High prevalence of diabetes among young First Nations Peoples with metabolic dysfunction-associated steatotic liver disease: a population-based study in Australia.

BACKGROUND: Liver disease is an important contributor to the mortality gap between First Nations Peoples and non-Indigenous Australian adults. Despite a high burden of metabolic comorbidities among First Nations Peoples, data about the epidemiology of metabolic dysfunction-associated steatotic liver disease (MASLD) in this population is scarce. METHODS: A retrospective analysis of all adults hospitalized with MASLD or metabolic dysfunction-associated steatohepatitis (MASH) with/without cirrhosis during 2007-2019 in the state of Queensland was performed. Patients were followed from the first admission with MASLD/MASH (identified based on validated algorithms) to decompensated cirrhosis and overall mortality. We explored differences according to Indigenous status using Multivariable Cox regression. FINDINGS: 439 First Nations Peoples and 7,547 non-Indigenous Australians were followed for a median of 4.6 years (interquartile range 2.7-7.2). Overall, women were overrepresented, but more so in the First Nations cohort (72.7% vs. 57.0%, p < 0.001). First Nations patients were younger, a higher proportion lived in remote and socioeconomic disadvantaged areas, and had higher comorbidity compared to non-Indigenous Australians (all p < 0.001). Diabetes, the most common comorbidity affecting both groups, was overrepresented in First Nations Peoples versus non-Indigenous Australians (43.5% vs. 30.8%, p < 0.001, respectively). Nineteen (4.3%) First Nations Peoples and 332 (4.4%) of non-Indigenous patients progressed to cirrhosis decompensation (9.0% [95%CI 4.5-17.7] vs. 7.7% [95%CI 6.6-8.9; p = 0.956] respectively within 10 years). In multivariable analysis, there was no association between Indigenous status and progression to decompensated cirrhosis (p = 0.759) and survival (p = 0.437). CONCLUSIONS: This study provides the first population-based epidemiological data on MASLD in First Nations Australians. The high prevalence of diabetes (that is associated with advanced fibrosis and liver disease mortality) among young First Nations Peoples with MASLD raises concern about future risk of progressive liver disease in this patient population. These data highlight the importance of early identification of MASLD, and providing culturally appropriate intervention to reduce disease progression in parallel with the management of cardiometabolic comorbidities.

Indications and outcomes of transjugular intrahepatic portosystemic shunt insertion in two regional Australian hepatology centres.

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) is an important therapy for complications of portal hypertension but remains underutilised in regional settings. AIMS: The aim of this study is to explore the demographics, indications, outcomes and complications in patients undergoing TIPS in two regional hepatology centres. METHODS: Retrospective analysis was undertaken of all patients undergoing TIPS at two regional centres between January 2017 and March 2023. The primary outcome measures were efficacy and complications of TIPS. Patient demographics (such as age, baseline liver severity scores and aetiology of liver disease) and indications for TIPS are detailed. RESULTS: Forty-eight patients underwent TIPS. Median age was 56 years (interquartile range (IQR): 46-65). The most common indications for TIPS were refractory ascites (n = 17) and failure of secondary prophylaxis of variceal bleeding (n = 13). Cumulative survival at 3 months and 1 year was 93% and 77% respectively. There was no significant difference in outcomes based on TIPS indication. The median number of paracenteses in patients undergoing TIPS for refractory ascites 1 year pre- and post-TIPS were 10 (IQR: 4.5-16) and 2 (IQR: 0-4) respectively (P < 0.001). There were no procedure-related deaths. Inpatient management of liver disease complications had a mean cost of $32 874.67 (SEM: 7779) in 1 year pre-TIPS compared with $12 304.70 (SEM: 3531.1) in 1 year post-TIPS (P < 0.001). CONCLUSIONS: TIPS is a safe and effective treatment to reduce complications of portal hypertension and can be performed successfully in the regional setting.

Diabetes mellitus and the progression of non-alcoholic fatty liver disease to decompensated cirrhosis: a retrospective cohort study.

