Publications by authors named "Leon Adams"

159 Publications

Role of the sympathetic nervous system in cardiometabolic control: implications for targeted multiorgan neuromodulation approaches.

J Hypertens 2021 Mar 3. Epub 2021 Mar 3.

Dobney Hypertension Centre, School of Medicine - Royal Perth Hospital Unit, Faculty of Medicine, Dentistry & Health Sciences, The University of Western Australia, Perth, Western Australia Department of Radiology, Alfred Hospital Department of Surgery, Central Clinical School, Monash University, Melbourne, Victoria Medical School, The University of Western Australia, Perth, Western Australia Baker Heart and Diabetes Institute, Melbourne, Victoria Department of Endocrinology, Medical School, The University of Western Australia Department of Radiology, Royal Perth Hospital, Perth, Western Australia Human Neurotransmitter Lab Neurovascular Hypertension & Kidney Disease Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria Departments of Cardiology and Nephrology, Royal Perth Hospital, Perth, Western Australia, Australia.

Sympathetic overdrive plays a key role in the perturbation of cardiometabolic homeostasis. Diet-induced and exercise-induced weight loss remains a key strategy to combat metabolic disorders, but is often difficult to achieve. Current pharmacological approaches result in variable responses in different patient cohorts and long-term efficacy may be limited by medication intolerance and nonadherence. A clinical need exists for complementary therapies to curb the burden of cardiometabolic diseases. One such approach may include interventional sympathetic neuromodulation of organs relevant to cardiometabolic control. The experience from catheter-based renal denervation studies clearly demonstrates the feasibility, safety and efficacy of such an approach. In analogy, denervation of the common hepatic artery is now feasible in humans and may prove to be similarly useful in modulating sympathetic overdrive directed towards the liver, pancreas and duodenum. Such a targeted multiorgan neuromodulation strategy may beneficially influence multiple aspects of the cardiometabolic disease continuum offering a holistic approach.
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http://dx.doi.org/10.1097/HJH.0000000000002839DOI Listing
March 2021

Combined renal and common hepatic artery denervation as a novel approach to reduce cardiometabolic risk: technical approach, feasibility and safety in a pre-clinical model.

Clin Res Cardiol 2021 Feb 26. Epub 2021 Feb 26.

Dobney Hypertension Centre, Faculty of Medicine, School of Medicine-Royal Perth Hospital Unit, Dentistry and Health Sciences, The University of Western Australia, Level 3, MRF Building, Rear 50 Murray St, Perth, WA, 6000, Australia.

Background: Cardiovascular and metabolic regulation is governed by neurohumoral signalling in relevant organs such as kidney, liver, pancreas, duodenum, adipose tissue, and skeletal muscle. Combined targeting of relevant neural outflows may provide a unique therapeutic opportunity for cardiometabolic disease.

Objectives: We aimed to investigate the feasibility, safety, and performance of a novel device-based approach for multi-organ denervation in a swine model over 30 and 90 days of follow-up.

Methods: Five Yorkshire cross pigs underwent combined percutaneous denervation in the renal arteries and the common hepatic artery (CHA) with the iRF Denervation System. Control animals (n = 3) were also studied. Specific energy doses were administered in the renal arteries and CHA. Blood was collected at 30 and 90 days. All animals had a pre-terminal procedure angiography. Tissue samples were collected for norepinephrine (NEPI) bioanalysis. Histopathological evaluation of collateral structures and tissues near the treatment sites was performed to assess treatment safety.

Results: All animals entered and exited the study in good health. No stenosis or vessel abnormalities were present. No significant changes in serum chemistry occurred. NEPI concentrations were significantly reduced in the liver (- 88%, p = 0.005), kidneys (- 78%, p < 0.001), pancreas (- 78%, p = 0.018) and duodenum (- 95%, p = 0.028) following multi-organ denervation treatment compared to control animals. Histologic findings were consistent with favourable tissue responses at 90 days follow-up.

Conclusions: Significant and sustained denervation of the treated organs was achieved at 90 days without major safety events. Our findings demonstrate the feasibility of multi-organ denervation using a novel iRF Denervation System in a single procedure.
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http://dx.doi.org/10.1007/s00392-021-01814-1DOI Listing
February 2021

Higher Undercarboxylated to Total Osteocalcin Ratio Is Associated With Reduced Physical Function and Increased 15-Year Falls-Related Hospitalizations: The Perth Longitudinal Study of Aging Women.

J Bone Miner Res 2021 Mar 3;36(3):523-530. Epub 2020 Dec 3.

Medical School, University Western Australia, Perth, Australia.

Evidence from animal models suggests that undercarboxylated osteocalcin (ucOC) is involved in muscle mass maintenance and strength. In humans, the ucOC to total (t)OC ratio may be related to muscle strength and perhaps physical function and falls risk, but data are limited. We tested the hypothesis that ucOC and ucOC/tOC ratio are associated with muscle function (muscle strength and physical function) in older women and 15-year falls-related hospitalizations. Serum tOC and ucOC were assessed in 1261 older women (mean age 75.2 ± 2.7 years) forming the Perth Longitudinal Study of Aging Women (1998 to 2013). Timed-up-and-go (TUG) and grip strength were assessed at baseline and at 5 years. Falls-related hospitalizations (14.5-year follow-up) were captured by the Hospital Morbidity Data Collection, via the Western Australian Data Linkage System. At baseline, women with higher ucOC/tOC ratio (quartile 4) had slower TUG performance compared with quartile 1 (~0.68 seconds, p < .01). Grip strength and 5-year change of TUG and grip were not different (p > .05) between quartiles. Fear of falling limiting house, outdoor, and combined activities was significantly different across quartiles (p < .05). Higher ucOC/tOC was significantly associated with poorer TUG performance at baseline and 5-year change in performance, increased walking aid use, and fear of falling (all p < .05). Higher ucOC was related to lower grip strength at baseline (p < .05) but not 5-year change in strength. Those with the highest ucOC/tOC had greater falls-related hospitalizations (unadjusted log rank, p = .004) remaining significant after adjusting for key variables (hazard ratio [HR] = 1.31, 95% confidence interval [CI] 1.09-1.57, p = .004). We identified a large proportion of older women with high ucOC/tOC ratio who had reduced physical function, including its long-term decline and increased risk of falls-related hospitalizations. Early identification of women at higher risk can enable prevention and intervention strategies to occur, reducing risk for injurious falls. © 2020 American Society for Bone and Mineral Research (ASBMR)..
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http://dx.doi.org/10.1002/jbmr.4208DOI Listing
March 2021

Administrative coding in electronic health care record-based research of NAFLD: an expert panel consensus statement.

