Search

Patricia C Valery,1,2 Christina M Bernardes,1 Katherine A Stuart,3 Gunter F Hartel,1 Steven M McPhail,4 Richard Skoien,5 Tony Rahman,6 Paul J Clark,7 Leigh U Horsfall,2,3 Kelly L Hayward,2 Rohit Gupta,8 Elizabeth E Powell2,3 1QIMR Berghofer Medical Research Institute, Herston, QLD, Australia; 2Centre for Liver Disease Research, Translational Research Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia; 3Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, QLD, Australia; 4Centre for Functioning and Health Research, Queensland Health and the School of Public Health and Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia; 5Department of Gastroenterology, Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia; 6Gastroenterology & Hepatology Department, The Prince Charles Hospital, Chermside, QLD, Australia; 7Department of Gastroenterology and Hepatology, Mater Hospitals, Brisbane, QLD, Australia; 8Department of Gastroenterology and Hepatology, Sunshine Coast University Hospital, Birtinya, QLD, AustraliaCorrespondence: Patricia C ValeryQIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD 4006, AustraliaTel +61 7 33620376Email Patricia.Valery@qimrberghofer.edu.auBackground: 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.Keywords: chronic liver disease, perceived needs, instrument validation, psychometric properties

Background: Non-alcoholic fatty liver disease (NAFLD) is caused by ectopic fat accumulation in the liver as a consequence of metabolic perturbations associated with obesity, type 2 diabetes, dyslipidemia, and insulin resistance. People with NAFLD may develop metabolic and cardiovascular complications and/or liver-related complications, especially fibrosis and hepatocellular carcinoma, associated with high morbidity and mortality. Due to the high and increasing prevalence of NAFLD, there is an urgent need to identify people at risk of developing liver fibrosis and complications. CC-chemokine ligand 2 (CCL2) is chemokine that attracts inflammatory monocytes to stressed or injured tissues. Infiltrating inflammatory monocytes and CCL2 are strongly implicated in the pathogenesis of liver disease in animal models; however, evidence in patient cohorts is conflicting., Methods: We investigated associations between circulating CCL2 and clinical parameters, including fibrosis assessed by liver stiffness measurement, in a cohort of 250 NAFLD patients. We also measured fatty acid binding protein 2 (FABP2), a putative biomarker of intestinal permeability in patients with liver disease, since pro-inflammatory gut-derived microbial products may induce inflammatory chemokines such as CCL2., Results: Serum CCL2 levels were weakly associated with liver stiffness, but the association was no longer significant after accounting for age, diabetes, and BMI in a multivariable model. Consistent with this, girth and BMI were the strongest predictors of elevated circulating CCL2. Serum FABP2 was weakly, but significantly, correlated with CCL2, and negatively correlated with estimated glomerular filtration rate., Conclusion: Circulating CCL2 and FABP2 are associated with NAFLD comorbidities but not liver disease progression in patients with NAFLD., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Background: 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., Aims: 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)., Methods: 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., Results: 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/m 2 . 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., Conclusion: 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., (© 2021 Royal Australasian College of Physicians.)