OBJECTIVE: To determine the incidence of decompensated cirrhosis and associated risk factors in people hospitalised with non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) with or without cirrhosis. DESIGN: Retrospective cohort study; analysis of linked Queensland Hospital Admitted Patient Data Collection, Queensland Registry of Births, Deaths and Marriages, and Queensland Cancer Register data. SETTING, PARTICIPANTS: Queensland residents aged 20 years or older admitted to Queensland hospitals with NAFLD/NASH during 1 July 2009 - 31 December 2018. MAIN OUTCOME MEASURES: Progression to decompensated cirrhosis (ascites, hepatic encephalopathy, or oesophageal variceal bleeding). RESULTS: We included data for 8006 patients in our analysis (10 082 admissions), including 4632 women (58%) and 2514 people with diabetes mellitus (31%); median follow-up time was 4.6 years (interquartile range, 2.7-7.2 years). Three hundred and fifty-one people (4.4%) experienced decompensated cirrhosis during the follow-up period. Of the 6900 people without cirrhosis, 4.5% (95% confidence interval [CI], 3.6-5.7%) experienced decompensated cirrhosis within ten years (mean, 0.5% per year; 95% CI, 0.4-0.6% per year); risk of progression was greater for people aged 70 years or older (v 20-39 years: adjusted hazard ratio [aHR], 4.7; 95% CI, 2.0-11.0) and those who had extrahepatic cancers (aHR, 5.0; 95% CI, 3.0-8.2), history of major cardiovascular events (aHR, 1.9; 95% CI, 1.2-3.1), or diabetes mellitus (aHR, 2.8; 95% CI, 2.0-3.9). Of the 1106 people with cirrhosis, 32.4% (95% CI, 27.2-38.3%) experienced decompensated cirrhosis within ten years (mean, 5.5% per year; 95% CI, 4.8-6.3% per year); risk of progression was greater for those with portal hypertension (aHR, 1.8; 95% CI, 1.3-2.7), extrahepatic cancer (aHR, 1.8; 95% CI, 1.1-2.9), or diabetes mellitus (aHR, 1.5; 95% CI, 1.1-2.0). Compared with people who had neither cirrhosis nor diabetes mellitus, the risk of decompensation was greater for people with cirrhosis (aHR, 10.7; 95% CI, 7.6-15.0) or cirrhosis and diabetes mellitus (aHR, 14.4; 95% CI, 10.1-20.6). CONCLUSIONS: Given the greater risk of progression to cirrhosis decompensation in people with diabetes mellitus, a disorder common in people with NAFLD/NASH, identifying advanced fibrosis and providing appropriate treatment for averting disease progression is vital.

Lower prevalence of elevated liver stiffness measurements in people with type 2 diabetes taking sodium-glucose co-transporter 2 inhibitors or glucagon-like peptide-1 receptor agonists.

INTRODUCTION AND OBJECTIVES: Among people with type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD) is very common and has an increased risk of clinically significant liver disease. The use of sodium-glucose co-transporter 2 (SGLT2i) inhibitors and glucagon-like peptide-1 (GLP-1a) receptor agonists is endorsed to reduce major cardiovascular events and/or progression of chronic kidney disease. Their prevalence of use in people with T2D and co-existent NAFLD remains unclear. We sought to determine the prevalence of use of these medications at two different time periods, and their association with prevalence of clinically significant liver disease. MATERIALS AND METHODS: Consecutive people with type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) were recruited from diabetes clinics between Jun-2021 and Jun-2022 ('current' cohort). Liver stiffness measurements (LSM) using FibroScan were performed. Medication data were collected prospectively at recruitment and verified with the dispensing pharmacy or general practitioner medical records. Data for a historical cohort with NAFLD and T2D recruited from the same clinics during 2015-2017 ('historical' cohort) were available. Logistic regression was used to evaluate factors associated with LSM <8.0 or ≥8 kPa (clinically significant fibrosis). RESULTS: There were 292 participants, 177 in the historical cohort and 115 in the current cohort. In the current cohort, 57.4% of patients with T2D and NAFLD were taking a GLP-1a and 42.6% were taking a SGLT2i; a 2.6 to 3.4-fold higher prevalence than in 2015-2017. A lower proportion of the current cohort (23.9% compared to 38.4%) had clinically significant fibrosis (LSM ≥8 kPa; p = 0.012). When the cohorts were pooled and differences adjusted for in multivariable logistic regression analysis, patients taking a GLP-1a or a SGLT2i were 2 times more likely to have a lower LSM (<8 kPa) compared to patients not taking these drugs (OR=2.05, 95%CI 1.07-3.94, p = 0.03 and OR 2.07 95%CI 1.04-4.11, p = 0.04, respectively). CONCLUSIONS: The observation of a lower LSM in people taking SGLT2i and/or GLP-1a following adjustment for other relevant clinico-demographic variables provides support for clinical trials to assess their efficacy in reducing the progression of NAFLD.

A discrete choice experiment to elicit preferences for a liver screening programme in Queensland, Australia: a mixed methods study to select attributes and levels.

