Search

Background: Psychosocial, lifestyle and practical needs are not routinely attended to during outpatient hepatology management, and little is known about the type and effectiveness of support services accessed by patients with cirrhosis. We quantified the type and use of community and allied health services in patients with cirrhosis. Methods: The study included 562 Australian adults with a diagnosis of cirrhosis. Health service use was assessed via questionnaire and via linkage to the Australian Medicare Benefits Schedule. Patient needs were assessed using the Supportive Needs Assessment tool for Cirrhosis (SNAC). Results: Although most patients (85.9%) used at least one community/allied health service for support with their liver disease, many reported requiring additional help with psychosocial (67.4%), lifestyle (34.3%) or practical needs (21.9%) that were not met by available services, or patients did not access services. A multidisciplinary care plan or case conference (in the 12 months prior to recruitment) was accessed by 48% of patients, 56.2% reported the use of a general practitioner for support with cirrhosis, and a dietician was the allied health clinician most accessed by patients (45.9%). Despite the high prevalence of psychosocial needs, there was relatively limited use of mental health and social work services (14.1% of patients reported the use of a psychologist), confirmed by a low prevalence of use of mental health services (17.7%) in the linked data. Conclusion: Patients with cirrhosis who have unmet complex physical and psychosocial needs require better strategies to increase their engagement with allied health and community services. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) has a global prevalence of 25% and is a leading cause of cirrhosis and hepatocellular carcinoma. NAFLD encompasses a disease continuum from steatosis with or without mild inflammation (non-alcoholic fatty liver), to non-alcoholic steatohepatitis (NASH), which is characterised by necroinflammation and faster fibrosis progression than non-alcoholic fatty liver. NAFLD has a bidirectional association with components of the metabolic syndrome, and type 2 diabetes increases the risk of cirrhosis and related complications. Although the leading causes of death in people with NAFLD are cardiovascular disease and extrahepatic malignancy, advanced liver fibrosis is a key prognostic marker for liver-related outcomes and overall mortality, and can be assessed with combinations of non-invasive tests. Patients with cirrhosis should be screened for hepatocellular carcinoma and oesophageal varices. There is currently no approved therapy for NAFLD, although several drugs are in advanced stages of development. Because of the complex pathophysiology and substantial heterogeneity of disease phenotypes, combination treatment is likely to be required for many patients with NAFLD. Healthy lifestyle and weight reduction remain crucial to the prevention and treatment of NAFLD. [ABSTRACT FROM AUTHOR]

Abstract: Haemochromatosis is most commonly due to the autosomal recessive inheritance of a C282Y substitution in the HFE protein, whereby both alleles of the corresponding gene are affected. The disease is characterised by an inappropriate increase in intestinal iron absorption due to reduced expression of the iron regulatory protein, hepcidin. Progressive iron deposition in parenchymal tissues may ultimately lead to liver and other organ toxicity. The characteristic biochemical abnormalities are raised serum ferritin and transferrin saturation, which can be used in conjunction with genetic tests and emerging magnetic resonance imaging‐based techniques to diagnose patients with the disorder. Progressive iron overload can manifest clinically as advanced fibrosis, cirrhosis and hepatocellular carcinoma. Enigmatically, the penetrance of both raised iron indices and clinically significant disease is incomplete in patients with hereditary haemochromatosis. Regardless, advanced clinical presentations of the disease have become less common due to increased awareness and earlier diagnosis. On the other hand, obesity and alcohol have been identified as major risk factors that can compound the risk of liver injury in people with hereditary (HFE) haemochromatosis. The prospect of modifying genes that may contribute to the clinical expression of the disease is the subject of ongoing research. Treatment with phlebotomy remains the first‐line therapy, and if instigated early leads to a normal life expectancy. A healthy, well‐balanced diet is recommended to be incorporated as part of the ongoing management of the disease. [ABSTRACT FROM AUTHOR]

In addition to their established roles in host defence, Toll-like Receptors (TLRs) have emerging roles in control of homeostasis, injury and wound repair. The dsRNA-sensing receptor, TLR3, has been particularly implicated in such processes in several different tissues including the skin, intestine and liver, as well as in the control of reparative mechanisms in the brain, heart and kidneys, following ischemia reperfusion injury. In this review, we provide an overview of TLR3 signalling and functions in inflammation, tissue damage and repair processes, as well as therapeutic opportunities that may arise in the future from knowledge of such pathways. [ABSTRACT FROM AUTHOR]

Although 60 years have passed since it became widely available on the therapeutic market, paracetamol dosage in patients with liver disease remains a controversial subject. Fulminant hepatic failure has been a well documented consequence of paracetamol overdose since its introduction, while short and long term use have both been associated with elevation of liver transaminases, a surrogate marker for acute liver injury. From these reports it has been assumed that paracetamol use should be restricted or the dosage reduced in patients with chronic liver disease. We review the factors that have been purported to increase risk of hepatocellular injury from paracetamol and the pharmacokinetic alterations in different pathologies of chronic liver disease which may affect this risk. We postulate that inadvertent under-dosing may result in concentrations too low to enable efficacy. Specific research to improve the evidence base for prescribing paracetamol in patients with different aetiologies of chronic liver disease is needed. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) proteins activate the unfolded protein response (UPR) in experimental models. The role of the UPR in the pathogenesis of HCV-induced liver injury has not been determined. Our aim was to investigate the role of the UPR in the pathogenesis of chronic HCV. Liver biopsy samples from 124 patients with chronic HCV and 24 HCV/HBV-negative subjects with histologically normal liver (NDL) were assessed. The hepatic mRNA expression of components of the UPR was measured by semi-quantitative real-time polymerase chain reaction. Glucose regulated protein (GRP) 78 protein expression was assessed by immunohistochemistry. The expression of GRP78 mRNA and growth arrest and damage inducible protein 34 (GADD34) mRNA was significantly lower in subjects with HCV than NDL ( P = 0.007 and P < 0.001, respectively). There was no significant difference in the expression of GRP94 mRNA, spliced X box binding protein 1 (sXBP1) mRNA, C/EBP homologous protein mRNA (CHOP) and ER degradation enhancing α-mannosidase-like protein (EDEM) mRNA and GRP78 protein between patients with HCV and NDL. There were no relationships between elements of the UPR and inflammation or fibrosis in patients with HCV. Downstream components of UPR were not activated in patients with chronic HCV. Therefore, the UPR may not play a prominent role in liver injury in patients with chronic HCV infection. [ABSTRACT FROM AUTHOR]

Background and Aims: Despite the benefits of modest weight reduction for overweight patients with chronic liver disease, long-term maintenance of weight loss is difficult to achieve in clinical practice. The aims of this study were to determine if a nutrition research protocol could be translated into clinical practice and meet the demand for dietetic service, to evaluate the effectiveness and resource implications of intensive lifestyle intervention for weight loss, and to assess the effectiveness of standard dietetic therapy as a treatment option for patients unable to attend the program. Method: Using a modified research protocol, an intensive weight reduction program was introduced into standard clinical care for overweight patients attending a tertiary hospital liver outpatient clinic. An audit of weight loss and cost outcomes was conducted. Results: Ninety-three patients were referred to the dietetic service for weight management. Of these, 50 enrolled in an intensive lifestyle intervention, 18 received standard dietetic therapy and 25 refused any intervention. After 6 months, 83% of patients in the intensive intervention achieved weight loss with a significant decrease in weight ( P < 0.001) and waist circumference ( P < 0.001). In contrast, only 24% of patients receiving standard dietetic therapy achieved weight loss with no significant change in mean weight or waist circumference. Cost per kilogram weight loss after intensive intervention was $AU31 and continuation of lifestyle intervention was calculated to be less than $AU100 per patient per year. Conclusions: A clinically based, intensive lifestyle intervention is a feasible treatment option for outpatient weight management in overweight patients with chronic liver disease. Providing patients who are unable to participate in intensive programs with standard dietetic therapy is not cost-effective. [ABSTRACT FROM AUTHOR]