Hepatology 2021 Jan 23. Epub 2021 Jan 23.

Transplantation and Liver Surgery Clinic, Helsinki University Hospital, Helsinki, Finland.

Background And Aims: Electronic health record (EHR)-based research allows the capture of large amounts of data, which is necessary in nonalcoholic fatty liver disease (NAFLD), where the risk of clinical liver outcomes is generally low. The lack of consensus on which International Classification of Disease (ICD) codes should be used as exposures and outcomes limits comparability and generalizability of results across studies. We aimed to establish consensus among a panel of experts on ICD codes that could become the reference standard and provide guidance around common methodological issues.

Approach And Results: Researchers with an interest in EHR-based NAFLD research were invited to collectively define which administrative codes are most appropriate for documenting exposures and outcomes. We used a modified Delphi approach to reach consensus on several commonly encountered methodological challenges in the field. After two rounds of revision, a high level of agreement (>67%) was reached on all items considered. Full consensus was achieved on a comprehensive list of administrative codes to be considered for inclusion and exclusion criteria in defining exposures and outcomes in EHR-based NAFLD research. We also provide suggestions on how to approach commonly encountered methodological issues and identify areas for future research.

Conclusions: This expert panel consensus statement can help harmonize and improve generalizability of EHR-based NAFLD research.
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http://dx.doi.org/10.1002/hep.31726DOI Listing
January 2021

Validation of fatty liver disease scoring systems for ultrasound diagnosed non-alcoholic fatty liver disease in adolescents.

Dig Liver Dis 2020 Dec 14. Epub 2020 Dec 14.

Menzies Institute for Medical Research, University of Tasmania. Electronic address:

Background And Aims: The incidence of non-alcoholic fatty liver disease (NAFLD) is increasing in young populations. However, there are inadequate data regarding diagnosis of NAFLD. We aimed to validate three scoring systems against a previous standard of suprailiac skinfold thickness for diagnosing NAFLD in population-based adolescents.

Methods: Seventeen-year-old adolescents (n = 899), participating in the Raine Study, attended a cross-sectional follow-up. NAFLD was diagnosed using liver ultrasound. Scores for Fatty liver index (FLI), Hepatic Steatosis Index (HSI) and Zhejiang University index (ZJU index) were calculated. Diagnostic accuracy of these diagnostic tests was evaluated through discrimination and calibration.

Results: NAFLD was diagnosed 9% in males and 15% in females. The three scoring systems demonstrated better discrimination performance for NAFLD in males (AUC was FLI:0.82, HSI: 0.83 and ZJU index: 0.83) compared to females (AUC was FLI: 0.67, HSI: 0.67 and ZJU index: 0.67). Suprailiac skinfold performed better than the scoring systems (overall AUC: 0.82; male AUC:0.88; female AUC:0.73). FLI had best calibration performance.

Conclusion: Suprailiac skinfold thickness was a better predictor of ultrasound-diagnosed NAFLD than the three diagnostic scoring systems investigated. The higher performance characteristics of the algorithmic scoring systems in males compared with females may have implications for use in population assessments.
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http://dx.doi.org/10.1016/j.dld.2020.11.037DOI Listing
December 2020

Hepascore predicts liver outcomes and all-cause mortality in long-term methotrexate users: A retrospective cohort study.

JGH Open 2020 Dec 21;4(6):1211-1216. Epub 2020 Oct 21.

School of Medicine and Pharmacology The University of Western Australia Perth Western Australia Australia.

Background And Aim: Methotrexate (MTX) is routinely used for immunological disorders, and its long-term use is associated with hepatotoxicity. The aim of this study was to investigate whether a serum liver fibrosis test (Hepascore) predicted the risk of adverse liver-related outcomes and mortality.

Methods: A total of 92 patients in Western Australia who had a long-term MTX intake history,from 2004 to 2016, were recruited and followed up from the first Hepascore to death or end of the study. Clinical data, all deaths, and liver-related outcomes (liver-related death and decompensation) were obtained from hospital, PathWest, and WA Data Linkage Unit databases.

Results: Nine deaths and four adverse liver-related outcomes occurred during the follow up of 354 person-years. The 5-year survival was 86.1%. The liver-related outcome free survival was 95.6%. Baseline Hepascore ≥0.84 was associated with advanced fibrosis on liver biopsy ( = 0.025). A baseline Hepascore ≥0.84 was significantly associated with higher risks for adverse liver-related outcomes ( < 0.001) and all-cause mortality ( = 0.001). Cox regression demonstrated that only baseline Hepascore ≥0.84 was independently associated with the increased risk of all-cause mortality (7.91 [1.52-41.29], = 0.014). Moreover, any Hepascore ≥0.84 found during follow up was independently associated with the increased risk of all-cause mortality (86.18 [4.03-1844.83], = 0.007).

Conclusions: This study demonstrated the potential importance of Hepascore monitoring in long-term MTX users. Patients with a Hepascore higher than 0.84 at any stage had increased mortality, but further studies are required to confirm this finding.
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http://dx.doi.org/10.1002/jgh3.12430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731826PMC
December 2020

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

Reply to Letter to the Editor HEP-20-2462 and HEP-20-2655.

Hepatology 2020 Dec 4. Epub 2020 Dec 4.

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

We thank the correspondents for their interest in our study regarding the development of ABIDE, a predictive model of hepatic decompensation in non-alcoholic fatty liver disease (NAFLD) patients with cirrhosis. We have previously published outcomes in the derivation cohort(1), and appreciate the opportunity to clarify our data. Significant alcohol intake (>20 g/d for men, >10 g/d for women) during 2 years prior to enrolment or during follow-up was a standard exclusion,(1) and only two patients were taking vitamin E.
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http://dx.doi.org/10.1002/hep.31666DOI Listing
December 2020

Changes in the Epidemiology of Hepatobiliary Disease Complicating Type 2 Diabetes over 25 Years: The Fremantle Diabetes Study.