BACKGROUND: In Australia, the overall prevalence of liver disease is increasing. Maximising uptake of community screening programmes by understanding patient preferences is integral to developing consumer-centred care models for liver disease. Discrete choice experiments (DCEs) are widely used to elicit preferences for various healthcare services. Attribute development is a vital component of a well-designed DCE and should be described in sufficient detail for others to assess the validity of outcomes. Hence, this study aimed to create a list of potential attributes and levels which can be used in a DCE study to elicit preferences for chronic liver disease screening programmes. METHODS: Key attributes were developed through a multi-stage, mixed methods design. Focus groups were held with consumers and health care providers on attributes of community screening programmes for liver disease. Stakeholders then prioritised attributes generated from the focus group in order of importance via an online prioritisation survey. The outcomes of the prioritisation exercise were then reviewed and refined by an expert panel to ensure clinically meaningful levels and relevance for a DCE survey. RESULTS: Fifteen attributes were generated during the focus group sessions deemed necessary to design liver disease screening services. Outcomes of the prioritisation exercise and expert panel stages recognised five attributes, with three levels each, for inclusion in a DCE survey to elicit consumer preferences for community screening for liver disease. This study also highlights broader social issues such as the stigma around liver disease that require careful consideration by policy makers when designing or implementing a liver screening programme. CONCLUSIONS: The attributes and levels identified will inform future DCE surveys to understand consumer preferences for community screening programmes for liver disease. In addition, the outcomes will help inform the implementation of the LOCATE-NAFLD programme in real-world practice, and could be relevant for other liver and non-liver related chronic disease screening programmes.

Retreatment for hepatitis C virus direct acting antiviral therapy virological failure in primary and tertiary settings: the REACH-C cohort.

Virological failure occurs in a small proportion of people treated for hepatitis C virus (HCV) with direct-acting antiviral (DAA) therapies. This study assessed retreatment for virological failure in a large real-world cohort. REACH-C is an Australian observational study (n=10843) evaluating treatment outcomes of sequential DAA initiations across 33 health services between March 2016 to June 2019. Virological failure retreatment data were collected until October 2020. Of 408 people with virological failure (81% male; median age 53; 38% cirrhosis; 56% genotype 3), 213 (54%) were retreated once; 15 were retreated twice. A range of genotype specific and pangenotypic DAAs were used to retreat virological failure in primary (n=56) and tertiary (n=157) settings. Following sofosbuvir/velpatasvir/voxilaprevir availability in 2019, the proportion retreated in primary care increased from 21% to 40% and median time to retreatment initiation declined from 294 to 152 days. Per-protocol (PP) sustained virological response (SVR12) was similar for people retreated in primary and tertiary settings (80% vs 81%; p=1.000). In regression analysis, sofosbuvir/velpatasvir/voxilaprevir (vs. other regimens) significantly decreased likelihood of second virological failure (PP SVR12 88% vs. 77%; adjusted odds ratio [AOR] 0.29; 95%CI 0.11-0.81); cirrhosis increased likelihood (PP SVR12 69% vs. 91%; AOR 4.26; 95%CI 1.64-11.09). Indigenous Australians had lower likelihood of retreatment initiation (AOR 0.36; 95%CI 0.15-0.81). Treatment setting and prescriber type were not associated with retreatment initiation or outcome. Virological failure can be effectively retreated in primary care. Expanded access to simplified retreatment regimens through decentralised models may increase retreatment uptake and reduce HCV-related mortality.

Assessment of clinically significant portal hypertension by two-dimensional shear wave elastography.

BACKGROUND AND AIMS: To evaluate two-dimensional shear wave elastography (2DSWE) in parallel with transient elastography (TE) for diagnosing clinically significant portal hypertension (CSPH) and high-risk varices (HRV) in patients with chronic liver disease. PATIENTS AND METHODS: Consecutive patients with suspicion of compensated advanced chronic liver disease (cACLD) [liver stiffness measurement (LSM) ≥ 10 kPa by TE, or morphological signs suggestive of cACLD on imaging], with no history of liver decompensation, underwent hepatic venous pressure gradient (HVPG) measurement, transjugular liver biopsy and esophagogastroduodenoscopy, which served as the reference methods for diagnosing CSPH, cACLD and HRV. All patients underwent LSM and spleen stiffness measurements (SSM) by 2DSWE and TE. RESULTS: Seventy-six (76) patients were included (78% men, mean age 62 years, body mass index 28.3 kg/m2 , 36.8% alcoholic, 30.3% non-alcoholic fatty liver disease, 14.5% viral hepatitis). Of them, 80.3%, 69.7%, 52.6% and 22.4% had cACLD, cirrhosis, CSPH and HRV respectively. LSM performed better than SSM in diagnosing CSPH and HRV. For CSPH, AUROCs (0.926 vs. 0.866), optimal cut-offs (20.1 vs. 20.2 kPa) and sensitivity/specificity (80.5%/94.3% vs. 77.5% /86.1%) were comparable for 2DSWE and TE. Ruling-out of CSPH by 2DSWE (LSM at cut-off with ≥90% sensitivity (13.5 kPa) and platelets ≥ 150 x 109 /L) performed comparably to TE, with 1/24 cases falsely classified as negative. For HRV, AUROCs were similar (0.875 2DSWE, 0.851 TE) with similar optimal LSM cut-offs enabling 100% sensitivity and ruling-out HRV. CONCLUSION: Liver stiffness measurement by 2DSWE appears to perform equally well as TE for diagnosing CSPH and ruling-out HRV in compensated chronic liver disease.