Background/Aims: Host factors such as increased body mass index (BMI) and genotype-specific viral factors contribute to the development of steatosis in patients with chronic hepatitis C (HCV). We hypothesized that host metabolic factors associated with increased BMI may play a role in disease progression.Methods: Fasting serum was collected from 160 patients with chronic HCV at the time of liver biopsy and 45 age, gender and BMI matched controls, and assessed for levels of insulin, c-peptide and leptin.Results: Patients with viral genotype 3 had more severe steatosis (P=0.0001) and developed stages 1 and 2 fibrosis at a younger age (P<0.05) than patients with genotype 1. For both genotypes, overweight patients had significantly more steatosis and increased insulin and leptin levels. In contrast to lean patients, there was a statistically significant increase in circulating insulin levels with increasing fibrosis in overweight patients with chronic HCV (P=0.03). Following multivariate analysis, insulin was independently associated with fibrosis (P=0.046) but not inflammation (P=0.83). There was no association between serum leptin levels and stage of fibrosis.Conclusions: Increasing circulating insulin levels may be a factor responsible for the association between BMI and fibrosis in patients with HCV, irrespective of viral genotype. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Aetiology is also a relevant factor."

The article presents information about the nonalcoholic fatty liver disease (NAFLD). NAFLD is an under-recognized manifestation of the metabolic syndrome. The term refers to a spectrum of fatty liver disease that occurs in the absence of significant alcohol consumption. Although only a minority of patients with NAFLD develop advanced liver disease, this condition is causing increasing alarm because of its marked prevalence. A recent large population-based study from the United States found a prevalence of 34%.

Aim: To explore the care experiences of Aboriginal and Torres Strait Islander Australians diagnosed with cirrhosis with a focus on support needed. Background: Cirrhosis disproportionately affects Indigenous Australians, and liver diseases contribute to the mortality gap between Indigenous and other Australian adults. Design: A qualitative study. Methods: Using yarning methods, Indigenous patients (n = 13) and support persons (n = 3) were interviewed by an Aboriginal researcher during April‐July, 2020. Thematic analysis was used to identify common themes using an inductive approach. Results: Six themes emerged. (1) Experience of diagnosis. This theme included stories of delays in the system, self‐awareness of signs and symptoms and relief of being diagnosed. (2) 'Shame, shame, shame'. Experiences of prejudices and discrimination from health professionals, the lack of understanding of cirrhosis among health professionals, and stories about alcohol cessation and counselling around alcohol cessation. (3) Health literacy. Participants' understanding of cirrhosis was variable. While the importance of knowledge was recognised, 'what works for someone might not work for others'. Several patients partnered with their support persons and clinicians to bridge the health literacy gap. (4) Sources of support included family and friends, transport facilities, health professionals and peers. (5) Positive and negative aspects of communication and patient consultation were discussed. (6) Psychosocial counselling to 'look after the caring side'. The need for more mental health care services was raised. Conclusion: Barriers related to poor health literacy, stigma and lack of practical and emotional support, and issues with communication and patient consultation, may lead to inequitable access to cirrhosis care and treatment for Indigenous Australians. Relevance to clinical practice: Gaining knowledge of the experiences of Indigenous Australians with cirrhosis is important for providing patient‐centred and culturally appropriate care. Liver specialist nurses have an important role in bridging the health literacy gap and in supporting Indigenous patients and families. [ABSTRACT FROM AUTHOR]

Background: Liver diseases are important contributors to the mortality gap between Indigenous and non‐Indigenous Australians. Aims: This cohort study examined factors associated with hospital admissions and healthcare outcomes among Indigenous Australians with cirrhosis. Methods: Patient‐reported outcomes were obtained by face‐to‐face interview (Chronic Liver Disease Questionnaire and Short Form 36 (SF‐36)). Clinical data were extracted from medical records and through data linkage for 534 patients (25 indigenous). Cumulative overall survival (Kaplan–Meier), rates of hospital admissions and emergency presentations, and costs were assessed by indigenous status. Incidence rate ratios (IRR; Poisson regression) were reported. Results: Indigenous Australians admitted to hospital with cirrhosis had lower educational status compared with non‐indigenous patients (79.2% vs 43.4%; P < 0.001). The two groups had, in general, similar clinical characteristics including disease severity (P = 0.78), presence of cirrhosis complications (P = 0.67), comorbidities (P = 0.62), rates of cirrhosis‐related admissions (P = 0.86) and 5‐year survival (P = 0.30). However, indigenous patients had a lower score in the SF‐36 domain related to bodily pain (P = 0.037), more cirrhosis admissions via the emergency department (IRR = 1.42, 95% confidence interval (CI) 1.10–1.83) and fewer planned cirrhosis admissions (IRR = 0.32, 95% CI 0.14–0.72). The total cost for cirrhosis‐related hospital admissions for 534 patients over 6 years (July 2012 to June 2018) was A$13.7 million. The cost of cirrhosis‐related hospital admissions was double for indigenous patients (cost ratio = 2.04, 95% CI 2.04–2.05). Conclusions: Our data highlight the disparities in health service use and patient‐reported outcomes, despite having similar clinical profiles. Integration between primary care, Aboriginal Community Controlled Health Organisations and liver specialists is critical for appropriate health service delivery and effective use of resources. Chronic liver disease costs the community dearly. [ABSTRACT FROM AUTHOR]