J Clin Med 2020 Oct 24;9(11). Epub 2020 Oct 24.

University of Western Australia Medical School, Fremantle Hospital, Fremantle 6959, WA, Australia.

Objective: To determine whether the incidence/outcome of hepatobiliary disease (HBD) has increased over recent decades in community-based Australians with and without type 2 diabetes (T2D).

Methods: Longitudinal data from the Fremantle Diabetes Study Phase I (FDS1; recruitment 1993-1996; = 1291 with T2D) and Phase II (FDS2; 2008-2011; = 1509) were analyzed. Participants with T2D from both Phases were age-, sex-, and postcode-matched 1:4 to people without diabetes. Incident HBD and associated mortality were ascertained from hospitalization, cancer registration, and/or death certification codes. Incidence rates (IRs) and IR ratios (IRRs) for those with versus without diabetes in FDS1 and FDS2 were calculated.

Results: HBD IRs for people without diabetes did not change between Phases. The IRR (95% CI) for people with T2D in FDS2 versus FDS1 was 1.30 (1.01-1.68) with the highest IRRs in participants aged <65 years. Non-alcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) events were 54% greater in FDS2 than FDS1 in the presence of greater abdominal adiposity. NAFLD/NASH was coded in one in 11 HBD events in FDS2 and in 10% of HBD deaths (<4% of total mortality).

Conclusions: HBD is more frequent in people with versus without T2D and this discrepancy is increasing. Hospitalizations/deaths due to NAFLD/NASH remain uncommon.
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http://dx.doi.org/10.3390/jcm9113409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690874PMC
October 2020

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

Association between remnant lipoprotein cholesterol levels and non-alcoholic fatty liver disease in adolescents.

JHEP Rep 2020 Dec 24;2(6):100150. Epub 2020 Jul 24.

Department of Gastroenterology and Hepatology, Fiona Stanley Hospital, Murdoch, WA, Australia.

Background & Aims: Remnant lipoprotein cholesterol (RLP-C) is an atherogenic lipid profile associated with non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD). With increased rates of CVD seen in adults with NAFLD, RLP-C has the potential to identify individuals with NAFLD who are at increased risk of CVD. This study examined in adolescents sex-different associations among RLP-C, NAFLD, and cardiometabolic risk factors, and whether RLP-C is associated with NAFLD beyond traditional cardiometabolic risk factors.

Methods: Adolescents in the Raine Study had anthropometry, clinical, biochemistry and arterial stiffness measurements recorded at 17 years of age. Fatty liver, subcutaneous and visceral adipose thickness were assessed using abdominal ultrasound. Relationships among RLP-C, NAFLD, liver biochemistry, insulin resistance, adipokines, adiposity and arterial stiffness were assessed.

Results: NAFLD was diagnosed in 15.1% (19.6% females and 10.7% males) of adolescents. Increasing RLP-C levels were associated with increasing severity of hepatic steatosis and metabolic syndrome. Adolescents with NAFLD and serum RLP-C levels in the highest quartile compared with the lowest quartile, had higher serum leptin, homeostatic model assessment of insulin resistance (HOMA-IR), high-sensitivity C-reactive protein, low-density-lipoprotein cholesterol, triglycerides, BMI, subcutaneous and visceral adipose thickness, systolic blood pressure and arterial stiffness, but lower adiponectin and high-density-lipoprotein cholesterol. Using multivariable logistic regression, RLP-C in the lowest quartile compared with the highest quartile was associated with 85% lower odds of NAFLD in males and 55% in females, after adjusting for waist circumference, leptin, ALT, adiponectin and HOMA-IR.

Conclusions: There is an association between RLP-C and NAFLD beyond traditional risk factors of adiposity and insulin resistance in adolescents. Although raised serum RLP-C levels were associated with the severity of hepatic steatosis and markers of cardiometabolic risk, lower serum RLP-C might reflect reduced cardiovascular risk.

Lay Summary: Remnant lipoprotein cholesterol (RLP-C) is a part of the blood cholesterol that is linked with heart disease and non-alcoholic fatty liver disease (NAFLD) in adults. In the Raine Study, teenagers with high RLP-C levels had more severe fat accumulation in their liver. Thus, RLP-C might be the hidden link between NAFLD and future risk of heart disease.
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http://dx.doi.org/10.1016/j.jhepr.2020.100150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495103PMC
December 2020

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

Hepatology 2020 Sep 25. Epub 2020 Sep 25.

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
September 2020

Trends and Outcomes in Simultaneous Liver and Kidney Transplantation in Australia and New Zealand.

Transplant Proc 2021 Jan-Feb;53(1):136-140. Epub 2020 Sep 12.

Nephrology Department, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia; Central Clinical School, University of Sydney, Sydney, New South Wales, Australia; Holdsworth House Medical Practice, Sydney, New South Wales, Australia.

Aim: Rates of simultaneous liver and kidney transplantation (SLKT) have increased, but indications for SLKT remain poorly defined. Additional data are needed to determine which patients benefit from SLKT to best direct use of scarce donor kidneys.

Methods: Data were extracted from the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) database for all SLKT performed until the end of 2017. Patients were divided by pretransplant dialysis status into no dialysis before SLKT (preemptive kidney transplant) and any dialysis before SLKT (nonpreemptive). Baseline characteristics and outcomes were compared.

Results: Between 1989 and 2017, inclusive, 84 SLKT procedures were performed in Australia, of which 24% were preemptive. Preemptive and nonpreemptive SLKT recipients did not significantly differ in age (P = .267), sex (P = .526), or ethnicity (P = .870). Over a median follow-up time of 4.5 years, preemptively transplanted patients had a statistically equivalent risk of kidney graft failure (hazard ratio (HR) 1.83, 95% confidence interval [CI]: 0.36-12.86, P = .474) and all-cause mortality (HR 1.69, 95% CI: 0.51-5.6, P = .226) compared to nonpreemptive patients. Overall, 1- and 5-year survival rates for all SLKTs were 92% (95% CI: 86-96) and 60% (95% CI: 45-75), respectively.