An exploration of barriers and facilitators to implementing a nonalcoholic fatty liver disease pathway for people with type 2 diabetes in primary care.

AIMS: We explored barriers and facilitators to the implementation of nonalcoholic fatty liver disease (NAFLD) pathway for people with diabetes to identify determinants of behaviour surrounding the diagnosis, assessment and management of NAFLD. METHODS: Health practitioners (n = 24) recruited from multidisciplinary diabetes clinics in primary care (n = 3) and hospital (n = 1) settings participated in four focus group discussions, and common themes were identified using thematic analysis. RESULTS: Lack of knowledge and access to resources were key factors that underpinned an inconsistent approach by clinicians to NAFLD diagnosis and risk stratification and impacted their confidence to discuss the diagnosis with patients. Participants often prioritised other medical issues above NAFLD due to lack of concern about liver-related consequences, reluctance to overburden patients with information, lack of time and perceived absence of accessible fibrosis tests. All participants agreed that implementation of a NAFLD pathway would improve patient care and the general practitioners proposed that screening for NAFLD could be incorporated into routine review cycles for type 2 diabetes. A consistent message from participants was that educating patients about their liver disease needs to be implemented in an integrated care pathway. CONCLUSIONS: From the perspectives of health practitioners, there is a gap in clinical practice for the implementation of clear, evidence-based guidelines for NAFLD in people with T2D. By focusing on comorbidity prevention and integrating NAFLD as a diabetes complication to be addressed during established cycles of care, many barriers to implementing a NAFLD pathway in primary care could be overcome.

The fate of indeterminate liver lesions: What proportion are precursors of hepatocellular carcinoma?

BACKGROUND: The natural history and incidence of hepatocellular carcinoma (HCC) arising from indeterminate liver lesions are not well described. We aimed to define the incidence of HCC in a cohort of patients undergoing surveillance by magnetic resonance imaging (MRI) and estimate any associations with incident HCC. METHODS: We performed a retrospective follow-up study, identifying MRI scans in which indeterminate lesions had been reported between January 2006 and January 2017. Subsequent MRI scan reports were reviewed for incident HCC arising from indeterminate lesions, data were extracted from electronic patient records and survival analysis performed to estimate associations with baseline factors. RESULTS: One hundred and nine patients with indeterminate lesions on MRI were identified. HCC developed in 19 (17%) patients over mean follow up of 4.6 years. Univariate Cox proportional hazards analysis found incident HCC to be significantly associated with baseline low platelet count (hazard ratio (HR) = 7.3 (95% confidence intervals (CI) 2.1-24.9), high serum alpha-fetoprotein level (HR = 2.7 (95% CI 1.0-7.1)) and alcohol consumption above fourteen units weekly (HR = 3.1 (95% CI 1.1-8.7)). Multivariate analysis, however, found that only low platelet count was independently associated with HCC (HR = 5.5 (95% CI 0.6-5.1)). CONCLUSIONS: HCC arises in approximately one fifth of indeterminate liver lesions over 4.6 years and is associated with a low platelet count at the time of first diagnosis of an indeterminate lesion. Incidence of HCC was more common in people with viral hepatitis and in those consuming > 14 units of alcohol per week. Our data may be used to support a strategy of enhanced surveillance in patients with indeterminate lesions.

Validation of the New Diagnostic Criteria for Clinically Significant Portal Hypertension by Platelets and Elastography.