Background: Optimal management of cirrhosis is complex, and patients often lack knowledge and skills, which can affect self-management. We assessed patient knowledge about cirrhosis and examined whether knowledge was associated with clinical outcomes, healthcare service use, and healthcare costs. A cross-sectional 'knowledge survey' was conducted during 2018-2020. We assessed patient knowledge about cirrhosis and explore whether knowledge was associated with clinical outcomes, healthcare service use, and costs.Methods: Patients with cirrhosis (n = 123) completed a 'knowledge survey'. We calculated the proportion of correct answers to eight questions deemed to be "key knowledge" about cirrhosis by an expert panel, and dichotomized patients as 'good knowledge'/'poor knowledge'. Clinical data, healthcare costs, and health-related quality of life (SF-36) were available.Results: 58.5% of patients had 'good knowledge' about cirrhosis. Higher education level was associated with higher odds of having 'good knowledge' about cirrhosis (adjusted-OR = 5.55, 95%CI 2.40-12.84). Compared to patients with 'poor knowledge', those with 'good knowledge' had a higher health status in the SF-36 physical functioning domain (p = 0.011), fewer cirrhosis-related admissions (adjusted incidence rate ratio [IRR] = 0.59, 95%CI 0.35-0.99) and emergency presentations (adj-IRR = 0.34, 95%CI 0.16-0.72), and more planned 1-day cirrhosis admissions (adj-IRR = 3.96, 95%CI 1.46-10.74). The total cost of cirrhosis admissions was lower for patients with 'good knowledge' (adj-IRR = 0.30, 95%CI 0.29-0.30).Conclusion: Poor disease knowledge is associated with increased use and total cost of healthcare services. Targeted educational interventions to improve patient knowledge may be an effective strategy to promote a more cost-effective use of healthcare services. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Histologically assessed hepatocyte ballooning is a key feature discriminating non-alcoholic steatohepatitis (NASH) from steatosis (NAFL). Reliable identification underpins patient inclusion in clinical trials and serves as a key regulatory-approved surrogate endpoint for drug efficacy. High inter/intra-observer variation in ballooning measured using the NASH CRN semi-quantitative score has been reported yet no actionable solutions have been proposed. A focused evaluation of hepatocyte ballooning recognition was conducted. Digitized slides were evaluated by 9 internationally recognized expert liver pathologists on 2 separate occasions: each pathologist independently marked every ballooned hepatocyte and later provided an overall non-NASH NAFL/NASH assessment. Interobserver variation was assessed and a 'concordance atlas' of ballooned hepatocytes generated to train second harmonic generation/two-photon excitation fluorescence imaging-based artificial intelligence (AI). The Fleiss kappa statistic for overall interobserver agreement for presence/absence of ballooning was 0.197 (95% CI 0.094–0.300), rising to 0.362 (0.258–0.465) with a ≥5-cell threshold. However, the intraclass correlation coefficient for consistency was higher (0.718 [0.511–0.900]), indicating 'moderate' agreement on ballooning burden. 133 ballooned cells were identified using a ≥5/9 majority to train AI ballooning detection (AI-pathologist pairwise concordance 19–42%, comparable to inter-pathologist pairwise concordance of between 8–75%). AI quantified change in ballooned cell burden in response to therapy in a separate slide set. The substantial divergence in hepatocyte ballooning identified amongst expert hepatopathologists suggests that ballooning is a spectrum, too subjective for its presence or complete absence to be unequivocally determined as a trial endpoint. A concordance atlas may be used to train AI assistive technologies to reproducibly quantify ballooned hepatocytes that standardize assessment of therapeutic efficacy. This atlas serves as a reference standard for ongoing work to refine how ballooning is classified by both pathologists and AI. For the first time, we show that, even amongst expert hepatopathologists, there is poor agreement regarding the number of ballooned hepatocytes seen on the same digitized histology images. This has important implications as the presence of ballooning is needed to establish the diagnosis of non-alcoholic steatohepatitis (NASH), and its unequivocal absence is one of the key requirements to show 'NASH resolution' to support drug efficacy in clinical trials. Artificial intelligence-based approaches may provide a more reliable way to assess the range of injury recorded as "hepatocyte ballooning". [Display omitted] • Hepatocyte ballooning identification underpins regulatory-approved drug efficacy endpoints in clinical trials. • We report substantial variation in ballooned cell identification by expert hepatopathologists. • Our data suggest that ballooning is too subjective for its presence or complete absence to be used as a trial endpoint. • A 'concordance atlas' of cells identified as ballooned by multiple pathologists can be used to train AI-based image analysis. • AI-based approaches may provide a more reliable way to assess the range of injury recorded as hepatocyte ballooning. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Obesity and liver diseases are associated with the disruption of the circadian clock that orchestrates mammalian physiology to optimize nutrient metabolism and storage. Here, we show that the activity of the circadian clock regulator Brain and Muscle Aryl hydrocarbon receptor nuclear translocator-like 1 (BMAL1) is perturbed during liver fibrosis in humans. To understand the impact of BMAL1 perturbation in obesity and liver diseases, we assessed the impact of a high fat diet or leptin deficiency on Bmal1 knockout mice. While Bmal1 knock- out mice were prone to obesity, they were protected against insulin resistance, hepatic steatosis, inflammation, and fibrosis. In addition, to direct the transcriptional regulation of metabolic programs by BMAL1, we show that the disruption of the growth hormone and sex hormone pathways plays a critical role in this protection. Similar endocrine perturbations correlate with the development of liver fibrosis in humans but were absent in hepatocyte-specific Bmal1 knockout mice. This suggests that systemic endocrine perturbation associated with the global disruption of BMAL1 activity is critical for the pathogenesis of metabolic and liver diseases. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) and depression are common disorders and have bidirectional contributing relationships to metabolic syndrome. We aimed to determine whether a fasting serum signature of recent, self-reported depressive symptoms could be identified in a heterogeneous NAFLD cohort using nuclear magnetic resonance (NMR)-based metabolomics integrated with clinical chemistry. Serum nuclear magnetic resonance (NMR) metabolite profiles and corresponding clinical chemistry were compared between patients with depressive symptoms in the last 12-months (n = 81) and patients without recent depressive symptoms (n = 137 controls) using multivariate statistics. Orthogonal partial least squares discriminant analysis (OPLS-DA) of the biochemical and metabolomic data identified NAFLD patients with recent depression with a cross-validated accuracy of 61.5%, independent of age, sex, medication, and other comorbidities. This led to the development of a diagnostic algorithm with AUC 0.83 for future testing in larger clinical cohorts. Serum triglycerides, VLDL cholesterol, and the inflammatory biomarker GlycA were key metabolites increased in patients with recent depressive symptoms, while serum glutamine level was reduced. Here, serum NMR metabolite analysis provides a link between disturbed lipid metabolism, inflammation, and active mental health issues in NAFLD, irrespective of disease severity. [ABSTRACT FROM AUTHOR]

Purpose: Understanding and responding to the supportive care needs of people with cirrhosis is essential to quality care. Indigenous Australians, Aboriginal and Torres Strait Islander people, are overrepresented amongst patients with cirrhosis. This study documented the nature and extent of supportive care needs of Indigenous Australians with cirrhosis, in comparison with non-Indigenous Australians. Patients and Methods: The supportive care needs of adult patients diagnosed with cirrhosis attending public hospitals in Queensland were assessed through the Supportive Needs Assessment tool for Cirrhosis (SNAC). Patients indicated how much additional help they needed on four subscales: 1. psychosocial issues; 2. practical and physical needs; 3. information needs; and 4. lifestyle changes. We examined the rate of moderate-to-high unmet needs based on Indigenous status (Poisson regression; incidence rate ratio (IRR)). Results: Indigenous (n=20) and non-Indigenous (n=438) patients included in the study had similar sociodemographic and clinical characteristics except for a lower educational level among Indigenous patients (p< 0.01). Most Indigenous patients (85.0%) reported having moderate-to-high unmet needs with at least one item in the SNAC tool. Following adjustment for key sociodemographic and clinical factors, Indigenous patients had a greater rate of moderate-to-high unmet needs overall (IRR=1.5, 95% CI 1.31– 1.72; p< 0.001), and specifically for psychosocial issues (IRR=1.7, 95% CI 1.39– 2.15; p< 0.001), and practical and physical needs subscales (IRR=1.5, 95% CI 1.22– 1.83; p< 0.001), compared to non-Indigenous patients. Conclusion: Indigenous Australians with cirrhosis more frequently had moderate-to-high unmet supportive care needs than non-Indigenous patients. Specific targeting of culturally appropriate supportive care for psychosocial, practical and physical needs may optimize cirrhosis care and improve the quality of life for Indigenous Australians with cirrhosis. [ABSTRACT FROM AUTHOR]