Conclusion: Kidney graft and overall patient survival were similar between patients with preemptive kidney transplant and those who were dialysis dependent.
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http://dx.doi.org/10.1016/j.transproceed.2020.08.030DOI Listing
April 2021

rs641738C>T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD: A meta-analysis.

J Hepatol 2021 Jan 31;74(1):20-30. Epub 2020 Aug 31.

MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK. Electronic address:

Background & Aims: A common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in NAFLD; however, these findings have not been consistently replicated in the literature. We aimed to establish whether rs641738C>T is a risk factor across the spectrum of NAFLD and to characterise its role in the regulation of related metabolic phenotypes through a meta-analysis.

Methods: We performed a meta-analysis of studies with data on the association between rs641738C>T genotype and liver fat, NAFLD histology, and serum alanine aminotransferase (ALT), lipids or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed a random effects meta-analysis using recessive, additive and dominant genetic models.

Results: Data from 1,066,175 participants (9,688 with liver biopsies) across 42 studies were included in the meta-analysis. rs641738C>T was associated with higher liver fat on CT/MRI (+0.03 standard deviations [95% CI 0.02-0.05], p = 4.8×10) and diagnosis of NAFLD (odds ratio [OR] 1.17 [95% CI 1.05-1.3], p = 0.003) in Caucasian adults. The variant was also positively associated with presence of advanced fibrosis (OR 1.22 [95% CI 1.03-1.45], p = 0.021) in Caucasian adults using a recessive model of inheritance (CC + CT vs. TT). Meta-analysis of data from previous GWAS found the variant to be associated with higher ALT (p = 0.002) and lower serum triglycerides (p = 1.5×10). rs641738C>T was not associated with fasting insulin and no effect was observed in children with NAFLD.

Conclusions: Our study validates rs641738C>T near MBOAT7 as a risk factor for the presence and severity of NAFLD in individuals of European descent.

Lay Summary: Fatty liver disease is a common condition where fat builds up in the liver, which can cause liver inflammation and scarring (including 'cirrhosis'). It is closely linked to obesity and diabetes, but some genes are also thought to be important. We did this study to see whether one specific change ('variant') in one gene ('MBOAT7') was linked to fatty liver disease. We took data from over 40 published studies and found that this variant near MBOAT7 is linked to more severe fatty liver disease. This means that drugs designed to work on MBOAT7 could be useful for treating fatty liver disease.
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http://dx.doi.org/10.1016/j.jhep.2020.08.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755037PMC
January 2021

Hepatocyte pyroptosis and release of inflammasome particles induce stellate cell activation and liver fibrosis.

J Hepatol 2021 Jan 4;74(1):156-167. Epub 2020 Aug 4.

Department of Pediatrics, University of California San Diego, La Jolla, CA, USA. Electronic address:

Background & Aims: Increased hepatocyte death contributes to the pathology of acute and chronic liver diseases. However, the role of hepatocyte pyroptosis and extracellular inflammasome release in liver disease is unknown.

Methods: We used primary mouse and human hepatocytes, hepatocyte-specific leucine 351 to proline Nlrp3CreA mice, and Gsdmd mice to investigate pyroptotic cell death in hepatocytes and its impact on liver inflammation and damage. Extracellular NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasomes were isolated from mutant NLRP3-YFP HEK cells and internalisation was studied in LX2 and primary human hepatic stellate cells. We also examined a cohort of 154 adult patients with biopsy-proven non-alcoholic fatty liver disease (Sir Charles Gairdner Hospital, Nedlands, Western Australia).

Results: We demonstrated that primary mouse and human hepatocytes can undergo pyroptosis upon NLRP3 inflammasome activation with subsequent release of NLRP3 inflammasome proteins that amplify and perpetuate inflammasome-driven fibrogenesis. Pyroptosis was inhibited by blocking caspase-1 and gasdermin D activation. The activated form of caspase-1 was detected in the livers and in serum from patients with non-alcoholic steatohepatitis and correlated with disease severity. Nlrp3CreA mice showed spontaneous liver fibrosis under normal chow diet, and increased sensitivity to liver damage and inflammation after treatment with low dose lipopolysaccharide. Mechanistically, hepatic stellate cells engulfed extracellular NLRP3 inflammasome particles leading to increased IL-1β secretion and α-smooth muscle actin expression. This effect was abrogated when cells were pre-treated with the endocytosis inhibitor cytochalasin B.

Conclusions: These results identify hepatocyte pyroptosis and release of inflammasome components as a novel mechanism to propagate liver injury and liver fibrosis development.

Lay Summary: Our findings identify a novel mechanism of inflammation in the liver. Experiments in cell cultures, mice, and human samples show that a specific form of cell death, called pyroptosis, leads to the release of complex inflammatory particles, the NLRP3 inflammasome, from inside hepatocytes into the extracellular space. From there they are taken up by other cells and thereby mediate inflammatory and pro-fibrogenic stress signals. The discovery of this mechanism may lead to novel treatments for chronic liver diseases in the future.
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http://dx.doi.org/10.1016/j.jhep.2020.07.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749849PMC
January 2021

Noninvasive Tests in the Assessment of NASH and NAFLD Fibrosis: Now and Into the Future.

Semin Liver Dis 2020 Nov 11;40(4):331-338. Epub 2020 Jun 11.

Department of Medicine, Gastroenterology and Hepatology Unit, University of Malaysia, Kuala Lumpur, Malaysia.

Noninvasive serum and imaging methods offer accessible, accurate, and safe assessment of fibrosis severity in nonalcoholic fatty liver disease. In contrast, current serum and imaging methods for the prediction of nonalcoholic steatohepatitis are not sufficiently accurate for routine clinical use. Serum fibrosis markers that incorporate direct measures of fibrogenesis (for example, hyaluronic acid) or fibrinolysis are generally more accurate than biomarkers not incorporating direct measures of fibrogenesis. Elastography methods are more accurate than serum markers for fibrosis assessment and particularly for the determination of cirrhosis, but have a significant failure and/or unreliability rate in obese individuals. To overcome this, combining serum and elastography methods in a sequential manner minimizes indeterminate results and maintains accuracy. The accuracy of current noninvasive methods for monitoring fibrosis response to treatment are limited; however, new tools derived from "omic" methodologies offer promise for the future.
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http://dx.doi.org/10.1055/s-0040-1713006DOI Listing
November 2020

Type 2 Diabetes and Metformin Use Associate With Outcomes of Patients With Nonalcoholic Steatohepatitis-Related, Child-Pugh A Cirrhosis.