BACKGROUND AND AIMS: We aimed to validate newly proposed noninvasive criteria for diagnosing clinically significant portal hypertension (CSPH) using liver stiffness measurements (LSM) by transient elastography (TE) and platelet count. METHODS: Diagnostic performance of these new criteria for CSPH (LSM ≥ 25 kPa to rule in and Plt ≥ 150 × 109/L + LSM ≤ 15 kPa to rule out CSPH) were retrospectively tested in an independent cohort of consecutive patients who underwent hepatic venous pressure gradient (HVPG) measurements and liver biopsy due to suspicion of compensated advanced chronic liver disease. Suspicion of cACLD was based on LSM ≥ 10 kPa by TE or results of liver imaging, without overt signs of CSPH. Patients with conditions known to affect results of LSM (ALT > 5 × ULN, liver congestion, extrahepatic biliary obstruction, infiltrative liver neoplasms) were excluded. RESULTS: Seventy six (76) patients were included: 78.9% males, mean age 62 years, 36.8% suffered from alcoholic, 30.3% nonalcoholic fatty liver disease, 14.5% chronic viral hepatitis, 30.3% were obese, 52.6% had HVPG ≥ 10 mmHg, 56.6% had platelet count ≥ 150 × 109/L. LSM ≥ 25 kPa had 88.9% specificity (95% CI 73.9-96.9) to rule in, whereas Plt ≥ 150 + LSM ≤ 15 kPa had 100% sensitivity (95% CI 91.1-100) to rule out CSPH. CONCLUSION: By using these simple noninvasive criteria 49/76 (64.5%) patients could be classified correctly for the presence/absence of CSPH, thus obviating the need for HVPG measurements.

Implementing the right care in the right place at the right time for non-alcoholic fatty liver disease (NAFLD-RRR study): a study protocol for a community care pathway for people with type 2 diabetes.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is an emerging epidemic that affects approximately half of all people with type 2 diabetes. Those with type 2 diabetes are a high-risk NAFLD subgroup because of their increased risk of clinically significant liver-related outcomes from NAFLD which include hepatocellular carcinoma, cirrhosis-related complications and liver disease mortality. They may benefit from early detection of disease as this would allow at risk patients to access hepatocellular carcinoma surveillance, emerging drug trials for NAFLD and specialist hepatology care prior to emergence of liver-related complications. METHODS: This is a prospective cohort study aimed at incorporating and assessing a community care pathway for liver fibrosis screening into routine care for type 2 diabetes. Patients undergo a point of care assessment of hepatic steatosis and stiffness using FibroScan at the time of the routine diabetes appointment or when attending the clinic for blood tests in preparation for this appointment. DISCUSSION: We propose that implementation of a community-based NAFLD diagnosis, risk-stratification, and referral pathway for people with type 2 diabetes is feasible, will provide earlier, targeted detection of advanced fibrosis, and reduce unnecessary referrals to hepatology outpatients for fibrosis risk assessment. Our study will provide important information about the feasibility of establishing a NAFLD pathway for people with type 2 diabetes in primary care. Ultimately, our findings will help direct spending and resource allocation for NAFLD in a high-risk population. Regular evaluation by stakeholders during implementation will help to create a reliable and sustainable community care pathway and establish a perpetual cycle of learning in primary care. TRIAL REGISTRATION: ANZCTR, ACTRN12621000330842 . Registered 23 March 2021.

Efficacy and Safety of Sofosbuvir/Velpatasvir/Voxilaprevir for Hepatitis C Virus (HCV) NS5A-Inhibitor Experienced Patients With Difficult to Cure Characteristics.

BACKGROUND: In clinical trials, hepatitis C virus (HCV) salvage treatment with sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) achieved an SVR12 rate of >95% in NS5A-experienced participants. Lower SVR12 rates have been reported in real-world studies, particularly for genotype (GT)3 infection and cirrhosis. We determined the efficacy and safety of SOF/VEL/VOX in a large real-world cohort. METHODS: We assessed the efficacy of salvage SOF/VEL/VOX for HCV infection in NS5A-inhibitor experienced participants with cirrhosis and portal hypertension, prior liver transplantation (LT) or severe extra-hepatic manifestations. SOF/VEL/VOX was available via an early access program. The primary outcome was SVR12. Secondary outcome was frequency of adverse events (AE). FINDINGS: Ninety-seven participants were included. Median age was 58, 82% were male, 78% had cirrhosis, most with portal hypertension (61%, n = 46/76), and 18% had prior-LT. Of the cirrhotic participants, 96% were Child-Turcotte-Pugh class A, and 4% were class B. Of the 72% with GT3, 76% were also cirrhotic. By intention-to-treat analysis, SVR12 rate was 85% (n = 82/97). Per protocol, the SVR12 rate was 90%, including 91% in GT1 (GT1a n = 18/18, GT1b n = 2/4), 89% in GT3 (n = 59/66) and 100% in GT6 (n = 3/3). SVR12 in participants with GT3 and cirrhosis was 90%. No predictors of non-SVR12 were identified. There were 4 serious AEs including 1 death and 3 hepatic decompensation events. NS5A resistance-associated substitutions detected at baseline did not affect SVR12. CONCLUSIONS: This real-world study confirms high efficacy of SOF/VEL/VOX for the treatment of difficult-to-cure NS5A-inhibitor experienced patients, including those with GT3 and cirrhosis. Treatment was well tolerated in most; however, serious AEs can occur in those with advanced liver disease.