Background Aims Methods Results Conclusion The optimal strategy to support primary care practitioners (PCP) to assess fibrosis severity in non‐alcoholic fatty liver disease (NAFLD) and thereby make appropriate management decisions remains unclear.To examine the feasibility of using a two‐step pathway that combined simple scores (NAFLD Fibrosis Score and Fibrosis‐4 Index) with transient elastography (FibroScan) to streamline NAFLD referrals from a ‘routine’ primary care population to specialist hepatology management clinics (HMC).The two‐step ‘Towards Collaborative Management of NAFLD’ (TCM‐NAFLD) fibrosis risk assessment pathway was implemented at two outer metropolitan primary healthcare practices in Brisbane. Patients aged ≥18 years with a new or established PCP‐diagnosis of NAFLD were eligible for assessment. The pathway triaged patients at ‘high risk’ of clinically significant fibrosis to HMC for specialist review, and ‘low risk’ patients to receive ongoing management and longitudinal follow up in primary care.A total of 162 patient assessments between June 2019 and December 2020 were included. Mean age was 58.7 ± 11.7 years, 30.9% were male, 54.3% had type 2 diabetes or impaired fasting glucose, and mean body mass index was 34.2 ± 6.9 kg/m2. A total 122 patients was considered ‘low risk’ for clinically significant fibrosis, two patients had incomplete assessments and 38 (23.5%) were triaged to HMC. Among 31 completed HMC assessments to date, 45.2% were considered to have clinically significant (or more advanced) fibrosis, representing 9.2% of 153 completed assessments.Implementation of the two‐step TCM‐NAFLD pathway streamlined hepatology referrals for NAFLD and may facilitate a more cost‐effective and targeted use of specialist hepatology resources. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and the third most common cause of cancer‐related death. Long‐term prognosis remains poor with treatment options frequently limited by advanced tumor stage, tumor location, or underlying liver dysfunction. Stereotactic ablative body radiotherapy (SABR) utilizes technological advances to deliver highly precise, tumoricidal doses of radiation. There is an emerging body of literature on SABR in HCC demonstrating high rates of local control in the order of 80–90% at 3 years. SABR is associated with a low risk of radiation‐induced liver disease or decompensation in appropriately selected HCC patients with compensated liver function and is now being incorporated into guidelines as an additional treatment option. This review outlines the emerging role of SABR in the multidisciplinary management of HCC and summarizes the current evidence for its use as an alternative ablative option for early‐stage disease, as a bridge to transplant, and as palliation for advanced‐stage disease. We outline specific considerations regarding patient selection, toxicities, and response assessment. Finally, we compare current international guidelines and recommendations for the use of SABR and summarize ongoing studies. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) affects 25% of the adult population globally. Since liver fibrosis is the most important predictor of liver-related complications in patients with NAFLD, identification of patients with advanced fibrosis among at-risk individuals is an important issue in clinical practice. Transient elastography is the best evaluated non-invasive method used in referral centres to assess liver fibrosis, however serum-based tests, such as the Enhanced Liver Fibrosis (ELF) score, have a practical advantage as first-line tests due to their wider availability and lower cost. We previously identified matrix metalloproteinase 7 (MMP7) as a serum biomarker of histological advanced fibrosis in a mixed-etiology patient cohort. In this study we aimed to determine the association between MMP7 and fibrosis, assessed by transient elastography, in patients with NAFLD. Serum MMP7 levels were measured in a cohort of 228 patients with NAFLD. Associations between MMP7, liver stiffness measurement (LSM), ELF score and clinical parameters were determined using logistic regression modelling. Serum MMP7 was associated with clinically significant fibrosis (LSM ≥ 8.2), independent of age, gender, BMI and diabetes. The addition of MMP7 significantly improved the diagnostic performance of the ELF test, particularly in patients over the age of 60. Combinations of serum biomarkers have the potential to improve the sensitivity and specificity of detection of advanced fibrosis in at-risk patients with NAFLD. We have demonstrated that serum MMP7 is independently associated with clinically significant fibrosis and improves the diagnostic performance of currently available tests in older patients. [ABSTRACT FROM AUTHOR]

People with chronic disease often have poor comprehension of their disease and medications, which can negatively affect health outcomes. In a randomised‐controlled trial, we found that patients with decompensated cirrhosis who received a pharmacist‐led, patient‐oriented education and medication management intervention (n = 57) had greater knowledge of cirrhosis and key self‐care tasks compared with usual care (n = 59). Intervention patients also experienced improved quality of life. Dedicated resources are needed to support implementation of evidence‐based measures at local centres to improve outcomes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: We report the development and psychometric testing of a Supportive Needs Assessment tool for Cirrhosis (SNAC). Methods: The 50-item SNAC was administered to patients (n=465) diagnosed with cirrhosis recruited from five metropolitan hospitals in Queensland, Australia. Items were assessed for ceiling and floor effects, and exploratory factor analysis was used to assess the factor structure. Identified factors were assessed for internal consistency and convergent validity to validated psychosocial tools. Results: Exploratory factor analysis identified 4 factors (39 items), which together accounted for 49.2% of the total variance. The 39-item SNAC met the requirements of a needs assessment tool and identified a range of needs important to patients with cirrhosis that were grouped in four subscales: "Psychosocial issues", "Practical and physical needs", "Information needs", and "Lifestyle changes". Cronbach's alpha values for the four subscales ranged from 0.64 to 0.92. Convergent validity was supported by a strong correlation between the total SNAC score and that of the Chronic Liver Disease Questionnaire (CLDQ; Spearman rho − 0.68; p< 0.001), and moderate correlations with the Distress Thermometer (Spearman rho 0.53; p< 0.001) and seven subscales of a generic health-related quality of life instrument (Short Form 36; Spearman rho ranged from − 0.48 to − 0.57; p< 0.001). The SNAC discriminated patient groups with respect to sex (p=0.013), age group (p< 0.001), and hospital admission status (admitted vs not; p< 0.001). Conclusion: These data provide initial evidence for the validity and reliability of the SNAC, an instrument designed to measure type and amount of perceived unmet practical and psychological needs of people diagnosed with cirrhosis. [ABSTRACT FROM AUTHOR]

