, these cells play a role in the lipid storage within the liver, having, thus providing a crucial nexus between inflammation and lipid metabolism. In this review, we will discuss the current knowledge on the dual role of dendritic cells in lipid accumulation, as wells as in the triggering of hepatic inflammation and hepatocytes cell death in metabolic steatohepatitis.
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http://dx.doi.org/10.3389/fimmu.2021.641240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021782PMC
March 2021

MAFLD: Now is the time to capitalize on the momentum.

J Hepatol 2021 May 12;74(5):1262-1263. Epub 2021 Feb 12.

Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2021.02.002DOI Listing
May 2021

Dual proteotoxic stress accelerates liver injury via activation of p62-Nrf2.

J Pathol 2021 May 18;254(1):80-91. Epub 2021 Mar 18.

Department of Medicine III, University Hospital Aachen, Aachen, Germany.

Protein accumulation is the hallmark of various neuronal, muscular, and other human disorders. It is also often seen in the liver as a major protein-secretory organ. For example, aggregation of mutated alpha1-antitrypsin (AAT), referred to as PiZ, is a characteristic feature of AAT deficiency, whereas retention of hepatitis B surface protein (HBs) is found in chronic hepatitis B (CHB) infection. We investigated the interaction of both proteotoxic stresses in humans and mice. Animals overexpressing both PiZ and HBs (HBs-PiZ mice) had greater liver injury, steatosis, and fibrosis. Later they exhibited higher hepatocellular carcinoma load and a more aggressive tumor subtype. Although PiZ and HBs displayed differing solubility properties and distinct distribution patterns, HBs-PiZ animals manifested retention of AAT/HBs in the degradatory pathway and a marked accumulation of the autophagy adaptor p62. Isolation of p62-containing particles revealed retained HBs/AAT and the lipophagy adapter perilipin-2. p62 build-up led to activation of the p62-Nrf2 axis and emergence of reactive oxygen species. Our results demonstrate that the simultaneous presence of two prevalent proteotoxic stresses promotes the development of liver injury due to protein retention and activation of the p62-Nrf2 axis. In humans, the PiZ variant was over-represented in CHB patients with advanced liver fibrosis (unadjusted odds ratio = 9.92 [1.15-85.39]). Current siRNA approaches targeting HBs/AAT should be considered for these individuals. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5643DOI Listing
May 2021

Caucasian lean subjects with non-alcoholic fatty liver disease share long-term prognosis of non-lean: time for reappraisal of BMI-driven approach?

Gut 2021 Feb 4. Epub 2021 Feb 4.

UCM Digestive Diseases and SeLiver Group, Virgen del Rocio University Hospital, Institute of Biomedicine of Seville, University of Seville, Seville, Spain.

Objective: The full phenotypic expression of non-alcoholic fatty liver disease (NAFLD) in lean subjects is incompletely characterised. We aimed to investigate prevalence, characteristics and long-term prognosis of Caucasian lean subjects with NAFLD.

Design: The study cohort comprises 1339 biopsy-proven NAFLD subjects from four countries (Italy, UK, Spain and Australia), stratified into lean and non-lean (body mass index (BMI)
Results: Lean patients represented 14.4% of the cohort and were predominantly of Italian origin (89%). They had less severe histological disease (lean vs non-lean: non-alcoholic steatohepatitis 54.1% vs 71.2% p<0.001; advanced fibrosis 10.1% vs 25.2% p<0.001), lower prevalence of diabetes (9.2% vs 31.4%, p<0.001), but no significant differences in the prevalence of the I148M variant (p=0.57). During a median follow-up of 94 months (>10 483 person-years), 4.7% of lean vs 7.7% of non-lean patients reported liver-related events (p=0.37). No difference in survival was observed compared with non-lean NAFLD (p=0.069).