It remains unclear whether screening for advanced fibrosis in the community can identify the subgroup of people with nonalcoholic fatty liver disease (NAFLD) at higher risk for development of liver-related complications. We aimed to determine the prognostic value of baseline noninvasive fibrosis tests for predicting liver-related outcomes and mortality in patients with NAFLD from type 2 diabetes (T2D) clinics or primary care. Patients (n = 243) who were screened for NAFLD with advanced fibrosis by using NAFLD fibrosis score (NFS), fibrosis 4 score (FIB-4), enhanced liver fibrosis (ELF) test, and liver stiffness measurements (LSMs) were followed up for clinical outcomes by review of electronic medical records. During a median follow-up of 50 months, decompensated liver disease or primary liver cancer occurred in 6 of 35 (17.1%) patients with baseline LSM > 13 kPa, 1 of 17 (5.9%) patients with LSM 9.5-13 kPa, and in no patients with LSM < 9.5 kPa. No patient with low-risk NFS developed liver decompensation or liver-related mortality. Following repeat NFSs at the end of follow-up, all patients with a liver-related complication were in the high-risk NFS category. Patients who developed liver-related complications were also more likely to have baseline high-risk FIB-4 scores or ELF test ≥9.8 compared to patients who did not develop liver outcomes. Conclusion: Liver fibrosis risk stratification in non-hepatology settings can identify the subset of patients at risk of liver-related complications. Although the rate of development of a decompensation event or hepatocellular carcinoma was low (2.1% per year) in our patients with compensated cirrhosis (LSM > 13 kPa), these events are projected to lead to a substantial increase in NAFLD-related disease burden over the next decade due to the high prevalence of NAFLD in people with obesity and T2D., (© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

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.

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.

Objective: The prevalence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) cirrhosis is often underestimated in healthcare and administrative databases that define disease burden using International Classification of Diseases (ICD) codes. This retrospective audit was conducted to explore the accuracy and limitations of the ICD, Tenth Revision, Australian Modification (ICD-10-AM) to detect NAFLD, metabolic risk factors (obesity and diabetes) and other aetiologies of chronic liver disease., Design/method: ICD-10-AM codes in 308 admitted patient encounters at two major Australian tertiary hospitals were compared with data abstracted from patients' electronic medical records. Accuracy of individual codes and grouped combinations was determined by calculating sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and Cohen's kappa coefficient (κ)., Results: The presence of an ICD-10-AM code accurately predicted the presence of NAFLD/NASH (PPV 91.2%) and obesity (PPV 91.6%) in most instances. However, codes underestimated the prevalence of NAFLD/NASH and obesity by 42.9% and 45.3%, respectively. Overall concordance between clinical documentation and 'grouped alcohol' codes (κ 0.75) and hepatitis C codes (κ 0.88) was high. Hepatitis B codes detected false-positive cases in patients with previous exposure (PPV 55.6%). Accuracy of codes to detect diabetes was excellent (sensitivity 95.8%; specificity 97.6%; PPV 94.9%; NPV 98.1%) with almost perfect concordance between codes and documentation in medical records (κ 0.93)., Conclusion: Recognition of the utility and limitations of ICD-10-AM codes to study the burden of NAFLD/NASH cirrhosis is imperative to inform public health strategies and appropriate investment of resources to manage this burgeoning chronic disease., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© 2020 The Authors. Internal Medicine Journal by Wiley Publishing Asia Pty Ltd on behalf of Royal Australasian College of Physicians.)