Background: Indigenous Australians experience greater health disadvantage and have a higher prevalence of many chronic health conditions. Liver diseases leading to cirrhosis are among the most common contributor to the mortality gap between Indigenous and other Australian adults. However, no comparative data exist assessing differences in presentation and patient outcomes between Indigenous and non-Indigenous Australians hospitalised with cirrhosis. Methods: Using data from the Hospital Admitted Patient Data Collection and the Death Registry, this retrospective, population-based, cohort study including all people hospitalised for cirrhosis in the state of Queensland during 2008–2017 examined rate of readmission (Poisson regression), cumulative survival (Kaplan–Meier), and assessed the differences in survival (Multivariable Cox regression) by Indigenous status. Predictor variables included demographic, health service characteristics and clinical data. Results: We studied 779 Indigenous and 10,642 non-Indigenous patients with cirrhosis. A higher proportion of Indigenous patients were younger than 50 years (346 [44%] vs. 2063 [19%] non-Indigenous patients), lived in most disadvantaged areas (395 [51%) vs. 2728 [26%]), had alcohol-related cirrhosis (547 [70%] vs. 5041 [47%]), had ascites (314 [40%] vs. 3555 [33%), and presented to hospital via the Emergency Department (510 [68%] vs. 4790 [47%]). Indigenous patients had 3.04 times the rate of non-cirrhosis readmissions (95%CI 2.98–3.10), 1.35 times the rate of cirrhosis-related readmissions (95%CI 1.29–1.41), and lower overall survival (17% vs. 27%; unadjusted hazard ratio (HR) = 1.16 95%CI 1.06–1.27), compared to non-Indigenous patients. Most of the survival deficit was explained by Emergency Department presentation (adj-HR = 1.03 95%CI 0.93–1.13), and alcohol-related aetiology (adj-HR = 1.08 95%CI 0.99–1.19). The remaining survival deficit was influenced by the other clinico-demographic and health service factors (final adj-HR = 1.08 95%CI 0.96–1.20). Conclusions: There was evidence of differential presentation, higher rates of readmissions, and poorer survival for Indigenous Australians with cirrhosis, compared to other Australians. The increased prevalence of Emergency Department presentation among Indigenous patients suggests missed opportunities for early intervention to prevent progressive cirrhosis complications and hospital readmissions. [ABSTRACT FROM AUTHOR]

Background and Purpose: Chronic liver diseases feature excessive collagen and matrix protein deposition or crosslinking that characterises fibrosis, leads to scar tissue, and disrupts liver functions. There is no effective treatment. This study investigated whether treatment with selective histone deacetylase (HDAC) inhibitors might specifically reduce type 2 inflammation in the injured liver, thereby attenuating fibrogenesis in mice.Experimental Approach: Thioacetamide (TAA) was used to induce hepatic inflammation, fibrosis, and liver damage in female C57BL/6 mice, similar to the clinical features of chronic human liver disease. We used eight inhibitors of different human HDAC enzymes to probe histological (IHC and TUNEL), biochemical and immunological changes (flow cytometry, qPCR, Legendplex, and ELISA) in pathology, fibrosis, hepatic immune cell flux, and inflammatory cytokine expression.Key Results: Inhibitors of class I, but not class II, HDAC enzymes potently suppressed chronic hepatic inflammation and fibrosis in mice, attenuating accumulation and activation of IL-33-dependent, but not IL-25-dependent, group 2 innate lymphoid cells (ILC2) and inhibiting type 2 inflammation that drives hepatic stellate cells to secrete excessive collagen and matrix proteins.Conclusions and Implications: The results show that potent and selective inhibitors of class I only HDAC enzymes profoundly inhibit hepatocyte death and type 2 inflammation to prevent TAA-induced liver fibrosis in mice. The specific HDAC enzymes identified here may be key promoters of inflammation in chronic liver fibrosis. [ABSTRACT FROM AUTHOR]

Abstract: Background: Non‐alcoholic fatty liver disease (NAFLD) is a common cause of incidental liver test abnormalities. General practitioners (GP) have a key role in identifying people with NAFLD at risk of significant liver disease. Recent specialist guidelines emphasise the use of fibrosis algorithms or serum biomarkers rather than routine liver tests, to assess advanced fibrosis. Aim: To evaluate primary care clinicians’ current approach to diagnosis, management and referral of NAFLD. Methods: A cross‐sectional survey of primary care clinicians was undertaken through a structured questionnaire about NAFLD. A convenience sample of general practice clinics and general practice conferences in Metropolitan Brisbane and regional south east Queensland was selected. Results: A total of 108 primary care clinicians completed the survey (participation rate 100%). Fifty‐one percent of respondents considered the prevalence of NAFLD in the general population to be ≤10%. Twenty‐four percent of respondents felt that liver enzymes were sufficiently sensitive to detect underlying NAFLD. Most respondents were unsure whether the Fibrosis 4 score (62.7% unsure) or Enhanced Liver Fibrosis score (63.7% unsure) could help to identify advanced fibrosis or cirrhosis. Although 47% of respondents said they would refer a patient to a Gastroenterologist/Hepatologist if they suspect the patient has NAFLD, 44.1% do not make any referrals. Of concern, 70.6% of clinicians said they were unlikely to refer a patient to Hepatology unless liver function tests are abnormal. Conclusion: Our findings demonstrate that many primary care clinicians underestimate the prevalence of NAFLD and under‐recognise the clinical spectrum of NAFLD and how this is assessed. [ABSTRACT FROM AUTHOR]

Many patients with chronic disease do not possess the knowledge and skills required to access and interpret appropriate health information. A pilot study in people with liver cirrhosis ( n = 50) identified that only 54% of patients could recall being given written information by a clinician and 64% had self-sought information, most commonly using the Internet. Many patients reported difficulties understanding the material and the majority wanted more accessible information. A pilot chronic disease educational booklet was well received by the study participants with 85% reporting it was helpful and 78% using it in between clinic appointments. [ABSTRACT FROM AUTHOR]

Background: People with decompensated cirrhosis require complex medical care and are often prescribed an intricate and frequently changing medication and lifestyle regimen. However, many patients mismanage their medications or have poor comprehension of their disease and self-management tasks. This can lead to harm, hospitalization, and death.Methods/design: A patient-oriented education and medication management intervention has been developed for implementation at a tertiary hospital hepatology outpatient center in Queensland, Australia. Consenting patients with decompensated cirrhosis will be randomly allocated to education intervention or usual care treatment arms when they attend routine follow-up appointments. In the usual care arm, participants will be reviewed by their hepatologist according to the current model of care in the hepatology clinic. In the intervention arm, participants will be reviewed by a clinical pharmacist to receive the education and medication management intervention at baseline in addition to review by their hepatologist. Intervention participants will also receive three further educational contacts from the clinical pharmacist within the following 6-month period, in addition to routine hepatologist review that is scheduled within this time frame. All participants will be surveyed at baseline and follow-up (approximately 6 months post-enrollment). Validated questionnaire tools will be used to determine participant adherence, medication beliefs, illness perceptions, and quality of life. Patients' knowledge of dietary and lifestyle modifications, their current medications, and other clinical data will be obtained from the survey, patient interview, and medical records. Patient outcome data will be collected at 52 weeks.Discussion: The intervention described within this protocol is ready to adapt and implement in hepatology ambulatory care centers globally. Investigation of potentially modifiable variables that may impact medication management, in addition to the effect of a clinical pharmacist-driven education and medication management intervention on modifying these variables, will provide valuable information for future management of these patients.Trial Registration: Australian and New Zealand Clinical Trial Registry identifier: ACTRN12616000780459 . Registered on 15 June 2016. [ABSTRACT FROM AUTHOR]

Background. Many people with chronic liver disease (CLD) are not detected until they present to hospital with advanced disease, when opportunities for intervention are reduced and morbidity is high. In order to build capacity and liver expertise in the community, it is important to focus liver healthcare resources in high-prevalence disease areas and specific populations with an identified need. The aim of the present study was to examine the geographic location of people seen in a tertiary hospital hepatology clinic, as well as ethnic and sociodemographic characteristics of these geographic areas. Methods. The geographic locations of hepatology out-patients were identified via the out-patient scheduling database and grouped into statistical area (SA) regions for demographic analysis using data compiled by the Australian Bureau of Statistics. Results. During the 3-month study period, 943 individuals from 71 SA Level 3 regions attended clinic. Nine SA Level 3 regions accounted for 55% of the entire patient cohort. Geographic clustering was seen especially for people living with chronic hepatitis B virus. There was a wide spectrum of socioeconomic advantage and disadvantage in areas with high liver disease prevalence. Conclusions. The geographic area from which people living with CLD travel to access liver health care is extensive. However, the greatest demand for tertiary liver disease speciality care is clustered within specific geographic areas. Outreach programs targeted to these areas may enhance liver disease-specific health service resourcing. [ABSTRACT FROM AUTHOR]

