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.

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.

Improving palliative and supportive care in advanced cirrhosis: the HepatoCare model of integrated collaborative care.

BACKGROUND: Patients with advanced cirrhosis experience an unpredictable disease trajectory but are infrequently referred to palliative care (PC) services and rarely undertake advance care planning (ACP). AIM: We assessed whether a novel model of care increased provision of meaningful PC in advanced cirrhosis compared with standard of care (SOC). METHODS: Thirty consecutive hepatology clinic outpatients with advanced cirrhosis, meeting one or more cirrhosis-related PC referral criteria, consented to treatment in the HepatoCare clinic (PC physician, specialist liver nurse, pharmacist) in parallel with usual specialist hepatology care. A control cohort of 30 consecutive outpatients with advanced cirrhosis undergoing SOC treatment was retrospectively identified for comparison. The primary outcome was provision of meaningful PC using HepatoCare versus SOC. Additional clinical outcomes were assessed over 12 months or until death and significant differences were identified. RESULTS: The intervention and control cohorts had similarly advanced cirrhosis (mean Child-Pugh scores 8.7 vs 8.2, P = 0.46; mean model for end-stage liver disease scores 14.4 vs 14.6, P = 0.88) but a lower 12-month mortality rate (33% HepatoCare vs 67% SOC; P = 0.02). The intervention cohort experienced higher uptake of formal ACP (100% vs 25% for the control cohort) and outpatient PC referral (100% vs 40%), and were more likely to die at home or in a PC bed/hospice (80% vs 30%). The majority of the HepatoCare cohort (81%) had medications safely deprescribed and experienced fewer unplanned admission days (470 vs 794). CONCLUSIONS: HepatoCare is a novel multidisciplinary model of care that integrates effective PC and specialist hepatology management to improve outcomes in advanced cirrhosis.

High Sustained Virologic Response Rates of Glecaprevir/Pibrentasvir in Patients With Dosing Interruption or Suboptimal Adherence.

INTRODUCTION: Pangenotypic, all-oral direct-acting antivirals, such as glecaprevir/pibrentasvir (G/P), are recommended for treatment of hepatitis C virus (HCV) infection. Concerns exist about the impact on efficacy in patients with suboptimal adherence, particularly with shorter treatment durations. These post hoc analyses evaluated adherence (based on pill count) in patients prescribed 8- or 12-week G/P, the impact of nonadherence on sustained virologic response at post-treatment week 12 (SVR12), factors associated with nonadherence, and efficacy in patients interrupting G/P treatment. METHODS: Data were pooled from 10 phase 3 clinical trials of treatment-naive patients with HCV genotype 1-6 without cirrhosis/with compensated cirrhosis (treatment adherence analysis) and 13 phase 3 clinical trials of all patients with HCV (interruption analysis). RESULTS: Among 2,149 patients included, overall mean adherence was 99.4%. Over the treatment duration, adherence decreased (weeks 0-4: 100%; weeks 5-8: 98.3%; and weeks 9-12: 97.1%) and the percentage of patients with ≥80% or ≥90% adherence declined. SVR12 rate in the intention-to-treat (ITT) population was 97.7% (modified ITT SVR12 99.3%) and remained high in nonadherent patients in the modified ITT population (<90%: 94.4%-100%; <80%: 83.3%-100%). Psychiatric disorders were associated with <80% adherence, and shorter treatment duration was associated with ≥80% adherence. Among 2,902 patients in the interruption analysis, 33 (1.1%) had a G/P treatment interruption of ≥1 day, with an SVR12 rate of 93.9% (31/33). No virologic failures occurred. DISCUSSION: These findings support the impact of treatment duration on adherence rates and further reinforce the concept of "treatment forgiveness" with direct-acting antivirals.

Management, outcomes and survival of an Australian IgG4-SC cohort: The MOSAIC study.