Performance of simple serum-based tests to exclude cirrhosis prior to hepatitis C treatment in non-hospital settings in Australia.

BACKGROUND: Current guidelines suggest using transient elastography (TE) or aspartate aminotransferase to platelet ratio index (APRI) score <1 to exclude cirrhosis prior to commencing treatment for hepatitis C virus (HCV). Recently, fibrosis-4 (FIB-4) <0.93 has been shown to have a high negative predictive value (NPV) for the presence of cirrhosis. AIMS: To assess FIB-4 and APRI in a cohort of HCV patients and to validate FIB-4 <0.93 in populations of HCV-infected individuals with differing cirrhosis prevalence, including secondary care, primary care and prisons. METHODS: From our treatment database, we identified patients with complete data (n = 793). We calculated FIB-4 and APRI and correlated this with the presence of cirrhosis, determined by TE. We analysed the performance of FIB-4 and APRI using area under the receiver operating curve analysis. We calculated sensitivity, specificity, positive predictive value, NPV and number of patients misclassified using published cut-offs in populations with varying cirrhosis prevalence. RESULTS: FIB-4 was superior to APRI for the diagnosis of cirrhosis (area under the receiver operating curve 0.868 vs 0.802). In secondary care (cirrhosis prevalence 32%), APRI <1 had a NPV of 80% and misclassified 14% of patients. FIB-4 <0.93 had a NPV of 97% and misclassified 1%. In primary care and prison (cirrhosis prevalence 13% and 8%), the NPV for APRI <1 was 93% and 96%, respectively, but 5% of patients with cirrhosis were misclassified. FIB-4 <0.93 had excellent NPV in both primary care (97%) and prisoners (100%). CONCLUSIONS: FIB-4 <0.93 is highly efficient at ruling out cirrhosis in HCV patients and allows TE to be appropriately avoided, thereby streamlining treatment algorithms.

Changing prevalence of aetiological factors and comorbidities among Australians hospitalised for cirrhosis.

BACKGROUND: The rate of hospital admissions for cirrhosis increased 1.3-fold during 2008-2016 in Queensland. Alcohol misuse was a contributing factor for cirrhosis in 55% of admissions and 40% of patients had at least one comorbidity. AIMS: To examine the temporal change in aetiology of liver disease and presence of comorbidity in patients admitted with cirrhosis. METHODS: Population-based retrospective cohort study of all people treated in hospital for cirrhosis (10 254 patients) in Queensland during 2008-2016. Data were sourced from Queensland Hospital Admitted Patient Data Collection. RESULTS: The commonest aetiology was alcohol (49.5%), followed by cryptogenic (unspecified cirrhosis; 28.5%), hepatitis C virus (19.3%), non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) (4.8%) and hepatitis B virus (HBV) (4.3%). The prevalence of alcohol-related (P = 0.41) and hepatitis C virus (P = 0.08) remained stable between 2008-2010 and 2014-2016, that of NAFLD/NASH, cryptogenic and HBV-cirrhosis increased by 67% (P < 0.00001), 27% (P < 0.00001) and 20% (P = 0.00019), respectively; 41.1% of patients had at least one comorbidity. The prevalence of type 2 diabetes nearly doubled (from 13.7% to 25.4%; P < 0.00001) between 2008-2010 and 2014-2016. CONCLUSIONS: Alcohol misuse was the most important aetiology. The importance of NAFLD/NASH, cryptogenic and HBV-cirrhosis and the burden of comorbidity increased during 2008-2016. Ongoing alcohol misuse and the increasing prevalence of NAFLD/NASH, cryptogenic cirrhosis and comorbid type 2 diabetes among admissions for cirrhosis has implications for public health interventions to reduce the burden of unhealthy lifestyle and metabolic disorders.

Is methotrexate hepatotoxicity associated with cumulative dose? A systematic review and meta-analysis.