Background and Aims: Non-invasive markers of liver fibrosis are urgently required, especially for use in non-specialist settings. The aim of this study was to identify novel serum biomarkers of advanced fibrosis. Methods: We performed an unbiased screen of 120 serum analytes including cytokines, chemokines and proteases in 70 patients (35 without fibrosis, 35 with cirrhosis on biopsy), and selected a panel of 44 candidate biomarkers, which were subsequently measured in a mixed-etiology cohort of 432 patients with known serum HA, PIIINP and TIMP1 (which comprise the validated Enhanced Liver Fibrosis (ELF) test). Multivariate logistic regression modelling was used to generate models for the prediction of advanced or significant fibrosis (METAVIR ≥F3 and ≥F2, respectively); in addition to identifying biomarkers of disease activity and steatohepatitis. Results: Seventeen analytes were significantly differentially expressed between patients with no advanced fibrosis and patients with advanced fibrosis, the most significant being hyaluronic acid (HA) and matrix metalloproteinase (MMP) 7 (p = 2.9E-41 and p = 1.0E-26, respectively). The optimal model for the prediction of advanced fibrosis comprised HA, MMP7, MMP1, alphafetoprotein (AFP) and the AST to platelet ratio index (APRI). We demonstrate enhanced diagnostic accuracy (AUROC = 0.938) compared to a model comprising HA, PIIINP and TIMP1 alone (ELF) (AUROC = 0.898, p<0.0001, De Long’s test). Conclusions: We have identified novel serum biomarkers of advanced liver fibrosis, which have the potential to enhance the diagnostic accuracy of established biomarkers. Our data suggest MMP7 is a valuable indicator of advanced fibrosis and may play a role in liver fibrogenesis. [ABSTRACT FROM AUTHOR]

Background: Cirrhosis patients are prescribed multiple medications for their liver disease and comorbidities. Discrepancies between medicines consumed by patients and those documented in the medical record may contribute to patient harm and impair disease management. The aim of the present study was to assess the magnitude and types of discrepancies among patient-reported and medical record-documented medications in patients with cirrhosis, and examine factors associated with such discrepancies.Methods: Fifty patients who attended a hospital hepatology outpatient clinic were interviewed using a questionnaire composed of mixed short-response and multiple-choice questions. Patients' reported medication use was compared with documentation in the hospital medical records and pharmacy database. Medication adherence was assessed using the 8-question ©Morisky Medication Adherence Scale (MMAS-8). The multivariate logistic regression model was constructed using clinically relevant and/or statistically significant variables as determined by univariate analysis. All p-values were 2-sided (α = 0.05).Results: Twenty-seven patients (54.0 %) had ≥1 discrepancy between reported and documented medicines. Patients with ≥1 discrepancy were older (p = 0.04) and multivariate analysis identified taking ≥5 conventional medicines or having a 'low' or 'medium' adherence ranking as independent predictors of discrepancy (adjusted OR 11.0 (95 % CI 1.8-67.4), 20.7 (95 % CI 1.3-337.7) and 49.0 (95 % CI 3.3-718.5) respectively). Concordance was highest for liver disease medicines (71.9 %) and lowest for complementary and alternative medicines (14.5 %) and respiratory medicines (0 %).Conclusion: There is significant discrepancy between sources of patient medication information within the hepatology clinic. Medication reconciliation and medicines-management intervention may address the complex relationship between medication discrepancies, number of medications and patient adherence identified in this study. [ABSTRACT FROM AUTHOR]

Background and Aims: Liver and systemic inflammatory factors influence monocyte phenotype and function, which has implications for hepatic recruitment and subsequent inflammatory and fibrogenic responses, as well as host defence. Methods: Peripheral blood monocyte surface marker (CD14, CD16, CD163, CSF1R, CCR2, CCR4, CCR5, CXCR3, CXCR4, CX3CR1, HLA-DR, CD62L, SIGLEC-1) expression and capacity for phagocytosis, oxidative burst and LPS-stimulated TNF production were assessed in patients with hepatitis C (HCV) (n = 39) or non-alcoholic fatty liver disease (NAFLD) (n = 34) (classified as non-advanced disease, compensated cirrhosis and decompensated cirrhosis) and healthy controls (n = 11) by flow cytometry. Results: The selected markers exhibited similar monocyte-subset-specific expression patterns between patients and controls. Monocyte phenotypic signatures differed between NAFLD and HCV patients, with an increased proportion of CD16+ non-classical monocytes in NAFLD, but increased expression of CXCR3 and CXCR4 in HCV. In both cohorts, monocyte CCR2 expression was reduced and CCR4 elevated over controls. CD62L expression was specifically elevated in patients with decompensated cirrhosis and positively correlated with the model-for-end-stage-liver-disease score. Functionally, monocytes from patients with decompensated cirrhosis had equal phagocytic capacity, but displayed features of dysfunction, characterised by lower HLA-DR expression and blunted oxidative responses. Lower monocyte TNF production in response to LPS stimulation correlated with time to death in 7 (46%) of the decompensated patients who died within 8 months of recruitment. Conclusions: Chronic HCV and NAFLD differentially affect circulating monocyte phenotype, suggesting specific injury-induced signals may contribute to hepatic monocyte recruitment and systemic activation state. Monocyte function, however, was similarly impaired in patients with both HCV and NAFLD, particularly in advanced disease, which likely contributes to the increased susceptibility to infection in these patients. [ABSTRACT FROM AUTHOR]

Background and Aims Current tools for risk stratification of chronic liver disease subjects are limited. We aimed to determine whether the serum-based ELF (Enhanced Liver Fibrosis) test predicted liver-related clinical outcomes, or progression to advanced liver disease, and to compare the performance of ELF to liver biopsy and non-invasive algorithms. Methods Three hundred patients with ELF scores assayed at the time of liver biopsy were followed up (median 6.1 years) for liver-related clinical outcomes ( n = 16) and clear evidence of progression to advanced fibrosis ( n = 18), by review of medical records and clinical data. Results Fourteen of 73 (19.2%) patients with ELF score indicative of advanced fibrosis (≥9.8, the manufacturer's cut-off) had a liver-related clinical outcome, compared to only two of 227 (<1%) patients with ELF score <9.8. In contrast, the simple scores APRI and FIB-4 would only have predicted subsequent decompensation in six and four patients respectively. A unit increase in ELF score was associated with a 2.53-fold increased risk of a liver-related event (adjusted for age and stage of fibrosis). In patients without advanced fibrosis on biopsy at recruitment, 55% (10/18) with an ELF score ≥9.8 showed clear evidence of progression to advanced fibrosis (after an average 6 years), whereas only 3.5% of those with an ELF score <9.8 (8/207) progressed (average 14 years). In these subjects, a unit increase in ELF score was associated with a 4.34-fold increased risk of progression. Conclusions The ELF score is a valuable tool for risk stratification of patients with chronic liver disease. [ABSTRACT FROM AUTHOR]