Objective: The utility of International Classification of Diseases (ICD) codes relies on the accuracy of clinical reporting and administrative coding, which may be influenced by country-specific codes and coding rules. This study explores the accuracy and limitations of the Australian Modification of the 10th revision of ICD (ICD-10-AM) to detect the presence of cirrhosis and a subset of key complications for the purpose of future large-scale epidemiological research and healthcare studies., Design/method: ICD-10-AM codes in a random sample of 540 admitted patient encounters at a major Australian tertiary hospital were compared with data abstracted from patients' medical records by four blinded clinicians. Accuracy of individual codes and grouped combinations was determined by calculating sensitivity, positive predictive value (PPV), negative predictive value and Cohen's kappa coefficient (κ)., Results: The PPVs for 'grouped cirrhosis' codes (0.96), hepatocellular carcinoma (0.97) ascites (0.97) and 'grouped varices' (0.95) were good (κ all >0.60). However, codes under-detected the prevalence of cirrhosis, ascites and varices (sensitivity 81.4%, 61.9% and 61.3%, respectively). Overall accuracy was lower for spontaneous bacterial peritonitis ('grouped' PPV 0.75; κ 0.73) and the poorest for encephalopathy ('grouped' PPV 0.55; κ 0.21). To optimise detection of cirrhosis-related encounters, an ICD-10-AM code algorithm was constructed and validated in an independent cohort of 116 patients with known cirrhosis., Conclusion: Multiple ICD-10-AM codes should be considered when using administrative databases to study the burden of cirrhosis and its complications in Australia, to avoid underestimation of the prevalence, morbidity, mortality and related resource utilisation from this burgeoning chronic disease., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background & Aims: There is limited knowledge regarding the longitudinal utility of biomarkers of fibrosis, such as the nonalcoholic fatty liver disease (NAFLD) fibrosis score (NFS) or the fibrosis-4 score (FIB-4) score. We examined longitudinal changes in the NFS and the FIB-4 score in patients with NAFLD, with and without clinically significant fibrosis (CSF)., Methods: We performed a retrospective study of 230 patients with NAFLD, collecting clinical and laboratory records to calculate NFS and FIB-4 scores at 6 monthly intervals for 5 years before hepatology assessment of fibrosis. Linear mixed models with random intercept and slope and adjusted for age at baseline were used to assess the progression of NFS and log-transformed FIB-4 scores over time in subjects with and without CSF, determined by liver stiffness measurements of 8.2 kPa or greater., Results: Patients had a median of 11 (minimum, 10; maximum, 11) retrospective observations over a median time period of 5 years (minimum, 4.5 y; maximum, 5 y). Of patients with low baseline NFS and FIB-4 scores, 31.11% and 37.76%, respectively, had CSF at the time of hepatology assessment. There was a correlation between NFS and log 10 FIB-4 over time (repeated measure r = 0.55; 95% CI, 0.52-0.59). The rate of increase in NFS and log 10 FIB-4 was significantly higher in patients with than without CSF (both P < .001). Predicted NFS increased by 0.17 and 0.06 units per year in subjects with and without CSF, respectively. Predicted log 10 FIB-4 score increased by 0.032 and 0.0003 units per year in subjects with and without CSF, respectively., Conclusions: Noninvasively measured fibrosis scores increase progressively in patients with NAFLD and CSF. Further studies are needed to determine whether repeated measurements can identify patients at risk for CSF., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Primary care physicians (PCPs) have the primary role in the diagnosis and management of nonalcoholic fatty liver disease (NAFLD), and in selecting patients for referral to a hepatologist for further evaluation. This study aimed to characterize PCP referrals for patients diagnosed with NAFLD at a major referral hospital, and to determine the severity of liver disease and patient pathway following evaluation in secondary care. New patients seen in the hepatology outpatient clinic (HOC) with a secondary care diagnosis of NAFLD were identified from the HOC scheduling database. PCP referrals for these patients were retrieved from the electronic medical records and reviewed by study clinicians, along with the hepatologists' clinic notes and letters. Over a 14-month period, 234 new PCP referrals received a diagnosis of NAFLD, accounting for 20.4% of the total number of new cases (n = 1,147) seen in the HOC. The 234 referrals were received from 170 individual PCPs at 135 practices. Most patients with NAFLD (88.5%) were referred for investigation of abnormal liver enzymes or other clinical concerns, including abnormal iron studies, hepatomegaly, and abdominal pain. Only 27 (11.5%) referrals included an assessment of liver disease severity. Following evaluation in the liver clinic, 175 patients (74.8%) were found to have a low risk of advanced fibrosis, and most (n = 159; 90.9%) were discharged back to their PCP for ongoing follow-up in primary care. Conclusion: In addition to better access to noninvasive fibrosis tests, educational strategies to enhance awareness and recognition of NAFLD as a cause for many of the initial concerns prompting patient referral might improve risk stratification and increase the appropriateness of PCP referrals., (© 2020 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.)