Conclusions: Caucasian lean subjects with NAFLD may progress to advanced liver disease, develop metabolic comorbidities and experience cardiovascular disease (CVD) as well as liver-related mortality, independent of longitudinal progression to obesity and genotype. These patients represent one end of a wide spectrum of phenotypic expression of NAFLD where the disease manifests at lower overall BMI thresholds.

Lay Summary: NAFLD may affect and progress in both obese and lean individuals. Lean subjects are predominantly males, have a younger age at diagnosis and are more prevalent in some geographic areas. During the follow-up, lean subjects can develop hepatic and extrahepatic disease, including metabolic comorbidities, in the absence of weight gain. These patients represent one end of a wide spectrum of phenotypic expression of NAFLD.
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http://dx.doi.org/10.1136/gutjnl-2020-322564DOI Listing
February 2021

NAFLD in Lean Asians.

Clin Liver Dis (Hoboken) 2020 Dec 13;16(6):240-243. Epub 2021 Jan 13.

Storr Liver Centre Westmead Institute for Medical Research Westmead Hospital and University of Sydney Westmead New South Wales Australia.

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http://dx.doi.org/10.1002/cld.930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805295PMC
December 2020

Yet more evidence that MAFLD is more than a name change.

J Hepatol 2021 Apr 13;74(4):977-979. Epub 2021 Jan 13.

Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2020.12.025DOI Listing
April 2021

MAFLD: A holistic view to redefining fatty liver disease.

J Hepatol 2021 Apr 13;74(4):983-985. Epub 2021 Jan 13.

Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2020.12.027DOI Listing
April 2021

MAFLD: A game changer redefining fatty liver disease for adults and children.

J Hepatol 2021 Apr 13;74(4):992-994. Epub 2021 Jan 13.

Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2021.01.004DOI Listing
April 2021

An aptamer-based drug delivery agent (CD133-apt-Dox) selectively and effectively kills liver cancer stem-like cells.

Cancer Lett 2021 03 19;501:124-132. Epub 2020 Dec 19.

Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney and Westmead Hospital, Westmead, NSW, 2145, Australia. Electronic address:

Liver cancer has no effective therapies, hence a poor survival. Cancer stem-like cells not only contribute to cancer initiation and progression, but also to drug resistance, cancer metastasis, and eventually treatment failure. Hence, any approaches that can effectively kill cancer stem-like cells hold a great potential for cancer treatment. CD133 is a robust marker for liver cancer stem-like cells. We developed a specific aptamer against CD133 (CD133-apt), and then loaded this aptamer with an anticancer drug doxorubicin (CD133-apt-Dox). The efficacy of CD133-apt-Dox in targeting liver cancer stem-like cells and its overall effect in treating liver cancer were investigated using multiple in vitro and in vivo studies including in patients-derived liver cancer organoids. We have observed that CD133-apt could preferably delivered doxorubicin to CD133-expressing cells with efficient drug accumulation and retention. CD133-apt-Dox impaired the self-renewal capacity of liver cancer stem-like cells and attenuated their stem-ness phenotypes in vitro or in vivo. CD133-apt-Dox significantly inhibited the growth of liver cancer cells and patients-derived organoids and reduced the growth of xenograft tumours in nude mice inhibited the growth of DEN-induced liver cancer in immunocompetent mice. Hence, aptamer-mediated targeting of CD133 is a highly promising approach for liver cancer therapy.
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http://dx.doi.org/10.1016/j.canlet.2020.12.022DOI Listing
March 2021

Genetic variation in the TLL1 gene is not associated with fibrosis in patients with metabolic associated fatty liver disease.

PLoS One 2020 11;15(12):e0243590. Epub 2020 Dec 11.

Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia.