Background: Macrophages play critical roles in liver regeneration, fibrosis development and resolution. They are among the first responders to liver injury and are implicated in orchestrating the fibrogenic response via multiple mechanisms. Macrophages are also intimately associated with the activated hepatic progenitor cell (HPC) niche or ductular reaction that develops in parallel with fibrosis. Among the many macrophage-derived mediators implicated in liver disease progression, a key role for macrophage-derived Wnt proteins in driving pro-regenerative HPC activation towards a hepatocellular fate has been suggested. Wnt proteins, in general, however, have been associated with both pro- and anti-fibrogenic activities in the liver and other organs. We investigated the role of macrophage-derived Wnt proteins in fibrogenesis and HPC activation in murine models of chronic liver disease by conditionally deleting Wntless expression, which encodes a chaperone essential for Wnt protein secretion, in LysM-Cre-expressing myeloid cells (LysM-Wls mice). Results: Fibrosis and HPC activation were exacerbated in LysM-Wls mice compared to littermate controls, in the absence of an apparent increase in myofibroblast activation or interstitial collagen mRNA expression, in both the TAA and CDE models of chronic liver disease. Increased Epcam mRNA levels paralleled the increased HPC activation and more mature ductular reactions, in LysM-Wls mice. Increased Epcam expression in LysM-Wls HPC was also observed, consistent with a more cholangiocytic phenotype. No differences in the mRNA expression levels of key pro-inflammatory and pro-fibrotic cytokines or the macrophage-derived HPC mitogen, Tweak, were observed. LysM-Wls mice exhibited increased expression of Timp1, encoding the key Mmp inhibitor Timp1 that blocks interstitial collagen degradation, and, in the TAA model, reduced expression of the anti-fibrotic matrix metalloproteinases, Mmp12 and Mmp13, suggesting a role for macrophage-derived Wnt proteins in restraining fibrogenesis during ongoing liver injury. Conclusion: In summary, these data suggest that macrophage-derived Wnt proteins possess anti-fibrogenic potential in chronic liver disease, which may be able to be manipulated for therapeutic benefit. [ABSTRACT FROM AUTHOR]

Background & Aims There is increasing need to identify individuals with advanced liver fibrosis, who are at risk of complications such as hepatocellular carcinoma. The commercially available enhanced liver fibrosis ( ELF) test provides a non-invasive assessment of fibrosis severity. This study was designed to determine the diagnostic accuracy of the manufacturer's cut-off value (≥9.8) in identifying advanced fibrosis. Methods The relationship between ELF score and fibrosis was examined using serum collected at time of liver biopsy for investigation of liver disease, particularly viral hepatitis. Fibrosis was staged using a modified METAVIR score. If available, liver tissue was recut and stained with Sirius red to determine collagen proportional area ( CPA) and subsinusoidal fibrosis ( SSF). Results Enhanced liver fibrosis score ≥9.8 had a sensitivity of 74.4% and specificity 92.4% for detecting advanced fibrosis. In the whole cohort ( n = 329), ELF score was more likely to incorrectly classify individuals if age was ≥45 years and METAVIR inflammatory grade was 2 or 3 (adjusted OR, odds ratio 3.71 and 2.62 respectively). In contrast, ELF score was less likely to misclassify individuals in the presence of steatosis ( OR 0.37). Neither SSF nor CPA explained the discordance in ELF score for patients with or without advanced fibrosis. Conclusion Although ELF score ≥9.8 reliably identifies advanced fibrosis in patients with chronic liver disease, both age and inflammatory activity need to be considered when interpreting the result. Importantly, ELF score performed well in the presence of steatosis and could thus be helpful in the assessment of fatty liver disease. [ABSTRACT FROM AUTHOR]

Bacterial infections, most commonly spontaneous bacterial peritonitis in patients with ascites, occur in one third of admitted patients with cirrhosis, and account for a 4-fold increase in mortality. Bacteria are isolated from less than 40% of ascites infections by culture, necessitating empirical antibiotic treatment, but culture-independent studies suggest bacteria are commonly present, even in the absence of overt infection. Widespread detection of low levels of bacteria in ascites, in the absence of peritonitis, suggests immune impairment may contribute to higher susceptibility to infection in cirrhotic patients. However, little is known about the role of ascites leukocyte composition and function in this context. We determined ascites bacterial composition by quantitative PCR and 16S rRNA gene sequencing in 25 patients with culture-negative, non-neutrocytic ascites, and compared microbiological data with ascites and peripheral blood leukocyte composition and phenotype. Bacterial DNA was detected in ascitic fluid from 23 of 25 patients, with significant positive correlations between bacterial DNA levels and poor 6-month clinical outcomes (death, readmission). Ascites leukocyte composition was variable, but dominated by macrophages or T lymphocytes, with lower numbers of B lymphocytes and natural killer cells. Consistent with the hypothesis that impaired innate immunity contributes to susceptibility to infection, high bacterial DNA burden was associated with reduced major histocompatibility complex class II expression on ascites (but not peripheral blood) monocytes/macrophages. These data indicate an association between the presence of ascites bacterial DNA and early death and readmission in patients with decompensated cirrhosis. They further suggest that impairment of innate immunity contributes to increased bacterial translocation, risk of peritonitis, or both. [ABSTRACT FROM AUTHOR]

Background and Aim Carbohydrate deficient transferrin (CDT) is the most specific serum biomarker of heavy alcohol consumption, defined as ⩾350-420g alcohol/week. Despite introduction of a standardized reference measurement technique, widespread use of CDT remains limited due to low sensitivity. The aim of this study was to determine the factors that affect diagnostic sensitivity in patients with sustained heavy alcohol intake. Methods Patients with a self-reported history of sustained heavy alcohol consumption were recruited from the hepatology outpatient department or medical wards. Each patient was interviewed with a validated structured questionnaire of alcohol consumption and CDT analysis using the standardized reference measurement technique with high performance liquid chromatography was performed on serum collected at time of interview. Results 52 patients were recruited: 19 from the hepatology outpatient department and 33 from general medical wards. Median alcohol intake was 1013 (range 366-5880) g/week over the preceding two week period. 26 patients had a diagnostic CDT based on a threshold value of %CDT >1.7 indicating heavy alcohol consumption, yielding a sensitivity of 50%. Overweight/obesity (defined as body mass index (BMI) ⩾25 kg/m2 in Caucasians and ⩾23.0 kg/m2 in Asians), female gender and presence of cirrhosis were independently associated with non-diagnostic %CDT (⩽1.7). Conclusions CDT has limited sensitivity as a biomarker of heavy alcohol consumption. Caution should be applied when ordering and interpreting %CDT results, particularly in women, patients with cirrhosis and those with an elevated BMI. [ABSTRACT FROM AUTHOR]