BACKGROUND/OBJECTIVE: Methotrexate (MTX) is widely used in various medical specialties. However, hepatotoxicity is an ongoing concern and this is thought to be directly associated with cumulative dose. We sought to synthesise the published literature to evaluate the association between methotrexate hepatotoxicity and cumulative dose. METHODS: A systematic review of Medline (PubMed) EMBASE, CINAHL and The Cochrane Library was performed. Full texts of articles were examined, and excluded articles were recorded with reasons for exclusion. A meta-analysis of correlation coefficients was performed using Fisher's z-transformation and a random effects model. Cochran's Q-test and the I2 statistic were calculated to assess heterogeneity. RESULTS: A total of 35 studies met inclusion criteria. Measures of hepatotoxicity were highly varied and included liver biopsy, elastography, FibroTest, biochemical tests and scoring systems (Fib-4, APRI, AST:ALT). Some studies analysed for the association with MTX cumulative dose using more than one modality. Overall, 38 analyses found no significant association between MTX cumulative dose and hepatoxicity vs eight that identified a significant association. The pooled correlation coefficient from five studies which utilised elastography was 0.18 (95% CI, -0.09 to 0.42), with significant heterogeneity between studies (P < 0.0001), I2  = 92%). CONCLUSIONS: Our synthesis of a large volume of studies in this review found no significant association between MTX cumulative dose and hepatotoxicity, both in terms of vote counting and with regard to the meta-analysis of correlation coefficients from studies that utilised elastography. This challenges the long-held belief that liver injury is a direct result of drug accumulation.

Protocol for a randomised trial testing a community fibrosis assessment service for patients with suspected non-alcoholic fatty liver disease: LOCal assessment and triage evaluation of non-alcoholic fatty liver disease (LOCATE-NAFLD).

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common type of chronic liver disease in Australia and its recent increase mirrors the obesity and type 2 diabetes epidemics. Currently, many patients who present to primary care with abnormal liver function tests or steatosis on liver ultrasound are referred for assessment in secondary care. Due to the large number of patients with NAFLD, this results in long waits for clinical and fibrosis assessment, placing unnecessary burden on the public hospital system. METHODS: We will conduct a 1:1 parallel randomised trial to compare two alternative models of care for NAFLD. Participants will be randomised to usual care or the LOCal Assessment and Triage Evaluation (LOCATE) model of care and followed for 1 year. We will recruit patients from the non-neighbouring Sunshine Coast and Metro South Hospital and Health Services (HHSs) in Queensland, Australia. Our primary outcome of interest is time to diagnosis of high-risk NAFLD, based on the number of participants in each arm of the study who receive a diagnosis of clinically significant fibrosis. Two hundred and 34 participants will give us a 95% power to detect a 50% reduction in the primary outcome of time to diagnosis of high-risk disease. We will also conduct an economic evaluation, evaluating the cost-effectiveness of the new model of care. We will also evaluate the implementation of the new model of care. DISCUSSION: It is anticipated that the results of this study will provide valuable new information regarding the management of NAFLD in the Australian setting. A relatively simple change to care could result in earlier identification of patients with significant liver disease and lower overall costs for the health system. Results will be directly disseminated to key staff for further distribution to consumers, policy- and decision-makers in the form of evidence briefs, plain language summaries and policy recommendations. TRIAL REGISTRATION: The trial was registered on 30 January, 2020 and can be found via ANZCTR - number ACTRN12620000158965.

Cardiovascular morbidity and mortality is increased post-liver transplantation even in recipients with no pre-existing risk factors.

BACKGROUND/AIMS: Post-liver transplant (LT) metabolic syndrome (PTMS) and cardiovascular (CVS) mortality are becoming increasingly prevalent following sustained improvements in post-LT survival. We investigated the prevalence and predictors of PTMS and CVS complications in a cohort of consecutive LT recipients. METHODS: We reviewed prospectively collected data of patients (n = 928) who underwent LT (1995-2013) and survived at least 1-year post-LT or died before that due to a major CVS complication. RESULTS: Median follow-up was 85 months (IQR = 106). The prevalence of PTMS was 22.4% and it developed de novo in 183 recipients (19.7%). A total of 187 (20.2%) patients developed at least one CVS event post-LT within a median of 49 months (IQR = 85). Overall mortality rate was 22.6% (n = 210). Causes of death were CVS events (n = 45, 21.4%), malignancies (21%), liver-related deaths (20%) and infections (6.7%). Independent predictors of major CVS events were: documented CVS disease pre-LT (Hazard Ratio (HR) = 3.330; 95% CI = 1.620-6.840), DM (HR = 1.120; 95% CI 1.030-1.220), hypertension (HR = 1.140; 95% CI 1.030-1.270), dyslipidaemia (HR = 1.140; 95% CI 1.050-1.240) and creatinine levels at 1 year (HR = 1.010; 95% CI = 1.005-1.013). Among LT recipients without pre-LT CVS disease or MS components (n = 432), 85 recipients developed ≥1 CVS events (19.7%) with independent predictors being DM (HR = 1.150; 95% CI = 1.010-1.320), creatinine levels at 1 year (HR = 1.020; 95% CI = 1.010-1.030) and hypertension (HR = 1.190; 95% CI = 1.040-1.360). CONCLUSIONS: Post-LT patients are at increased risk of CVS morbidity even in the absence of pre-existing metabolic risk factors. Renal sparing immunosuppressive protocols might reduce CVS events post-LT.