Clin Gastroenterol Hepatol 2021 Jan 8;19(1):136-145.e6. Epub 2020 May 8.

Medical School, Faculty of Health and Medical Sciences, The University of Western Australia, Nedlands, Australia; Department of Hepatology, Sir Charles Gairdner Hospital, Nedlands Australia.

Background & Aims: Factors that affect outcomes of patients with nonalcoholic steatohepatitis (NASH)-related cirrhosis are unclear. We studied associations of type 2 diabetes, levels of hemoglobin A1c (HbA1c), and use of antidiabetic medications with survival and liver-related events in patients with NASH and compensated cirrhosis.

Methods: We collected data from 299 patients with biopsy-proven NASH with Child-Pugh A cirrhosis from tertiary hospitals in Spain, Australia, Hong Kong, and Cuba, from April 1995 through December 2016. We obtained information on the presence of type 2 diabetes, level of HbA1c, and use of antidiabetic medications. Cox proportional and competing risk models were used to estimate and compare rates of transplant-free survival, hepatic decompensation, and hepatocellular carcinoma (HCC).

Results: A total of 212 patients had type 2 diabetes at baseline and 8 of 87 patients developed diabetes during a median follow-up time of 5.1 years (range, 0.5-10.0 y). A lower proportion of patients with diabetes survived the entire follow-up period (38%) than of patients with no diabetes (81%) (adjusted hazard ratio [aHR], 4.23; 95% CI, 1.93-9.29). Higher proportions of patients with diabetes also had hepatic decompensation (51% vs 26% of patients with no diabetes; aHR, 2.03; 95% CI, 1.005-4.11) and HCC (25% vs 7% of patients with no diabetes; aHR, 5.42; 95% CI, 1.74-16.80). Averaged annual HbA1c levels over time were not associated with outcomes. Metformin use over time was associated with a significant reduction in risk of death or liver transplantation (aHR, 0.41; 95% CI, 0.26-0.45), hepatic decompensation (aHR, 0.80; 95% CI, 0.74-0.97), and HCC (aHR, 0.78; 95% CI, 0.69-0.96). Metformin significantly reduced the risk of hepatic decompensation and HCC only in subjects with HbA1c levels greater than 7.0% (aHR, 0.97; 95% CI, 0.95-0.99 and aHR, 0.67; 95% CI, 0.43-0.94, respectively).

Conclusions: In an international cohort of patients with biopsy-proven NASH and Child-Pugh A cirrhosis, type 2 diabetes increased the risk of death and liver-related outcomes, including HCC. Patients who took metformin had higher rates of survival and lower rates of decompensation and HCC.
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http://dx.doi.org/10.1016/j.cgh.2020.04.083DOI Listing
January 2021

Screening for non-alcoholic fatty liver disease in community setting: A cohort study using controlled attenuation parameter-transient elastography.

JGH Open 2020 Apr 4;4(2):245-250. Epub 2019 Sep 4.

Department of Medicine, Division of Gastroenterology, Faculty of Medicine Chulalongkorn University Bangkok Thailand.

Background/aim: The global problems of chronic liver disease and non-alcoholic fatty liver disease (NAFLD) are increasing. We examined the prevalence of NAFLD and significant liver stiffness in an asymptomatic population and identified the predictors of significant fibrosis in NAFLD.

Method: We prospectively enrolled Thai subjects, aged 18-80 years, from four regions (Bangkok, Central, North, South) of Thailand from March 2013 to November 2016. All participants underwent controlled attenuation parameter (CAP) measurement for liver fat quantification and transient elastography (TE) for liver stiffness measurement (LSM). NAFLD was defined as liver fat ≥10% (CAP ≥ 306 dB/m). Of 1145 participants, 782 (68.3%) were eligible for analysis.

Result: The mean age ± standard deviation (SD) was 53.1 ± 4.6 years, and 71.6% were female. The mean ± SD values of CAP and LSM of the overall cohort were 241.9 ± 61.4 dB/m and 5.5 ± 3.8 kPa, respectively. The prevalence of NAFLD was 18.0%, whereas 5.4% of the cohort had nonobese NAFLD (BMI < 25 kg/m), and 2.8% had lean NAFLD (BMI < 23 kg/m). The prevalence of significant liver fibrosis (≥F2) in NAFLD subjects was 18.4%. On multivariate analysis, the degree of significant fibrosis in NAFLD was significantly associated with male gender and a history of dyslipidemia.

Conclusion: NAFLD with significant fibrosis (≥F2) is prevalent in asymptomatic populations. The predictors of significant fibrosis in NAFLD were male gender and dyslipidemia. Screening for NAFLD using CAP/TE in asymptomatic populations should be considered in hospitals with available facilities.
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http://dx.doi.org/10.1002/jgh3.12252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144791PMC
April 2020

A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement.

J Hepatol 2020 07 8;73(1):202-209. Epub 2020 Apr 8.

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

The exclusion of other chronic liver diseases including "excess" alcohol intake has until now been necessary to establish a diagnosis of metabolic dysfunction-associated fatty liver disease (MAFLD). However, given our current understanding of the pathogenesis of MAFLD and its rising prevalence, "positive criteria" to diagnose the disease are required. In this work, a panel of international experts from 22 countries propose a new definition for the diagnosis of MAFLD that is both comprehensive and simple, and is independent of other liver diseases. The criteria are based on evidence of hepatic steatosis, in addition to one of the following three criteria, namely overweight/obesity, presence of type 2 diabetes mellitus, or evidence of metabolic dysregulation. We propose that disease assessment and stratification of severity should extend beyond a simple dichotomous classification to steatohepatitis vs. non-steatohepatitis. The group also suggests a set of criteria to define MAFLD-associated cirrhosis and proposes a conceptual framework to consider other causes of fatty liver disease. Finally, we bring clarity to the distinction between diagnostic criteria and inclusion criteria for research studies and clinical trials. Reaching consensus on the criteria for MAFLD will help unify the terminology (e.g. for ICD-coding), enhance the legitimacy of clinical practice and clinical trials, improve clinical care and move the clinical and scientific field of liver research forward.
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http://dx.doi.org/10.1016/j.jhep.2020.03.039DOI Listing
July 2020

Comparative Effectiveness of Entecavir Versus Tenofovir for Preventing Hepatocellular Carcinoma in Patients with Chronic Hepatitis B: A Systematic Review and Meta-Analysis.