People with decompensated cirrhosis are often prescribed a complex regimen of therapeutic and prophylactic medications. In other chronic diseases, polypharmacy increases the risk of medication misadventure and medication-related problems (MRPs), with associated increased morbidity, mortality, and health care costs. This study examined MRPs in a cohort of ambulatory patients with a history of decompensated cirrhosis who were enrolled in a randomized controlled trial of a pharmacist-led, patient-oriented medication education intervention and assessed the association between MRPs and patient outcomes. A total of 375 MRPs were identified among 57 intervention patients (median, 6.0; interquartile range, 3.5-8.0 per patient; maximum 17). Nonadherence (31.5%) and indication issues (29.1%) were the most prevalent MRP types. The risk of potential harm associated with MRPs was low in 18.9% of instances, medium in 33.1%, and high in 48.0%, as categorized by a clinician panel using a risk matrix tool. Patients had a greater incidence rate of high-risk MRPs if they had a higher Child-Pugh score (incidence rate ratio [IRR], 1.31; 95% confidence interval [CI], 1.09-1.56); greater comorbidity burden (IRR, 1.15; 95% CI, 1.02-1.29); and were taking more medications (IRR, 1.12; 95% CI, 1.04-1.22). A total of 221 MRPs (58.9%) were resolved following pharmacist intervention. A greater proportion of high-risk MRPs were resolved compared to those of low and medium risk (68.9% versus 49.7%; P  < 0.001). During the 12-month follow-up period, intervention patients had a lower incidence rate of unplanned admissions compared to usual care (IRR, 0.52; 95% CI, 0.30-0.92). Conclusion : High-risk MRPs are prevalent among adults with decompensated cirrhosis. Pharmacist intervention facilitated identification and resolution of high-risk MRPs and was associated with reduced incidence rate of unplanned hospital admissions in this group.

Noninvasive serum biomarkers (nonalcoholic fatty liver disease fibrosis score [NFS], fibrosis 4 score [FIB-4], or enhanced liver fibrosis [ELF] test) are recommended as first-line tools to determine the risk of advanced fibrosis in nonalcoholic fatty liver disease. We aimed to assess the utility of a pragmatic approach to screening for clinically significant fibrosis in primary care and diabetes clinics. We recruited 252 patients from an endocrine clinic or primary care facility. Anthropometric measurements, ELF test, ultrasound, and liver stiffness measurements (LSMs) were performed. Clinically significant fibrosis was defined as LSM ≥8.2 kPa or ELF ≥9.8. A subgroup of patients underwent liver biopsy (n = 48) or had imaging diagnostic of cirrhosis (n = 14). Patients were 57.3 ± 12.3 years old with a high prevalence of metabolic syndrome (84.5%), type 2 diabetes (82.5%), and body mass index (BMI) ≥40 kg/m 2 (21.8%). LSM met quality criteria in 230 (91.3%) patients. NFS and FIB-4 combined had a high negative predictive value (90.0%) for excluding LSM ≥8.2 kPa. However, 84.1% of patients had indeterminate or high NFS or FIB-4 scores requiring further assessment. LSM ≥8.2 kPa and ELF ≥9.8 were present in 31.3% and 28.6% of patients, respectively. Following adjustment for age, BMI, sex, and presence of advanced fibrosis, older age was independently associated with ELF ≥9.8 (adjusted odds ratio, 1.14; 95% confidence interval, 1.06-1.24), whereas increasing BMI was independently associated with LSM ≥8.2 kPa (adjusted odds ratio, 1.15; 95% confidence interval, 1.01-1.30). Concordant LSM <8.2 kPa and ELF <9.8 and concordant LSM ≥8.2 kPa and ELF ≥9.8 had a high negative predictive value (91.7%) and positive predictive value (95.8%) for excluding and identifying clinically significant fibrosis, respectively. Conclusion: Simple scoring tools alone lack accuracy. LSM accuracy is influenced by severe obesity, whereas age impacts the ELF test. Further studies are required to confirm whether combining LSM and ELF may enhance accuracy and confidence in identifying clinically significant fibrosis. ( Hepatology Communications 2018; 00:000-000).