Background A reliable biomarker is required in hepatology clinics for detection and follow-up of heavy alcohol consumption. Carbohydrate-deficient transferrin ( CDT) increases with sustained heavy alcohol consumption and is the most specific biomarker of ethanol ( Et OH) consumption. Recent introduction of a standardized method for measuring CDT has improved its clinical application. This study was designed to determine whether alcohol-independent factors influence CDT levels in patients with chronic liver disease ( CLD). Methods The relationship between serum % CDT and self-reported history of alcohol consumption was examined in 254 patients referred for evaluation of liver disease. CDT analysis was performed on serum collected at time of liver biopsy. Results CDT levels were not affected by severity or etiology of nonalcoholic liver disease. Thirteen of 254 subjects had a % CDT >1.7, predictive of heavy alcohol intake, 6 of whom did not acknowledge heavy drinking. Twelve of these 13 subjects were suspected heavy drinkers on review of their medical records and clinical results. Conversely, not all acknowledged heavy drinkers had % CDT >1.7. Heavy drinkers with a body mass index (BMI) in the overweight or obese range had significantly lower % CDT than lean heavy drinkers. This persisted even when lean body weight was used as an approximation of the Et OH volume of distribution. Conclusions An elevated BMI reduces the diagnostic utility of CDT at higher alcohol intake in subjects with CLD using the standardized method. In a hepatology outpatient setting, this assay is likely to be useful to confirm suspicion of heavy drinking in subjects who are not overweight, but cannot reliably identify moderate drinkers or heavy drinkers who are overweight. [ABSTRACT FROM AUTHOR]

Discrepancies between the medicines consumed by patients and those documented in the medical record can affect medication safety. We aimed to characterize medication discrepancies and medication regimen complexity over time in a cohort of outpatients with decompensated cirrhosis, and evaluate the impact of pharmacist-led intervention on discrepancies and patient outcomes. In a randomized-controlled trial (n = 57 intervention and n = 57 usual care participants), medication reconciliation and patient-oriented education delivered over a six-month period was associated with a 45% reduction in the incidence rate of 'high' risk discrepancies (IRR = 0.55, 95%CI = 0.31–0.96) compared to usual care. For each additional 'high' risk discrepancy at baseline, the odds of having ≥ 1 unplanned medication-related admission during a 12-month follow-up period increased by 25% (adj-OR = 1.25, 95%CI = 0.97–1.63) independently of the Child–Pugh score and a history of variceal bleeding. Among participants with complete follow-up, intervention patients were 3-fold less likely to have an unplanned medication-related admission (adj-OR = 0.27, 95%CI = 0.07–0.97) compared to usual care. There was no association between medication discrepancies and mortality. Medication regimen complexity, frequent changes to the regimen and hepatic encephalopathy were associated with discrepancies. Medication reconciliation may improve medication safety by facilitating communication between patients and clinicians about 'current' therapies and identifying potentially inappropriate medicines that may lead to harm. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Liver macrophages are a heterogeneous cell population that produces factors involved in fibrogenesis and matrix turnover, including matrix metalloproteinase ( MMP) -9. During liver injury, their close proximity to hepatic progenitor cells and the ductular reaction may enable them to regulate liver repair and fibrosis. Aims To enumerate and characterise liver macrophages in patients with chronic hepatitis C, to determine whether a distinct population of macrophages is associated with the ductular reaction and portal fibrosis. Methods Immunostaining for macrophage markers ( CD68, CD163, CCR2), the ductular reaction (keratin-7) and MMP-9 was performed in liver biopsy sections from patients with chronic hepatitis C virus ( HCV) ( n = 85). Results Portal tracts were more densely populated with macrophages (10.5 ± 0.36 macrophages/HPF) than lobules (7.2 ± 0.16 macrophages/HPF, P < 0.001) and macrophages were found in close proximity to the ductular reaction. ≥30% of portal and periductal macrophages expressed MMP-9 and these were significantly associated with increasing stage of fibrosis ( rs = 0.58, 0.68, respectively, both P < 0.001). In contrast, MMP-9+ macrophages were largely absent in lobular regions and non-diseased liver. Hepatic MMP-9 mRNA levels and gelatinolytic activity were significantly associated with stage of fibrosis ( r s = 0.47, r s = 0.89, respectively, both P < 0.001). Furthermore, a second distinct CCR2+ macrophage population was localised to the centrilobular regions and was predominantly absent from portal and periductal areas. Conclusions These findings demonstrate significant regional differences in macrophage phenotypes, suggesting that there are at least two populations of liver macrophages. We propose that these populations have distinct contributions to the pathogenesis of chronic HCV-related liver disease. [ABSTRACT FROM AUTHOR]

Background/Aims: Currently the diagnosis and severity of hepatic steatosis can be established accurately only by liver biopsy. Previous small studies found that steatosis measured by magnetic resonance spectroscopy (MRS) and imaging (MRI) correlated with histological assessment of liver triglyceride content. However, the accuracy of MRS/MRI for grading the severity of steatosis has not been addressed. The aims of this study were (1) to determine whether MRS and MRI can discriminate grades of steatosis in a large cohort of consecutive patients with a wide spectrum of liver disease aetiology and severity (2) to evaluate the effect of hepatic fibrosis, inflammation and iron on quantitation of intrahepatocellular lipid (IHCL) by these techniques. Methods: Ninety-four sequential patients who underwent percutaneous liver biopsy or liver resection had MRS and MRI (Dixon in phase/out of phase (Dixon IP/OP) and with/without fat saturation (±FS) images) to determine IHCL. Histology was used as the reference standard. Results: Close relationships were observed between the percentage of steatosis estimated by histology and MRS/MRI (r s =0.88 p <0.001 for all techniques). However, separate equations were required for the percentage of steatosis to avoid underestimation by imaging for patients with moderate or advanced fibrosis. All techniques had good diagnostic accuracy for mild steatosis (AUROC⩾0.87) as well as moderate/severe steatosis (AUROC⩾0.89). Hepatic inflammation and mild iron deposition (Perls’ grade 1 and 2) did not interfere with estimation of steatosis by imaging. Conclusions: MRS and MRI had good accuracy for grading the severity of steatosis in subjects with liver disease, provided that stage of fibrosis was considered. [Copyright &y& Elsevier]

Background/Aims: Increased expression of sterol regulatory element binding protein (SREBP)-1c, a transcription factor regulating lipogenesis, has been reported in HCV core protein-transfected hepatocytes. Our aim was to investigate the role of SREBP-1c in the pathogenesis of HCV-related steatosis. Methods: One hundred and twenty-four patients with HCV and 13 subjects with histologically normal liver (NDL) were studied. The mRNA expression of SREBP-1c, fatty acid synthase (FAS), glycerol-3-phosphate acyltransferase (GPAT) and microsomal triglyceride transfer protein (MTP) was measured by qPCR, and SREBP-1 protein quantitated by immunohistochemistry. Results: There was no significant difference in the hepatic expression of SREBP-1c mRNA between subjects with HCV and NDL. In patients with HCV, a significant negative relationship was seen between hepatic SREBP-1c mRNA expression and grade of steatosis (r s =−0.28, p =0.002), stage of fibrosis (r s =−0.375, p <0.001) and severity of inflammation (r s =−0.313, p <0.001). These relationships were observed for patients infected with either viral genotype 1 or 3. Following multivariate logistic regression analysis, hepatic SREBP-1c expression remained independently associated with fibrosis (p =0.008) and hepatic inflammation (p =0.005). HCV-infected patients with HOMA>2 had significantly higher expression of FAS mRNA than HCV-infected subjects with HOMA⩽2 (p =0.006) and NDL (p =0.016). Conclusions: SREBP-1c may not play a prominent role in the pathogenesis of HCV-related steatosis. [Copyright &y& Elsevier]