Metabolic associated fatty liver disease (MAFLD) is the most prevalent liver disease in Western nations, with high heritability. A recent study of Japanese patients with the disease suggested that TLL1 rs17047200 is associated with fibrosis; whether a similar association is observed in Caucasian patients with MAFLD is unknown. We investigated the association of the TLL1 rs17047200 polymorphism with liver fibrosis in a cohort of Caucasian patients with MAFLD (n = 728). We also investigated whether TLL1 expression is altered during liver injury in humans, in murine models of fibrosis, and in in-vitro. While TLL1 expression is upregulated in the liver of humans with MAFLD and in mice, the rs17047200 variant was not associated with fibrosis or any other histological features, or with hepatic TLL1 expression. In conclusion, the TLL1 rs17047200 variant is not a risk variant for fibrosis in Caucasian patients with MAFLD. However, TLL1 could be involved in the pathogenesis of liver fibrosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243590PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732106PMC
January 2021

When a new definition overhauls perceptions of MAFLD related cirrhosis care.

Hepatobiliary Surg Nutr 2020 Dec;9(6):801-804

MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

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http://dx.doi.org/10.21037/hbsn-20-725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720042PMC
December 2020

Metabolic associated fatty liver disease and cancer risk: causal role or epiphenomenon?

Hepatobiliary Surg Nutr 2020 Dec;9(6):774-776

Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead, NSW, Australia.

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http://dx.doi.org/10.21037/hbsn.2020.03.05DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720060PMC
December 2020

A Sequential Algorithm Combining ADAPT and Liver Stiffness Can Stage Metabolic-Associated Fatty Liver Disease in Hospital-Based and Primary Care Patients.

Am J Gastroenterol 2021 05;116(5):984-993

Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.

Introduction: Metabolic-associated fatty liver disease is common, with fibrosis the major determinant of adverse outcomes. Population-based screening tools with high diagnostic accuracy for the staging of fibrosis are lacking.

Methods: Three independent cohorts, 2 with both liver biopsy and liver stiffness measurements (LSMs, n = 254 and 65) and a population sample (n = 713), were studied. The performance of a recently developed noninvasive algorithm (ADAPT [age, diabetes, PRO-C3 and platelets panel]) as well as aspartate aminotransferase-to-platelet ratio index, fibrosis-4, nonalcoholic fatty liver disease fibrosis score, and LSM was used to stage patients for significant (≥F2) and advanced (≥F3) fibrosis.

Results: In the hospital-based cohorts, the N-terminal propeptide of type 3 collagen (Pro-C3) increased with fibrosis stage (P < 0.0001) and independently associated with advanced fibrosis (odds ratio = 1.091, 95% confidence interval [CI]: 1.053-1.113, P = 0.0001). ADAPT showed areas under the receiver operating characteristics curve of 0.831 (95% CI: 0.779-0.875) in the derivation and 0.879 (95% CI: 0.774-0.946) in the validation cohort for advanced fibrosis. This was superior to the existing fibrosis scores, aspartate aminotransferase-to-platelet ratio index, fibrosis-4, BARD (BMI, aspartate aminotransferase to alanine aminotransferase ratio [AAR], diabetes), and nonalcoholic fatty liver disease fibrosis score in most comparisons and comparable with LSM. Serial use of ADAPT and LSM had diagnostic accuracy of 92.5%, with 98% and 100% negative predictive value in the derivation and validation cohorts, respectively. In the population cohort, PRO-C3 associated with advanced fibrosis (P = 0.04), while ADAPT had a negative predictive value of 98% for excluding advanced fibrosis.

Discussion: PRO-C3 and ADAPT reliably exclude advanced fibrosis in low-risk populations. The serial combination of ADAPT with LSM has high diagnostic accuracy with a low requirement for liver biopsy. The proposed algorithm would help stratify those who need biopsies and narrow down those patients who would need to be referred to specialty clinics.
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http://dx.doi.org/10.14309/ajg.0000000000001059DOI Listing
May 2021

Cross-Linked Multimeric Pro-Peptides of Type III Collagen (PC3X) in Hepatocellular Carcinoma - A Biomarker That Provides Additional Prognostic Value in AFP Positive Patients.

J Hepatocell Carcinoma 2020 9;7:301-313. Epub 2020 Nov 9.

Biomarkers & Research, Nordic Bioscience, Herlev, Denmark.