BACKGROUND AND AIMS: IgG4 sclerosing cholangitis (IgG4-SC) is the biliary component of the multisystem IgG4-related disease. We aimed to investigate the clinical features, demographics, treatment response and outcomes of IgG4-SC in a large Australian cohort. METHODS: We conducted nationwide retrospective cohort via the Australian Liver Association Clinical Trials Network (ALA-CRN). 39 sites were invited to participate. IgG4-SC was defined by the clinical diagnostic criteria established by the Japanese Biliary Association in 2012. Data were collected on patient demographic, clinical and laboratory information, presenting features, response to therapy and clinical outcomes. RESULTS: 67 patients meet inclusion criteria from 22 sites. 76% were male with mean age of 63.3 ± 14.5 years and a median IgG4 level of 3.6 g/L [0.09-67.1]. The most frequent presenting symptom was jaundice (62%) and abdominal pain (42%) and Type 1 biliary stricturing (52%) at the distal common bile duct was the most frequent biliary tract finding. Prednisolone was used as a primary treatment in 61 (91%) and partial or complete response occurred in 95% of subjects. Relapse was common (42%) in those who ceased medical therapy. After a median follow up of 3.9 years there was one hepatocellular carcinoma and no cholangiocarcinomas. CONCLUSIONS: Our study confirms the preponderance of IgG4-SC in males and highlights the steroid response nature of this condition although relapse is common after steroid cessation. Progression to malignancy was uncommon.

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.

Serum MicroRNAs as Biomarkers in Hepatitis C: Preliminary Evidence of a MicroRNA Panel for the Diagnosis of Hepatocellular Carcinoma.

Early diagnosis of cirrhosis and hepatocellular carcinoma (HCC) due to chronic Hepatitis C (CHC) remain clinical priorities. In this pilot study, we assessed serum microRNA (miRNA) expression to distinguish cirrhosis and HCC, alone and in combination with the aminotransferase-to-platelet ratio (APRI), Fibrosis 4 (FIB-4), and alpha-fetoprotein (AFP). Sixty CHC patients were subdivided into 3 cohorts: Mild disease (fibrosis stage F0-2; n = 20); cirrhosis (n = 20); and cirrhosis with HCC (n = 20). Circulating miRNA signatures were determined using a liver-specific real-time quantitative reverse transcription PCR (qRT-PCR) microarray assessing 372 miRNAs simultaneously. Differentially-expressed miRNA candidates were independently validated using qRT-PCR. Serum miRNA-409-3p was increased in cirrhosis versus mild disease. In HCC versus cirrhosis, miRNA-486-5p was increased, whereas miRNA-122-5p and miRNA-151a-5p were decreased. A logistic regression model-generated panel, consisting of miRNA-122-5p + miRNA-409-3p, distinguished cirrhosis from mild disease (area under the curve, AUC = 0.80; sensitivity = 85%, specificity = 70%; p < 0.001). When combined with FIB-4 or APRI, performance was improved with AUC = 0.89 (p < 0.001) and 0.87 (p < 0.001), respectively. A panel consisting of miRNA-122-5p + miRNA-486-5p + miRNA-142-3p distinguished HCC from cirrhosis (AUC = 0.94; sensitivity = 80%, specificity = 95%; p < 0.001), outperforming AFP (AUC = 0.64, p = 0.065). Serum miRNAs are differentially expressed across the spectrum of disease severity in CHC. MicroRNAs have great potential as diagnostic biomarkers in CHC, particularly in HCC where they outperform the only currently-used biomarker, AFP.

Efficacy and Safety of Mycophenolate Mofetil in Patients With Autoimmune Hepatitis and Suboptimal Outcomes After Standard Therapy.