Hepatology 2021 Jan 6;73(1):68-78. Epub 2020 Nov 6.

Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, CA.

Background And Aims: Chronic hepatitis B (CHB) can lead to hepatocellular carcinoma (HCC). While both tenofovir disoproxil (TDF) and entecavir (ETV) have been shown to reduce the risk of HCC, their comparative effectiveness is unclear. We estimated the comparative effectiveness of these two agents in reducing the risk of HCC in patients with CHB, through a systematic review and meta-analysis.

Approach And Results: We searched multiple electronic databases from January 1, 1998, to October 31, 2019, for randomized controlled trials and observational comparative effectiveness studies in adults with CHB treated with ETV compared to TDF, reporting the incidence of HCC (minimum follow-up 12 months). Primary outcome was incidence of HCC, calculated as incidence rate ratio (IRR) with 95% confidence interval (CI, unadjusted analysis) and hazard ratio (HR) with 95% CI (adjusted analysis, where reported). Of 1,971 records identified, 14 studies (263,947 person-years) were included for quantitative analysis. On unadjusted meta-analysis of 14 studies, the risk of HCC was not statistically different between ETV and TDF (IRR, 1.28; 95% CI, 0.99-1.66). When using available adjusted data (multivariate or propensity-matched data), the risk of HCC among patients treated with ETV was 27% higher when compared to TDF (seven studies; 95% CI, 1.01-1.60, P = 0.04). Additional analysis of adjusted data when separately reported among patients with cirrhosis demonstrated an adjusted HR of 0.90 (95% CI, 0.66-1.23), suggesting no difference between ETV-treated and TDF-treated groups. The overall confidence in estimates was very low (observational studies, high heterogeneity).

Conclusions: TDF may be associated with lower risk of HCC when compared to ETV.
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http://dx.doi.org/10.1002/hep.31267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022893PMC
January 2021

Bile acids associate with specific gut microbiota, low-level alcohol consumption and liver fibrosis in patients with non-alcoholic fatty liver disease.

Liver Int 2020 06 24;40(6):1356-1365. Epub 2020 Apr 24.

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

Background: Bile acids (BAs) are synthesized by the liver and modified by gut bacteria, and may play an intermediary role between the gut microbiome and liver in promoting fibrosis in non-alcoholic fatty liver disease (NAFLD). We investigated the associations between serum and faecal BAs, gut microbiome and fibrosis in patients with and without NAFLD and examined the impact of diet and alcohol consumption on these relationships.

Methods: Adult patients (n = 122) underwent liver biopsy and BAs characterization by high-performance liquid chromatography/mass spectrometry. Gut microbiome composition was analysed using next-generation 16S rRNA sequencing. Diet and alcohol intake were determined by 3-day food diary.

Results: Serum and faecal BA concentrations increased progressively among non-NAFLD controls (n = 55), NAFLD patients with no/mild fibrosis (F0-2, n = 58) and NAFLD with advanced fibrosis (F3/4, n = 9). Progressive increases in serum BAs were driven by primary conjugated BAs including glycocholic acid [GCA] and secondary conjugated BAs. In contrast, faecal BA increase was driven by secondary unconjugated BAs (predominately deoxycholic acid [DCA]). Serum GCA levels and faecal DCA levels correlated with the abundance of Bacteroidaceae and Lachnospiraceae, and stool secondary BAs with an unclassifiable family of the order Bacteroidales (Bacteroidales;other). These bacterial taxa were also associated with advanced fibrosis. Modest alcohol consumption was positively correlated with faecal DCA levels and relative abundance of Lachnospiracaea and Bacteroidales;other.

Conclusions: Higher serum and faecal BA levels are associated with advanced fibrosis in NAFLD. Specific gut bacteria link alterations in BA profiles and advanced fibrosis, and may be influenced by low-level alcohol consumption.
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http://dx.doi.org/10.1111/liv.14453DOI Listing
June 2020

Advances in non-invasive assessment of hepatic fibrosis.

Gut 2020 07 17;69(7):1343-1352. Epub 2020 Feb 17.

Medicine and Pharmacology, The University of Western Australia, Nedlands, Western Australia, Australia.

Liver fibrosis should be assessed in all individuals with chronic liver disease as it predicts the risk of future liver-related morbidity and thus need for treatment, monitoring and surveillance. Non-invasive fibrosis tests (NITs) overcome many limitations of liver biopsy and are now routinely incorporated into specialist clinical practice. Simple serum-based tests (eg, Fibrosis Score 4, non-alcoholic fatty liver disease Fibrosis Score) consist of readily available biochemical surrogates and clinical risk factors for liver fibrosis (eg, age and sex). These have been extensively validated across a spectrum of chronic liver diseases, however, tend to be less accurate than more 'complex' serum tests, which incorporate direct measures of fibrogenesis or fibrolysis (eg, hyaluronic acid, N-terminal propeptide of type three collagen). Elastography methods quantify liver stiffness as a marker of fibrosis and are more accurate than simple serum NITs, however, suffer increasing rates of unreliability with increasing obesity. MR elastography appears more accurate than sonographic elastography and is not significantly impacted by obesity but is costly with limited availability. NITs are valuable for excluding advanced fibrosis or cirrhosis, however, are not sufficiently predictive when used in isolation. Combining serum and elastography techniques increases diagnostic accuracy and can be used as screening and confirmatory tests, respectively. Unfortunately, NITs have not yet been demonstrated to accurately reflect fibrosis change in response to treatment, limiting their role in disease monitoring. However, recent studies have demonstrated lipidomic, proteomic and gut microbiome profiles as well as microRNA signatures to be promising techniques for fibrosis assessment in the future.
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http://dx.doi.org/10.1136/gutjnl-2018-317593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7945956PMC
July 2020

Nonalcoholic fatty liver disease burden: Australia, 2019-2030.