Purpose: Non-invasive biomarkers for diagnosing and prognosing hepatocellular carcinoma (HCC) are urgently needed. Cirrhosis is present in 80-90% of HCC patients. Cirrhosis is characterized by deposition and cross-linking of collagens that have crucial roles in HCC initiation and progression. We evaluated circulating cross-linked pro-peptides of type III collagen (PC3X) as a diagnostic and prognostic biomarker for HCC.

Patients And Methods: PC3X was measured by ELISA in plasma from patients with HCC (n=79), cirrhosis (n=86), non-cirrhotic hepatitis-B infection (n=74) and from healthy controls (n=44). PC3X was compared to the liver fibrosis marker PRO-C3 and the HCC tumor-cell derived marker alpha-fetoprotein (AFP). Diagnostic and prognostic potential was evaluated by AUROC and by calculating hazard ratios (HR) for progression-free survival (PFS) and overall survival (OS).

Results: PC3X, PRO-C3 and AFP were significantly elevated in patients with HCC compared to other liver diseases and healthy controls (=0.0002, 0.0001). In patients with normal AFP (<20 IU/mL), PC3X and PRO-C3 separated HCC from cirrhosis with an AUROC of 0.72 and 0.68, respectively. High PC3X and AFP predicted for poor PFS (HR=1.80, =0.032; HR=1.70, =0.031) and OS (HR=2.12, =0.024; HR=2.55; =0.003), whereas PRO-C3 did not (PFS: HR=1.19, =0.059 and OS: HR=1.12, =0.324). PC3X was independent of AFP (PFS: HR=1.74, =0.045 and OS: HR=2.21, =0.018) and combining the two improved prognostic value (PFS: HR=2.66, =0.004 and OS: HR=5.86, <0.0001).

Conclusion: PC3X is associated with HCC independent of AFP and provides diagnostic and prognostic value for HCC patients. If validated, this suggests that PC3X has biomarker potential for HCC.
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http://dx.doi.org/10.2147/JHC.S275008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665576PMC
November 2020

Reply to: Suboptimal accuracy of GES score to stratify post SVR HCC risk in a single-centre cohort of European cirrhotics.

Liver Int 2021 05 23;41(5):1155-1156. Epub 2020 Nov 23.

Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia.

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http://dx.doi.org/10.1111/liv.14724DOI Listing
May 2021

Redefining fatty liver disease: an international patient perspective.

Lancet Gastroenterol Hepatol 2021 01 5;6(1):73-79. Epub 2020 Oct 5.

Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead, NSW, Australia. Electronic address:

Despite its increased recognition as a major health threat, fatty liver disease associated with metabolic dysfunction remains largely underdiagnosed and undertreated. An international consensus panel has called for the disease to be renamed from non-alcoholic fatty liver disease (NAFLD) to metabolic-associated fatty liver disease (MAFLD) and has suggested how the disease should be diagnosed. This Viewpoint explores the call from the perspective of patient advocacy groups. Patients are well aware of the negative consequences of the NAFLD acronym. This advocacy group enthusiastically endorses the call to reframe the disease, which we believe will ultimately have a positive effect on patient care and quality of life and, through this effect, will reduce the burden on health-care systems. For patients, policy makers, health planners, donors, and non-hepatologists, the new acronym MAFLD is clear, squarely placing the disease as a manifestation of metabolic dysfunction and improving understanding at a public health and patient level. The authors from representative patient groups are supportive of this change, particularly as the new acronym is meaningful to all citizens as well as governments and policy makers, and, above all, is devoid of any stigma.
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http://dx.doi.org/10.1016/S2468-1253(20)30294-6DOI Listing
January 2021

The Asian Pacific Association for the Study of the Liver clinical practice guidelines for the diagnosis and management of metabolic associated fatty liver disease.

Hepatol Int 2020 Dec 1;14(6):889-919. Epub 2020 Oct 1.

Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead, NSW, 2145, Australia.

Metabolic associated fatty liver disease (MAFLD) is the principal worldwide cause of liver disease and affects nearly a quarter of the global population. The objective of this work was to present the clinical practice guidelines of the Asian Pacific Association for the Study of the Liver (APASL) on MAFLD. The guidelines cover various aspects of MAFLD including its epidemiology, diagnosis, screening, assessment, and treatment. The document is intended for practical use and for setting the stage for advancing clinical practice, knowledge, and research of MAFLD in adults, with specific reference to special groups as necessary. The guidelines also seek to improve patient care and awareness of the disease and assist stakeholders in the decision-making process by providing evidence-based data. The guidelines take into consideration the burden of clinical management for the healthcare sector.
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http://dx.doi.org/10.1007/s12072-020-10094-2DOI Listing
December 2020

MAFLD identifies patients with significant hepatic fibrosis better than NAFLD.

Liver Int 2020 12;40(12):3018-3030

Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.

Background & Aims: Diagnostic criteria for metabolic associated fatty liver disease (MAFLD) have been proposed, but not validated. We aimed to compare the diagnostic accuracy of the MAFLD definition vs the existing NAFLD criteria to identify patients with significant fibrosis and to characterize the impact of mild alcohol intake.

Methods: We enrolled 765 Japanese patients with fatty liver (median age 54 years). MAFLD and NAFLD were diagnosed in 79.6% and 70.7% of patients respectively. Significant fibrosis was defined by FIB-4 index ≥1.3 and liver stiffness ≥6.6 kPa using shear wave elastography. Mild alcohol intake was defined as <20 g/day. Factors associated with significant fibrosis were analysed by logistic regression and decision-tree analyses.

Results: Liver stiffness was higher in MAFLD compared to NAFLD (7.7 vs 6.8 kPa, P = .0010). In logistic regression, MAFLD (OR 4.401; 95% CI 2.144-10.629; P < .0001), alcohol intake (OR 1.761; 95% CI 1.081-2.853; P = .0234), and NAFLD (OR 1.721; 95%CI 1.009-2.951; P = .0463) were independently associated with significant fibrosis. By decision-tree analysis, MAFLD, but not NAFLD or alcohol consumption was the initial classifier for significant fibrosis. The sensitivity for detecting significant fibrosis was higher for MAFLD than NAFLD (93.9% vs 73.0%). In patients with MAFLD, even mild alcohol intake was associated with an increase in the prevalence of significant fibrosis (25.0% vs 15.5%; P = .0181).

Conclusions: The MAFLD definition better identifies a group with fatty liver and significant fibrosis evaluated by non-invasive tests. Moreover, in patients with MAFLD, even mild alcohol consumption is associated with worsening of hepatic fibrosis measures.
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http://dx.doi.org/10.1111/liv.14675DOI Listing
December 2020

ABIDE: An Accurate Predictive Model of Liver Decompensation in Patients With Nonalcoholic Fatty Liver-Related Cirrhosis.

Hepatology 2021 Jun 19;73(6):2238-2250. Epub 2021 Apr 19.

Medical School, Faculty of Health and Medical Sciences, The University of Western Australia, Nedlands, WA, Australia.

Background And Aims: Nonalcoholic fatty liver disease (NAFLD) is an increasingly important cause of liver cirrhosis and subsequent complications. We retrospectively developed and validated a model to predict hepatic decompensation in patients with NAFLD and cirrhosis and compared this with currently available models.