Cost-comparison analysis of FIB-4, ELF and fibroscan in community pathways for non-alcoholic fatty liver disease.

BACKGROUND: The identification of patients with advanced liver fibrosis secondary to non-alcoholic fatty liver disease (NAFLD) remains challenging. Using non-invasive liver fibrosis tests (NILT) in primary care may permit earlier detection of patients with clinically significant disease for specialist review, and reduce unnecessary referral of patients with mild disease. We constructed an analytical model to assess the clinical and cost differentials of such strategies. METHODS: A probabilistic decisional model simulated a cohort of 1000 NAFLD patients over 1 year from a healthcare payer perspective. Simulations compared standard care (SC) (scenario 1) to: Scenario 2: FIB-4 for all patients followed by Enhanced Liver Fibrosis (ELF) test for patients with indeterminate FIB-4 results; Scenario 3: FIB-4 followed by fibroscan for indeterminate FIB-4; Scenario 4: ELF alone; and Scenario 5: fibroscan alone. Model estimates were derived from the published literature. The primary outcome was cost per case of advanced fibrosis detected. RESULTS: Introduction of NILT increased detection of advanced fibrosis over 1 year by 114, 118, 129 and 137% compared to SC in scenarios 2, 3, 4 and 5 respectively with reduction in unnecessary referrals by 85, 78, 71 and 42% respectively. The cost per case of advanced fibrosis (METAVIR ≥F3) detected was £25,543, £8932, £9083, £9487 and £10,351 in scenarios 1, 2, 3, 4 and 5 respectively. Total budget spend was reduced by 25.2, 22.7, 15.1 and 4.0% in Scenarios 2, 3, 4 and 5 compared to £670 K at baseline. CONCLUSION: Our analyses suggest that the use of NILT in primary care can increases early detection of advanced liver fibrosis and reduce unnecessary referral of patients with mild disease and is cost efficient. Adopting a two-tier approach improves resource utilization.

Administration of Albumin Solution Increases Serum Levels of Albumin in Patients With Chronic Liver Failure in a Single-Arm Feasibility Trial.

BACKGROUND & AIMS: Infections are life-threatening to patients with acute decompensation and acute-on-chronic liver failure (AD/ACLF). Patients with AD/ACLF have prostaglandin E2-mediated immune suppression, which can be reversed by administration of albumin; infusion of 20% human albumin solution (HAS) might improve outcomes of infections. We performed a feasibility study to determine optimal trial design, assess safety, and validate laboratory assessments of immune function to inform design of a phase 3 trial. METHODS: We performed a prospective multicenter, single-arm, open-label trial of 79 patients with AD/ACLF and levels of albumin lower than 30 g/L, seen at 10 hospitals in the United Kingdom from May through December 2015. Patients were given daily infusions of 20% HAS, based on serum levels, for 14 days or until discharge from the hospital. Rates of infection, organ dysfunction, and in-hospital mortality were recorded. The primary end point was daily serum albumin level during the treatment period. Success would be demonstrated if 60% achieved and maintained serum albumin levels at or above 30 g/L on at least one third of days with recorded levels. RESULTS: The patients' mean model for end-stage disease score was 20.9 ± 6.6. The primary end point (albumin ≥30 g/L on at least one third of days recorded) was achieved by 68 of the 79 patients; 75% of administrations were in accordance with suggested dosing regimen. Mean treatment duration was 10.3 days (104 ± 678 mL administered). There were 8 deaths and 13 serious adverse events, considered by the independent data-monitoring committee to be consistent with those expected. Twelve of 13 patients that developed either respiratory or cardiovascular dysfunction (based on ward-based clinical definitions) as their only organ dysfunction were alive at 30 days compared with 1 of 3 that developed renal dysfunction. Only 1 case of brain dysfunction was recorded. CONCLUSIONS: In a feasibility trial, we found that administration of HAS increased serum levels of albumin in patients with AD/ACLF. The dosing regimen was acceptable at multiple sites and deemed safe by an independent data-monitoring committee. We also developed a robust system to record infections. The poor prognosis for patients with renal dysfunction was confirmed. However, patients with cardiovascular or respiratory dysfunction had good outcomes, which is counterintuitive. Severe encephalopathy appeared substantially under-reported, indicating that ward-based assessment of these parameters cannot be recorded with sufficient accuracy for use as a primary outcome in phase 3 trials. Trial registration no: EudraCT 2014-002300-24 and ISRCTN14174793.