Aims: To examine the relationship between steatosis quantified by controlled attenuation parameter (CAP) values and glycaemic/metabolic control., Methods: 230 patients, recruited from an Endocrine clinic or primary care underwent routine Hepatology assessment, with liver stiffness measurements and simultaneous CAP. Multivariable logistic regression was performed to identify potential predictors of Metabolic Syndrome (MetS), HbA1c ≥ 7%, use of insulin, hypertriglyceridaemia and CAP ≥ 300 dB/m., Results: Patients were 56.7 ± 12.3 years of age with a high prevalence of MetS (83.5%), T2DM (81.3%), and BMI ≥ 40 kg/m 2 (18%). Median CAP score was 344 dB/m, ranging from 128 to 400 dB/m. BMI (aOR 1.140 95% CI 1.068-1.216), requirement for insulin (aOR 2.599 95% CI 1.212-5.575), and serum ALT (aOR 1.018 95% CI 1.004-1.033) were independently associated with CAP ≥ 300 dB/m. Patients with CAP interquartile range < 40 (68%) had a higher median serum ALT level (p = 0.029), greater prevalence of BMI ≥ 40 kg/m 2 (p = 0.020) and higher median CAP score (p < 0.001). Patients with higher CAP scores were more likely to have MetS (aOR 1.011 95% CI 1.003-1.019), HBA1c ≥ 7 (aOR 1.010 95% CI 1.003-1.016), requirement for insulin (aOR 1.007 95% CI 1.002-1.013) and hypertriglyceridemia (aOR 1.007 95% CI 1.002-1.013)., Conclusions: Our data demonstrate that an elevated CAP reflects suboptimal metabolic control. In diabetic patients with NAFLD, CAP may be a useful point-of-care test to identify patients at risk of poorly controlled metabolic comorbidities or advanced diabetes., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Chronic liver disease (CLD) is associated with tissue-destructive fibrosis. Considering that common mechanisms drive fibrosis across etiologies, and that steatosis is an important cofactor for pathology, we performed RNA sequencing on liver biopsies of patients with different fibrosis stages, resulting from infection with hepatitis C virus (HCV) (with or without steatosis) or fatty liver disease. In combination with enhanced liver fibrosis score correlation analysis, we reveal a common set of genes associated with advanced fibrosis, as exemplified by those encoding the transcription factor ETS-homologous factor (EHF) and the extracellular matrix protein versican (VCAN). We identified 17 fibrosis-associated genes as candidate EHF targets and demonstrated that EHF regulates multiple fibrosis-associated genes, including VCAN, in hepatic stellate cells. Serum VCAN levels were also elevated in advanced fibrosis patients. Comparing biopsies from patients with HCV with or without steatosis, we identified a steatosis-enriched gene set associated with advanced fibrosis, validating follistatin-like protein 1 (FSTL1) as an exemplar of this profile. In patients with advanced fibrosis, serum FSTL1 levels were elevated in those with steatosis (versus those without). Liver Fstl1 mRNA levels were also elevated in murine CLD models. We thus reveal a common gene signature for CLD-associated liver fibrosis and potential biomarkers and/or targets for steatosis-associated liver fibrosis.

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., (© 2017 Royal Australasian College of Physicians.)