Approach And Results: Baseline variables from an international cohort of 299 patients with biopsy-proven NAFLD with compensated cirrhosis were examined to construct a model using competing risk multivariate regression and Akaike/Bayesian information criteria. Validation was performed in 244 patients with biopsy-proven NAFLD cirrhosis from the United States. Prognostic accuracy was compared with the NAFLD fibrosis score (NFS), fibrosis-4 (FIB-4), Model for End-Stage Liver Disease (MELD), Child-Turcotte-Pugh (CTP), and albumin-bilirubin (ALBI)-FIB-4 score using time-dependent area under the curve (tAUC) analysis. During a median follow-up of 5.6 years (range 2.4-14.1) and 5.4 years (range 1.5-13.8), hepatic decompensation occurred in 81 and 132 patients in the derivation and validation cohorts, respectively. In the derivation cohort, independent predictors of hepatic decompensation (Aspartate aminotransferase/alanine aminotransferase ratio, Bilirubin, International normalized ratio, type 2 Diabetes, and Esophageal varices) were combined into the ABIDE model. Patients with a score ≥4.1 compared with those with a score <4.1 had a higher risk of decompensation (subhazard ratio, 6.7; 95% confidence interval [CI], 4.0-11.2; P < 0.001), a greater 5-year cumulative incidence (37% vs. 6%, P < 0.001), and shorter mean duration to decompensation (3.8 vs 6.7 years, P < 0.001). The accuracy of the ABIDE model at 5 years was good in the derivation (tAUC, 0.80; 95% CI, 0.73-0.84) and validation cohorts (0.78; 95% CI, 0.74-0.81) and was significantly more accurate than the NFS (0.72), FIB-4 (0.74), MELD (0.69), CTP (0.72), and ALBI-FIB-4 (0.73) (all P < 0.001).

Conclusions: In patients with NAFLD and compensated cirrhosis, ABIDE, a predictive model of routine clinical measures, predicts future hepatic decompensation.
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http://dx.doi.org/10.1002/hep.31576DOI Listing
June 2021

GES: A validated simple score to predict the risk of HCC in patients with HCV-GT4-associated advanced liver fibrosis after oral antivirals.

Liver Int 2020 11;40(11):2828-2833

Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia.

Background & Aims: Hepatocellular carcinoma (HCC) risk persists after hepatitis C virus (HCV) eradication with direct-acting antivirals (DAAs), particularly in patients with cirrhosis. Identifying those who are likely to develop HCC is a critical unmet medical need. Our aim is to develop a score that offers individualized patient HCC risk prediction.

Methods: This two-centre prospective study included 4400 patients, with cirrhosis and advanced fibrosis who achieved a sustained virologic response (SVR), including 2372 patients (derivation cohort). HCC-associated factors were identified by multivariable Cox regression analysis to develop a scoring model for prediction of HCC risk; and subsequently internally and externally validated in two independent cohorts of 687 and 1341 patients.

Results: In the derivation cohort, the median follow-up was 23.51 ± 8.21 months, during which 109 patients (4.7%) developed HCC. Age, sex, serum albumin, α fetoprotein and pretreatment fibrosis stage were identified as risk factors for HCC. A simple predictive model (GES) score was constructed. The 2-year cumulative HCC incidence using Kaplan-Meier method was 1.2%, 3.3% and 7.1% in the low-risk, medium-risk and high-risk groups respectively. Internal and external validation showed highly significant difference among the three risk groups (P < .001) with regard to cumulative HCC risk. GES score has high predictive ability value (Harrell's C statistic 0.801), that remained robustly consistent across two independent validation cohorts (Harrell's C statistic 0.812 and 0.816).

Conclusion: GES score is simple with validated good predictive ability for the development of HCC after eradication of HCV and may be useful for HCC risk stratification in those patients.
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http://dx.doi.org/10.1111/liv.14666DOI Listing
November 2020

Reply to: correspondence regarding "A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement": Bringing evidence to the NAFLD-MAFLD debate.

J Hepatol 2020 12 12;73(6):1575. Epub 2020 Sep 12.

Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2020.07.045DOI Listing
December 2020

Reply to: Correspondence on "A new definition for metabolic associated fatty liver disease: an international expert consensus statement": MAFLD: Moving from a concept to practice.

J Hepatol 2020 11 13;73(5):1268-1269. Epub 2020 Aug 13.

Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2020.06.036DOI Listing
November 2020
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