BACKGROUND & AIMS: Little is known about outcomes of patients with autoimmune hepatitis (AIH) who have a suboptimal outcome to standard therapy and are then given mycophenolate mofetil as rescue therapy. We evaluated the efficacy and safety of mycophenolate mofetil in patients failed by or intolerant to corticosteroids, with or without azathioprine. METHODS: We performed a retrospective study of 105 patients with AIH who received mycophenolate mofetil therapy after an inadequate response or intolerance to standard therapy (98% received combination therapy with corticosteroids plus thiopurines). Patients were recruited from 17 liver clinics via the Australian Liver Association Clinical Research Network. We reviewed records for baseline demographic features and characteristics of liver disease, initial therapy, mycophenolate mofetil indications, treatment outcome, and side effects. The primary outcome was biochemical remission, defined as levels of alanine and aspartate transferase and IgG level within the normal reference range, with or without normal liver histology within the first 2 years of treatment. RESULTS: The indication for mycophenolate mofetil therapy was non-response to treatment for 40% of cases and intolerance to therapy for 60%. Overall, 63 patients (60%) achieved biochemical remission following a median 12 weeks treatment with mycophenolate mofetil. The proportion of patients who achieved biochemical remission was similar between patients receiving mycophenolate mofetil for non-response to standard therapy (57%) and patients with intolerance to standard therapy (62%). However, a lower proportion of patients with cirrhosis achieved biochemical remission (47%) than patients without cirrhosis (6%) (P = .07). Serious adverse events occurred in 3 patients (2.7%) including 1 death, and 10 patients (9.2%) discontinued mycophenolate mofetil because of adverse events. CONCLUSION: In this retrospective study of patients with AIH who received mycophenolate mofetil as a rescue therapy, we found the drug to be well tolerated and moderately effective, inducing biochemical remission in 60% of subjects. Rates of response are lower and rates of infection are higher in patients with AIH and cirrhosis. Prospective studies of mycophenolate mofetil are warranted for this population.

Exploratory study into the unmet supportive needs of people diagnosed with cirrhosis in Queensland, Australia.

BACKGROUND: Many patients with cirrhosis follow complex medication and dietary regimens, and those with decompensated cirrhosis suffer debilitating complications. These factors impact activities of daily living and quality of life. AIMS: To explore the concerns and challenges of people with cirrhosis and their use of support services and to also describe health professionals' (HP) perspectives of patients' concerns. METHODS: This is a cross-sectional study at a tertiary liver clinic involving 50 patients and 54 HP. Data were collected using structured questionnaires. The study includes patients' report of their challenges/problems now that they have cirrhosis ('patient-volunteered concerns') and HP' report of patients' concerns. Both also ranked a list of 10 potential concerns. RESULTS: Patients were, on average, 58 years old (SD = 10.2), mostly male (78%), Caucasian (86%) and with compensated cirrhosis (60%). The patients' most common volunteered concerns related to managing symptoms, emotional issues and disease. Most ranked 'developing liver cancer' (79%), 'losing ability to do daily tasks for yourself' (76%), 'fear of dying' (64%) and 'fear of the unknown' (64%) as priority concerns. Regarding the use of support services, 24% of patients had accessed a dietician, 20% a pharmacist and 18% a psychologist. From the HP' perspective, the patients' most significant challenges related to managing disease (65%) and symptoms (48%), access to healthcare (56%) and information/knowledge (48%). CONCLUSIONS: Our findings demonstrate that cirrhosis (its symptoms, complications and treatment) is associated with significant concerns for patients. The discrepancies between the views of HP and patients suggest that we may not be measuring or addressing patients' needs appropriately.

Efficacy and safety of ombitasvir/paritaprevir/r and dasabuvir compared to IFN-containing regimens in genotype 1 HCV patients: The MALACHITE-I/II trials.