Aim: To investigate the impact of medication beliefs, illness perceptions and quality of life on medication adherence in people with decompensated cirrhosis., Methods: One hundred adults with decompensated cirrhosis completed a structured questionnaire when they attended for routine outpatient hepatology review. Measures of self-reported medication adherence (Morisky Medication Adherence Scale), beliefs surrounding medications (Beliefs about Medicines Questionnaire), perceptions of illness and medicines (Brief Illness Perception Questionnaire), and quality of life (Chronic Liver Disease Questionnaire) were examined. Clinical data were obtained via patient history and review of medical records. Least absolute shrinkage and selection operator and stepwise backwards regression techniques were used to construct the multivariable logistic regression model. Statistical significance was set at alpha = 0.05., Results: Medication adherence was "High" in 42% of participants, "Medium" in 37%, and "Low" in 21%. Compared to patients with "High" adherence, those with "Medium" or "Low" adherence were more likely to report difficulty affording their medications ( P < 0.001), lower perception of treatment helpfulness ( P = 0.003) and stronger medication concerns relative to medication necessity beliefs ( P = 0.003). People with "Low" adherence also experienced greater symptom burden and poorer quality of life, including more frequent abdominal pain ( P = 0.023), shortness of breath ( P = 0.030), and emotional disturbances ( P = 0.050). Multivariable analysis identified having stronger medication concerns relative to necessity beliefs (Necessity-Concerns Differential ≤ 5, OR = 3.66, 95%CI: 1.18-11.40) and more frequent shortness of breath (shortness of breath score ≤ 3, OR = 3.87, 95%CI: 1.22-12.25) as independent predictors of "Low"adherence., Conclusion: The association between "Low" adherence and patients having strong concerns or doubting the necessity or helpfulness of their medications should be explored further given the clinical relevance., Competing Interests: Conflict-of-interest statement: None.

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., (© 2017 Royal Australasian College of Physicians.)

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.

An observational study describing the number and type of chronic conditions and medications taken by diabetic patients with NAFLD and identifying characteristics that may impact liver disease severity or clinical management.Adults with type 2 diabetes have a high prevalence of nonalcoholic fatty liver disease (NAFLD) and increased risk of developing advanced liver disease. Appropriate management should consider the characteristics of the diabetic NAFLD population, as comorbid conditions and medications may increase the complexity of treatment strategies.Diabetic patients with NAFLD at risk of clinically significant liver disease (as assessed by the FIB-4 or NAFLD fibrosis scores) were recruited consecutively from the Endocrine clinic or primary care. Medical conditions, medication history, anthropometric measurements, and laboratory tests were obtained during assessment. NAFLD severity was classified by transient elastography and liver ultrasound into "no advanced disease" (LSM < 8.2 kPa) or "clinically significant liver disease" (LSM ≥ 8.2 kPa).The most common coexistent chronic conditions were metabolic syndrome (94%), self-reported "depression" (44%), ischaemic heart disease (32%), and obstructive sleep apnoea (32%). Polypharmacy or hyperpolypharmacy was present in 59% and 31% of patients respectively. Elevated LSM (≥ 8.2 kPa) suggesting significant liver disease was present in 37% of this at-risk cohort. Increasing obesity and abdominal girth were both independently associated with likelihood of having significant liver disease.There is a high burden of multimorbidity and polypharmacy in diabetic NAFLD patients, highlighting the importance of multidisciplinary management to address their complex health care needs and ensure optimal medical treatment.

Aim: To examine the association between lifetime alcohol consumption and significant liver disease in type 2 diabetic patients with NAFLD., Methods: A cross-sectional study assessing 151 patients with NAFLD at risk of clinically significant liver disease. NAFLD fibrosis severity was classified by transient elastography; liver stiffness measurements ≥8.2 kPa defined significant fibrosis. Lifetime drinking history classified patients into nondrinkers, light drinkers (always ≤20 g/day), and moderate drinkers (any period with intake >20 g/day)., Result: Compared with lifetime nondrinkers, light and moderate drinkers were more likely to be male ( p = 0.008) and to be Caucasian ( p = 0.007) and to have a history of cigarette smoking ( p = 0.000), obstructive sleep apnea ( p = 0.003), and self-reported depression ( p = 0.003). Moderate drinkers required ≥3 hypoglycemic agents to maintain diabetic control ( p = 0.041) and fibrate medication to lower blood triglyceride levels ( p = 0.044). Compared to lifetime nondrinkers, light drinkers had 1.79 (95% CI: 0.67-4.82; p = 0.247) and moderate drinkers had 0.91 (95% CI: 0.27-3.10; p = 0.881) times the odds of having liver stiffness measurements ≥8.2 kPa (adjusted for age, gender, and body mass index)., Conclusions: In diabetic patients with NAFLD, light or moderate lifetime alcohol consumption was not significantly associated with liver fibrosis. The impact of lifetime alcohol intake on fibrosis progression and diabetic comorbidities, in particular obstructive sleep apnea and hypertriglyceridemia, requires further investigation.