J Gastroenterol Hepatol 2020 Sep 26;35(9):1628-1635. Epub 2020 Feb 26.

School of Medicine, University of Sydney, Sydney, New South Wales, Australia.

Background And Aim: Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) account for a large and growing proportion of liver disease burden globally. The burden of NAFLD/NASH manifests in increasing levels of advanced liver disease and primary liver cancer in Australia. A Markov model was used to forecast NAFLD burden in Australia through 2030.

Methods: A model was used to estimate fibrosis progression, primary liver cancer, and liver deaths among the Australian NAFLD population, with changes in incident NAFLD cases based on long-term trends for changes in the prevalence of obesity. Published estimates and surveillance data were applied to build and validate the model projections, including surveillance data for the incidence of liver cancer.

Results: Prevalent NAFLD cases were projected to increase 25% from the current burden (5 551 000 [4 748 000-6 306 000] cases in 2019) to 7 024 000 [5 838 000-7 886 000] cases in 2030. The projected increase in the number of NASH cases (40%) was greater than that of NAFLD cases. Incident cases of advanced liver disease are projected to increase up to 85% by 2030, and incident NAFLD liver deaths are estimated to increase 85% from 1900 (1100-3300) deaths in 2019 to 3500 (2100-6100) deaths in 2030.

Conclusions: Restraining growth of the obese and diabetic populations, along with potential therapeutic options, will be essential for mitigating disease burden.
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http://dx.doi.org/10.1111/jgh.15009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540570PMC
September 2020

Lifestyle modification in NAFLD/NASH: Facts and figures.

JHEP Rep 2019 Dec 5;1(6):468-479. Epub 2019 Nov 5.

Medical School, The University of Western Australia, Perth, WA, Australia.

The development of non-alcoholic fatty liver disease is closely linked to lifestyle factors, namely excessive caloric intake coupled with reduced physical activity and exercise. This review aims to examine the evidence behind lifestyle change as a tool to improve hepatic steatosis and liver histology in patients with non-alcoholic fatty liver disease/non-alcoholic steatohepatitis. Furthermore, potential barriers to adopting lifestyle changes and strategies to overcome these barriers in the clinical setting are discussed.
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http://dx.doi.org/10.1016/j.jhepr.2019.10.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005657PMC
December 2019

The MAAPE score in intermediate and advanced hepatocellular carcinoma treated with Yttrium-90 resin microsphere radioembolization.

J Gastroenterol Hepatol 2020 Nov 23;35(11):1945-1952. Epub 2020 Feb 23.

Medical School, University of Western Australia, Nedlands, Western Australia, Australia.

Background And Aim: Yttrium-90 resin microsphere radioembolization (RE) is not recommended for routine use in intermediate or advanced hepatocellular carcinoma (HCC) by recent guidelines. This study aims to establish pre-treatment variables which predict survival in HCC patients treated with RE to identify those who will benefit most from it, and to inform patient selection for future trials.

Methods: Single center, retrospective study of consecutive patients with HCC treated with RE from 2007 to 2018. Patients included if undergoing their first RE treatment for intermediate or advanced HCC; a Child-Pugh score of B7 or less; and a performance status of 1 or less. Multivariable Cox regression identified variables that were significantly associated with survival. A predictive score was developed based upon coefficients from the fitted Cox regression model, and cubic spline regression was used to identify prognostic groups.

Results: One hundred thirteen patients with intermediate (53.1%) and advanced HCC (45.1%) followed for a median of 13.2 months were included. Variables associated with superior survival used to derive the MAAPE score were lower Model for End-Stage Liver Disease score (≤ 7), lower Alpha-fetoprotein (≤ 150 IU/L), higher serum Albumin (> 37 g/L), absence of Portal vein tumor thrombus, and better performance status (Eastern Cooperative Oncology Group = 0). Three survival prognostic groups were identified: good (median overall survival 25.0 months), average (15.3 months), and poor (6.3 months) (overall log-rank test, P < 0.001).

Conclusion: The MAAPE score accurately identifies HCC patients in whom RE is safe and effective. This will allow for optimal patient selection for future trials of RE versus systemic therapy.
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http://dx.doi.org/10.1111/jgh.15008DOI Listing
November 2020

The relationship between abdominal pain and emotional wellbeing in children and adolescents in the Raine Study.

Sci Rep 2020 02 3;10(1):1646. Epub 2020 Feb 3.

Department of Gastroenterology and Hepatology, Fiona Stanley Hospital, Murdoch, WA, Australia.

Abdominal pain is a common reason for medical visits. We examined the prevalence, gastrointestinal, and emotional significance of abdominal pain in a population-based cohort serially followed up from birth to 17 years. Children and adolescents from Generation 2 of the Raine Study participated in comprehensive cross-sectional assessments at ages 2, 5, 8, 10, 14 and 17 years. At 17 years, medical history, general health, gastrointestinal symptoms, medications, health practitioner attendance, and self-rated unhappiness were recorded. Longitudinal data regarding abdominal pain or unhappiness, from serial questionnaires, were analysed to identify factors associated with abdominal pain and adverse emotional health at age 17 years. Females experienced more abdominal pain than males at all ages (p < 0.05). Seventeen-year-old adolescents with abdominal pain reported a higher prevalence of depression, anxiety, being bullied at school, and poorer health status than those without abdominal pain (p < 0.05 for all). Abdominal pain and unhappiness during childhood and mid-adolescence were prospectively associated with recurrent abdominal pain, anxiety, depression and unhappiness during late adolescence (p < 0.05 for all). In conclusion, abdominal pain in children and adolescents associates with depression, anxiety, being bullied, unhappiness and reduced overall health-rating during adolescence. Awareness of these factors may guide management decisions.
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http://dx.doi.org/10.1038/s41598-020-58543-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997389PMC
February 2020

Decreased Physical Working Capacity in Adolescents With Nonalcoholic Fatty Liver Disease Associates With Reduced Iron Availability.

Clin Gastroenterol Hepatol 2020 Jun 16;18(7):1584-1591. Epub 2019 Oct 16.