BACKGROUND & AIMS: Telaprevir plus pegylated interferon/ribavirin (TPV+PegIFN/RBV) remains a therapeutic option for chronic hepatitis C virus (HCV) genotype (GT) 1 infection in many regions. We conducted two open-label, phase IIIb trials comparing safety and efficacy of all-oral ombitasvir/paritaprevir/ritonavir and dasabuvir±ribavirin (OBV/PTV/r+DSV±RBV) and TPV+PegIFN/RBV. METHODS: Treatment-naïve (MALACHITE-I) or PegIFN/RBV-experienced (MALACHITE-II) non-cirrhotic, chronic HCV GT1-infected patients were randomized to OBV/PTV/r+DSV+weight-based RBV, OBV/PTV/r+DSV (treatment-naïve, GT1b-infected patients only), or 12weeks of TPV+PegIFN+weight-based RBV and 12-36 additional weeks of PegIFN/RBV. The primary endpoint was sustained virologic response 12weeks post-treatment (SVR12). Patient-reported outcome questionnaires evaluated mental and physical health during the studies. RESULTS: Three hundred eleven treatment-naïve and 148 treatment-experienced patients were randomized and dosed. Among treatment-naïve patients, SVR12 rates were 97% (67/69) and 82% (28/34), respectively, in OBV/PTV/r+DSV+RBV and TPV+PegIFN/RBV-treated GT1a-infected patients; SVR12 rates were 99% (83/84), 98% (81/83), and 78% (32/41) in OBV/PTV/r+DSV+RBV, OBV/PTV/r+DSV, and TPV+PegIFN/RBV-treated GT1b-infected patients. Among treatment-experienced patients, SVR12 rates were 99% (100/101) and 66% (31/47) with OBV/PTV/r+DSV+RBV and TPV+PegIFN/RBV. Mental and physical health were generally better with OBV/PTV/r+DSV±RBV than TPV+PegIFN/RBV. Rates of discontinuation due to adverse events (0-1% and 8-11%, respectively, p<0.05) and rates of hemoglobin decline to <10g/dl (0-4% and 34-47%, respectively, p<0.05) were lower for OBV/PTV/r+DSV±RBV than TPV+PegIFN/RBV. CONCLUSIONS: Among non-cirrhotic, HCV GT1-infected patients, SVR12 rates were 97-99% with 12week, multi-targeted OBV/PTV/r+DSV±RBV regimens and 66-82% with 24-48 total weeks of TPV+PegIFN/RBV. OBV/PTV/r+DSV±RBV was associated with a generally better mental and physical health, more favorable tolerability, and lower rates of treatment discontinuation due to adverse events.

The portal inflammatory infiltrate and ductular reaction in human nonalcoholic fatty liver disease.

UNLABELLED: Although nonalcoholic fatty liver disease (NAFLD) is conventionally assessed histologically for lobular features of inflammation, development of portal fibrosis appears to be associated with disease progression. We investigated the composition of the portal inflammatory infiltrate and its relationship to the ductular reaction (DR), a second portal phenomenon implicated in fibrogenesis. The portal inflammatory infiltrate may contribute directly to fibrogenesis as well as influence the fate of the DR hepatic progenitor cells (HPCs), regulating the balance between liver repair and fibrosis. The presence of portal inflammation in NAFLD was strongly correlated with disease severity (fibrosis stage) and the DR. The portal infiltrate was characterized by immunostaining NAFLD liver biopsy sections (n = 33) for broad leukocyte subset markers (CD68, CD3, CD8, CD4, CD20, and neutrophil elastase) and selected inflammatory markers (matrix metalloproteinase 9 and interleukin [IL]-17). Cells expressing all markers examined were identified throughout the liver lobules and in portal tracts, although portal tracts were more densely populated (P < 0.01), and dominated by CD68(+) macrophages and CD8(+) lymphocytes, at all stages of disease. An increase in portal macrophages in NAFLD patients with steatosis alone (P < 0.01) was the earliest change detected, even before elevated expression of the proinflammatory cytokines, IL1B and TNF, in patients with early NASH (P < 0.05). Portal and periductal accumulation of all other cell types examined occurred in progressed NASH (all P < 0.05). CONCLUSION: Knowledge of the complex cellular composition of the portal inflammatory infiltrate and HPC/DR niche in NAFLD will shape future functional studies to elucidate the contribution of portal inflammation to HPC differentiation and NAFLD pathogenesis.

Evolving concepts in the pathogenesis of NASH: beyond steatosis and inflammation.