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., Competing Interests: The authors have declared that no competing interests exist.

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.

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., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Ascites, the most frequent complication of cirrhosis, is associated with poor prognosis and reduced quality of life. Recurrent hospital admissions are common and often unplanned, resulting in increased use of hospital services., Aims: To examine use of hospital services by patients with cirrhosis and ascites requiring paracentesis, and to investigate factors associated with early unplanned readmission., Methods: A retrospective review of the medical chart and clinical databases was performed for patients who underwent paracentesis between October 2011 and October 2012. Clinical parameters at index admission were compared between patients with and without early unplanned hospital readmissions., Results: The 41 patients requiring paracentesis had 127 hospital admissions, 1164 occupied bed days and 733 medical imaging services. Most admissions (80.3%) were for management of ascites, of which 41.2% were unplanned. Of those eligible, 69.7% were readmitted and 42.4% had an early unplanned readmission. Twelve patients died and nine developed spontaneous bacterial peritonitis. Of those eligible for readmission, more patients died (P = 0.008) and/or developed spontaneous bacterial peritonitis (P = 0.027) if they had an early unplanned readmission during the study period. Markers of liver disease, as well as haemoglobin (P = 0.029), haematocrit (P = 0.024) and previous heavy alcohol use (P = 0.021) at index admission, were associated with early unplanned readmission., Conclusion: Patients with cirrhosis and ascites comprise a small population who account for substantial use of hospital services. Markers of disease severity may identify patients at increased risk of early readmission. Alternative models of care should be considered to reduce unplanned hospital admissions, healthcare costs and pressure on emergency services., (© 2014 The Authors; Internal Medicine Journal © 2014 Royal Australasian College of Physicians.)

Background and Aim: Carbohydrate deficient transferrin (CDT) is the most specific serum biomarker of heavy alcohol consumption, defined as ≥ 350-420 g 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.

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 (EtOH) 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 EtOH 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., (Copyright © 2013 by the Research Society on Alcoholism.)

Background: Alcohol is an important primary and comorbid cause of liver injury in patients referred for investigation and management of liver disease. Early assessment and documentation of alcohol consumption is therefore essential, and recommended in both general practice and hospital settings., Aims: To determine the extent and accuracy of documentation of alcohol consumption in patients referred for evaluation of liver disease., Methods: Patients were interviewed using a structured questionnaire. The medical records of all patients interviewed were reviewed to obtain information from the referral letter and the hepatology consultations., Results: Eighty-three patients were surveyed. Only 14 referrals had an informative alcohol history, despite 27 patients admitting risky alcohol consumption at the initial hepatology consultation. Ninety per cent of initial consultations had an informative alcohol history documented, whereas only 56% of patients attending a follow-up appointment had informative documentation. Assessment of alcohol consumption was comparable between the hepatology consultation and the structured questionnaire, but four subjects had substantially different alcohol histories. Alcohol Use Disorders Identification Test identified all patients reporting harmful alcohol consumption on the questionnaire., Conclusions: Hazardous alcohol use is prevalent in subjects attending hepatology clinics, but informative alcohol histories, which are crucial to patient management, are rarely documented in referrals. Screening tools improve documentation and accuracy of alcohol histories, and their use by general practitioners and hospital clinicians would improve detection rates of hazardous drinking and allow earlier intervention. Systematic use of screening tools in hepatology clinics will provide opportunities for education and reinforce recommendations to reduce hazardous or harmful alcohol consumption., (© 2013 The Authors; Internal Medicine Journal © 2013 Royal Australasian College of Physicians.)