Department of Gastroenterology, Fiona Stanley Fremantle Hospital Group, Perth, Australia; School of Medical and Health Sciences, Edith Cowan University, Perth, Australia.

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is common and related to obesity and insulin resistance. Iron metabolism is impaired in obese individuals and iron deficiency has been associated with physical inactivity. We investigated whether iron bioavailability is reduced in patients with NAFLD and contributes to reduced cardiorespiratory fitness.

Methods: We collected information on weight-adjusted, submaximal physical work capacity (PWC), ultrasound-determined hepatic steatosis, iron indices, and hematologic and metabolic parameters from 390 female and 458 male participants of the Raine Study-a longitudinal study of disease development in 2868 children in Western Australia. X and linear regression analyses were used to compare characteristics of study participants according to NAFLD status at age 17 years.

Results: Fourteen percent of the cohort had NAFLD. PWC was significantly reduced in adolescents with NAFLD compared to adolescents without NAFLD (reduction of 0.17 W/kg, P = .0003, adjusted for sex and body mass index [BMI]). Iron bioavailability (assessed by mean corpuscular volume [MCV], mean corpuscular haemoglobin [MCH], transferrin saturation, and serum levels of iron) was inversely correlated with BMI in adolescents with NAFLD (P ≤ .01 for all, adjusted for sex) but not in adolescents without NAFLD (P > .30). MCV and MCH correlated with PWC (MCV, P = .002 for female and P = .0003 male participants; MCH, P = .004 for female and P = .01 for male participants), irrespective of NAFLD status. Reduced PWC was associated with lower transferrin saturation in adolescents with NAFLD (reduction of 0.012 W/kg per unit decrease in transferrin saturation, P = .007) but not in adolescents without NAFLD (reduction of 0.001 W/kg, P = .40), adjusted for sex. This association was independent of MCV or MCH.

Conclusions: In a well-defined cohort of adolescents, we found NAFLD to be associated with decreased cardiorespiratory fitness, independent of BMI. The relationship between transferrin saturation and PWC in adolescents with NAFLD indicates that functional iron deficiency might contribute to reductions in cardiorespiratory fitness.
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http://dx.doi.org/10.1016/j.cgh.2019.10.017DOI Listing
June 2020

Standardising the interpretation of liver biopsies in non-alcoholic fatty liver disease clinical trials.

Aliment Pharmacol Ther 2019 11 3;50(10):1100-1111. Epub 2019 Oct 3.

London, ON, Canada.

Background: There is substantial variation in how histologic definitions and scoring systems of non-alcoholic fatty liver disease (NAFLD) are operationalised.

Aim: To develop a consensus-based framework for standardising histologic assessment of liver biopsies in clinical trials of NAFLD.

Methods: An expert panel of 14 liver pathologists and three hepatologists was assembled. Using modified RAND/University of California Los Angeles appropriateness methodology, 130 items derived from literature review and expert opinion were rated by each panel member on a 1-9 scale. Disagreement was defined as ≥5 ratings in the lowest (1-3) and highest (7-9) categories. Items were classified as inappropriate (median 1-3.5 without disagreement), uncertain (median 3.5-6.5 or any median with disagreement) or appropriate (median 6.5-9 without disagreement). Survey results were discussed as a group before voting.

Results: Current measures of disease activity and fibrosis may not fully capture important features of non-alcoholic steatohepatitis (NASH). Alternative methods to evaluate ballooning degeneration are needed. Panellists were uncertain whether portal inflammation, degree of steatosis and Mallory-Denk bodies are important measures of disease activity. Furthermore, it was felt that current staging systems do not capture the full spectrum of fibrosis in NASH. A consensus definition and sub-stages for bridging fibrosis are needed. The severity of perisinusoidal fibrosis should be captured at all stages. Lastly, a method to evaluate features of fibrosis regression should be developed.

Conclusion: The operating properties of the modifications proposed should be evaluated prospectively to determine reliability and responsiveness.
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http://dx.doi.org/10.1111/apt.15503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817398PMC
November 2019

The 20% Rule of NASH Progression: The Natural History of Advanced Fibrosis and Cirrhosis Caused by NASH.

Hepatology 2019 12;70(6):1885-1888

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

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http://dx.doi.org/10.1002/hep.30946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504908PMC
December 2019

Lean NAFLD: A Distinct Entity Shaped by Differential Metabolic Adaptation.

Hepatology 2020 04 24;71(4):1213-1227. Epub 2020 Jan 24.

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

Background And Aims: Nonalcoholic fatty liver disease (NAFLD) affects a quarter of the adult population. A significant subset of patients are lean, but their underlying pathophysiology is not well understood.

Approach And Results: We investigated the role of bile acids (BAs) and the gut microbiome in the pathogenesis of lean NAFLD. BA and fibroblast growth factor (FGF) 19 levels (a surrogate for intestinal farnesoid X receptor [FXR] activity), patatin-like phospholipase domain containing 3 (PNPLA3), and transmembrane 6 superfamily member 2 (TM6SF2) variants, and gut microbiota profiles in lean and nonlean NAFLD were investigated in a cohort of Caucasian patients with biopsy-proven NAFLD (n = 538), lean healthy controls (n = 30), and experimental murine models. Patients with lean NAFLD had a more favorable metabolic and histological profile compared with those with nonlean NAFLD (P < 0.05 for all). BA levels were significantly higher in NAFLD with advanced compared with earlier stages of liver fibrosis. Patients with lean NAFLD had higher serum secondary BA and FGF19 levels and reduced 7-alpha-hydroxy-4-cholesten-3-one (C4) levels (P < 0.05 for all). These differences were more profound in early compared with advanced stages of fibrosis (P < 0.05 for both). Lean patients demonstrated an altered gut microbiota profile. Similar findings were demonstrated in lean and nonlean murine models of NAFLD. Treating mice with an apical sodium-dependent BA transporter inhibitor (SC-435) resulted in marked increases in fgf15, a shift in the BA and microbiota profiles, and improved steatohepatitis in the lean model.

Conclusions: Differences in metabolic adaptation between patients with lean and nonlean NAFLD, at least in part, explain the pathophysiology and provide options for therapy.
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http://dx.doi.org/10.1002/hep.30908DOI Listing
April 2020