Non-alcoholic steatohepatitis (NASH) is characterised by hepatic steatosis and inflammation and, in some patients, progressive fibrosis leading to cirrhosis. An understanding of the pathogenesis of NASH is still evolving but current evidence suggests multiple metabolic factors critically disrupt homeostasis and induce an inflammatory cascade and ensuing fibrosis. The mechanisms underlying these changes and the complex inter-cellular interactions that mediate fibrogenesis are yet to be fully elucidated. Lipotoxicity, in the setting of excess free fatty acids, obesity, and insulin resistance, appears to be the central driver of cellular injury via oxidative stress. Hepatocyte apoptosis and/or senescence contribute to activation of the inflammasome via a variety of intra- and inter-cellular signalling mechanisms leading to fibrosis. Current evidence suggests that periportal components, including the ductular reaction and expansion of the hepatic progenitor cell compartment, may be involved and that the Th17 response may mediate disease progression. This review aims to provide an overview of the pathogenesis of NASH and summarises the evidence pertaining to key mechanisms implicated in the transition from steatosis and inflammation to fibrosis. Currently there are limited treatments for NASH although an increasing understanding of its pathogenesis will likely improve the development and use of interventions in the future.

Australians with metabolic dysfunction-associated steatotic liver disease have a twofold increase in the incidence of cancer.

Background and Aim: Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with an increased risk of extrahepatic morbidity. We compared the incidence of cancers in adults admitted to Queensland hospitals with MASLD with that for the Queensland population and examined the association between cirrhosis and type 2 diabetes and the development of extrahepatic cancers. Methods: In this retrospective study, we identified all cancers (Queensland Cancer Registry) after the first hospitalization with MASLD during Jul-2007 to Dec-2019, estimated age-standardized incidence (ASI) of cancers, and compared that with the ASI in the Queensland population (incidence rate ratios [IRR]). Among the MASLD cohort, we examined the association between diabetes and cancer risk (Cox regression). Median follow-up was 3.8 years (54 204 person-years). Results: Totally 1104 new cancers were diagnosed in 1018 patients (8.9% of 9771 non-cirrhotic and 1712 adults with cirrhosis). The ASI (all cancers) of 1668.2 per 100 000 person-years in men (95% CI 1523.7-1827.4) and 1284.0 per 100 000 person-years in women (95% CI 1169.6-1408.2) was 2-fold higher than that of the Queensland population (IRR = 1.94, 95% CI 1.75-2.16 and IRR = 1.99, 95% CI 1.78-2.22, respectively). Incidence of stomach cancer, unknown primary, and pancreas was 3- to 5-fold higher compared to the general population (all P < 0.001). In multivariable analysis of the MASLD cohort, older age (e.g. ≥70 years adjusted hazard ratio [adj-HR] = 4.59, 95% CI 3.61-5.83), male gender (adj-HR = 1.20, 95% CI 1.05-1.37), and cirrhosis (adj-HR = 1.37, 95% CI 1.11-1.70) were independently associated with extrahepatic cancer risk, while diabetes was not. Conclusions: Our findings will help to raise awareness among clinicians about the importance of cancer vigilance in this patient group.

Heterogeneity of fibrosis patterns in non-alcoholic fatty liver disease supports the presence of multiple fibrogenic pathways.

BACKGROUND: Adult non-alcoholic fatty liver disease (NAFLD) involves lobular necroinflammatory activity and fibrosis is typically centrilobular, whereas paediatric NAFLD has predominantly portal fibrosis. The reasons for these differences are unclear. We aimed to determine (a) how centrilobular and portal fibrosis in children relate to histological parameters; and (b) whether atypical fibrosis patterns exist in adults that are unexplained by current fibrogenesis models. METHODS: Histological features of paediatric (n = 38) and adult (n = 56) NAFLD were assessed using conventional scoring systems. Keratin-7 immunostaining was used to assess hepatic progenitor cell numbers and the ductular reaction. Centrilobular and portal components of fibrosis were independently scored and fibrosis patterns were classified according to accepted types. Post-treatment (rosiglitazone/gastric banding) biopsies were also examined in adults. RESULTS: Twenty-six children (68.4%) had portal-predominant fibrosis, although the typical "adult" pattern was seen in 11 (28.9%). Portal fibrosis was associated with a ductular reaction (P = 0.021) and hepatic progenitor cell expansion (P < 0.001), whereas centrilobular fibrosis was associated with lobular inflammation (P = 0.026) and ballooning (P = 0.001). Before intervention, six adults (10.7%) had atypical fibrosis including 3 (5.4%) with a previously unrecognized pattern of very fine, non-zonal sinusoidal fibrosis. Despite improvements in steatosis and inflammation, more patients developed this unusual pattern after intervention with most having had surgery (9 of 10 adults; P < 0.001). CONCLUSION: Differing associations with portal and centrilobular fibrosis in children and atypical fibrosis patterns in adults suggest that multiple fibrogenic pathways exist in NAFLD. This has implications for therapy and understanding pathogenesis.

Use of standardised assessment forms in referrals to hepatology outpatient services: implications for accurate triaging of patients with chronic hepatitis C.

OBJECTIVES: To determine the spectrum of disease among non-urgent referrals to a tertiary hospital hepatology outpatient clinic, assess the adequacy of referral information in terms of risk stratification and determine whether a specifically designed referral template altered urgency for specialist assessment. METHODS: A snapshot of the waiting list of a hepatology clinic at a tertiary hospital was taken from the scheduling database. Information was retrieved from referrals and attached investigations. Updated information was requested from subjects and their current general practitioner. RESULTS: Hepatitis C virus accounted for 68.7% of the 1223 reviewed referrals. Clinical information provided by referring clinicians was often incomplete. Provision of updated information identified the presence of comorbidities (obesity, 'heavy' alcohol consumption, mental health issues) and altered the need or urgency for specialist assessment in 22% of cases. CONCLUSIONS: Hepatitis C virus accounts for the majority of non-urgent referrals waiting to access hepatology outpatient consultations. Using a standardised assessment form as part of the referral process provides more information on comorbidities and risk factors and facilitates more accurate triaging of clinical urgency. Wider adoption of this strategy may increase appropriate access to hepatology services and reduce the future burden of cirrhosis and hepatocellular cancer. WHAT IS KNOWN ABOUT THE TOPIC? Little published data are available that describe the content and standard of hepatology referrals, or the urgency with which these patients need to be reviewed. Inadequate clinical information impairs the ability to accurately triage referrals and may lead to delays in access. WHAT DOES THE PAPER ADD? Almost 70% of reviewed referrals were for management of patients with hepatitis C virus infection, confirming this condition remains a major priority area in liver disease. Clinical information provided by referring clinicians was often incomplete, impairing the ability to accurately triage referrals. Only a minority of referrals provided information about relevant comorbidities (alcohol intake, injecting drug use, mental health issues and obesity) that negatively impact on the progression of liver disease or the response to antiviral treatment. WHAT ARE THE IMPLICATIONS FOR PRACTITIONERS? Hepatitis C virus remains a major health priority area in liver disease, increasing the future burden of cirrhosis and hepatocellular cancer. Many referred patients have comorbidities that increase their risk of progressive liver disease and related complications. Strategies to increase recognition and management of liver disease and its comorbidities in the community are required. The use of a standardised assessment form in referrals to hepatology outpatient services may assist with triaging of patients and improve access to appropriate care.

Changing Prevalence of Medication Use in People with Cirrhosis: A Retrospective Cohort Study Using Pharmaceutical Benefits Scheme Data.

BACKGROUND: Safe and appropriate use of medicines is essential to improve health outcomes in cirrhosis. However, little is known about the number and type of medicines dispensed to people with cirrhosis in Australia, as this predominantly occurs in the community. We aimed to characterise the prescriptions dispensed to people with cirrhosis and explore changes in the use of medication groups over time. METHODS: Pharmaceutical Benefits Scheme data between 1 January 2016 and 30 June 2020 was extracted for consenting CirCare participants (multi-site, prospective, observational study). Prescriptions dispensed from cirrhosis diagnosis until liver transplant or death were included. Safety classifications for dispensed medicines were defined using published evidence-based recommendations. The pattern of medication use was analysed in 6-monthly time intervals. Generalised estimating equations models were used to estimate the change in consumption of medicines over time. RESULTS: Five hundred twenty-two patients (mean age 60 years, 70% male, 34% decompensated at recruitment) were dispensed 89,615 prescriptions during the follow-up period, representing a median of 136 [interquartile range (IQR) 62-237] prescriptions and a median of 16 (IQR 11-23) unique medicines per patient (total n = 9306 medicines). The most commonly used medicines were proton pump inhibitors (PPIs) (dispensed at least once to 73% of patients), opioids (68%) and antibiotics (89%). Polypharmacy was prevalent, with 59-69% of observed participants in each time period dispensed five or more unique medicines. Prescription medication use increased over time (p < 0.001) independently of age, comorbidity burden and liver disease aetiology. The likelihood of taking PPIs, opioids, antidepressants and inhaled medicines also increased with each successive time period. Use of angiotensin therapies, metformin and statins differed over time between patients with compensated versus decompensated cirrhosis. General practitioners prescribed 69% of dispensed medicines, including a higher proportion of 'unsafe' and 'safety unknown' medicines compared with consultants/specialists (p < 0.001). CONCLUSIONS: Polypharmacy is common in people with cirrhosis and some medication groups may be overused. Pharmacovigilance is required and future medication safety efforts should target high-risk prescribing practices and promote medication rationalisation in the community.

Triage of referrals to outpatient hepatology services: an ineffective tool to prioritise patients?

BACKGROUND: Appropriate and uniform prioritisation ('triaging') of outpatient referrals is critical to good patient outcomes, equity of access to services and efficient use of resources. OBJECTIVE: To determine whether there is uniformity in the allocation of triage categories for hepatology outpatient referrals at public hospitals in Queensland. METHODS: A series of 10 recent hepatology referrals were de-identified for both patient and referring clinician details and sent to nine gastroenterology or hepatology centres throughout Queensland. Consultant gastroenterologists and hepatologists (n=25) were asked to triage the referrals using the process in place in their centre. Responses were de-identified and analysed. Each case was reviewed and allocated an 'agreed triage category' based upon the majority view of respondents. RESULTS: Nineteen responses were received. There was substantial variation amongst consultants in the allocation of triage categories. Although almost two-thirds of respondents agreed with the majority view in 60-80% of cases, none agreed with the majority for every case and some agreed in as few as 50% cases. Disagreement with the majority view of an appropriate triage category was not associated with geography or specialist experience. CONCLUSIONS: Variability in triage categorisation suggests that similar cases may be allocated different priorities by those responsible for determining the urgency of outpatient review. This has implications for equity of access to treatment. The development of triage guidelines and formal training in their implementation, along with periodic audits of triage practices in different centres, may reduce variability.

Utility and limitations of Hepascore and transient elastography to detect advanced hepatic fibrosis in HFE hemochromatosis.

Aspartate aminotransferase-to-platelet ratio index (APRI) and Fibrosis-4 Index (Fib4) have been validated against liver biopsy for detecting advanced hepatic fibrosis in HFE hemochromatosis. We determined the diagnostic utility for advanced hepatic fibrosis of Hepascore and transient elastography compared with APRI and Fib4 in 134 newly diagnosed HFE hemochromatosis subjects with serum ferritin levels > 300 µg/L using area under the receiver operator characteristic curve (AUROC) analysis and APRI- (> 0.44) or Fib4- (> 1.1) cut-offs for AHF, or a combination of both. Compared with APRI, Hepascore demonstrated an AUROC for advanced fibrosis of 0.69 (95% CI 0.56-0.83; sensitivity = 69%, specificity = 65%; P = 0.01) at a cut-off of 0.22. Using a combination of APRI and Fib4, the AUROC for Hepascore for advanced fibrosis was 0.70 (95% CI 0.54-0.86, P = 0.02). Hepascore was not diagnostic for detection of advanced fibrosis using the Fib4 cut-off. Elastography was not diagnostic using either APRI or Fib4 cut-offs. Hepascore and elastography detected significantly fewer true positive or true negative cases of advanced fibrosis compared with APRI and Fib4, except in subjects with serum ferritin levels > 1000 µg/L. In comparison with APRI or Fib4, Hepascore or elastography may underdiagnose advanced fibrosis in HFE Hemochromatosis, except in individuals with serum ferritin levels > 1000 µg/L.

The Patient's Perspective in Cirrhosis: Unmet Supportive Care Needs Differ by Disease Severity, Etiology, and Age.

Patients with cirrhosis have significant physical, psychological, and practical needs. We documented patients' perceived need for support with these issues and the differences with increasing liver disease severity, etiology, and age. Using the supportive needs assessment tool for cirrhosis (SNAC), we examined the rate of moderate-to-high unmet needs (Poisson regression; incidence rate ratio [IRR]) and the correlation between needs and sociodemographic/clinical characteristics (multivariable linear regression) in 458 Australians adults with cirrhosis. Primary liver disease etiology was alcohol in 37.6% of patients, chronic viral hepatitis C in 25.5%, and nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) in 23.8%. A total of 64.6% of patients had Child-Pugh class A cirrhosis. Most patients (81.2%) had at least one moderate-to-high unmet need item; more than 25% reported a moderate-to-high need for help with "lack of energy," "sleep poorly," "feel unwell," "worry about … illness getting worse (liver cancer)," "have anxiety/stress," and "difficulty with daily tasks." Adjusting for key sociodemographic/clinical factors, patients with Child-Pugh C had a greater rate of "practical and physical needs" (vs. Child-Pugh A; IRR = 2.94, 95% confidence interval [CI] 2.57-3.37), patients with NAFLD/NASH had a greater rate of needs with "lifestyle changes" (vs. alcohol; IRR = 1.81, 95% CI 1.18-2.77) and "practical and physical needs" (IRR = 1.43, 95% CI 1.23-1.65), and patients aged ≥65 years had fewer needs overall (vs. 18-64 years; IRR = 0.70, 95% CI 0.64-0.76). Higher overall SNAC scores were associated with Child-Pugh B and C (both P < 0.001), NAFLD/NASH (P = 0.028), patients with "no partner, do not live alone" (P = 0.004), unemployment (P = 0.039), ascites (P = 0.022), and dyslipidemia (P = 0.024) compared with their counterparts. Conclusion: Very high levels of needs were reported by patients with cirrhosis. This information is important to tailor patient-centered care and facilitate timely interventions or referral to support services.

Assessment of health-related quality of life and health utilities in Australian patients with cirrhosis.

BACKGROUND AND AIM: Health-related quality-of-life measurements are important to understand lived experiences of patients who have cirrhosis. These measures also inform economic evaluations by modelling quality-adjusted life years (QALYs). We aimed to describe health-related quality of life, specifically multiattribute utility (scale anchors of death = 0.00 and full health = 1.00), across various stages and etiologies of cirrhosis. METHODS: Face-to-face interviews were used to collect Short Form 36 (SF-36) questionnaire responses from CirCare study participants with cirrhosis (June 2017 to December 2018). The severity of cirrhosis was assessed using the Child-Pugh score classified as class A (5-6 points), B (7-9), or C (10-15) and by the absence ("compensated") versus presence ("decompensated") of cirrhosis-related complications. RESULTS: Patients (n = 562, average 59.8 years [SD = 11.0], male 69.9%) had a range of primary etiologies (alcohol-related 35.2%, chronic hepatitis C 25.4%, non-alcoholic fatty liver disease (NAFLD) 25.1%, chronic hepatitis B 5.9%, "other" 8.4%). Significantly lower (all P < 0.001) mean multiattribute utility was observed in the health states of patients with decompensated (mean = 0.62, SD = 0.15) versus compensated cirrhosis (mean = 0.68, SD = 0.12), Child-Pugh class C (mean = 0.59, SD = 0.15) or B (mean = 0.63, SD = 0.15) versus A (mean = 0.68, SD = 0.16), and between those of working age (18-64 years; mean = 0.64, SD = 0.16) versus those aged 65+ years (mean = 0.70, SD = 0.16). The greatest decrements in health-related quality of life relative to Australian population norms were observed across physical SF-36 domains. CONCLUSIONS: Persons with more advanced cirrhosis report greater life impacts. Estimates from this study are suitable for informing economic evaluations, particularly cost-utility modelling, which captures the benefits of effective prevention, surveillance, and treatments on both the quality and quantity of patients' lives.