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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 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.)

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.

Background: Many patients with cirrhosis follow complex medication and dietary regimens, and those with decompensated cirrhosis suffer debilitating complications. These factors impact activities of daily living and quality of life., Aims: To explore the concerns and challenges of people with cirrhosis and their use of support services and to also describe health professionals' (HP) perspectives of patients' concerns., Methods: This is a cross-sectional study at a tertiary liver clinic involving 50 patients and 54 HP. Data were collected using structured questionnaires. The study includes patients' report of their challenges/problems now that they have cirrhosis ('patient-volunteered concerns') and HP' report of patients' concerns. Both also ranked a list of 10 potential concerns., Results: Patients were, on average, 58 years old (SD = 10.2), mostly male (78%), Caucasian (86%) and with compensated cirrhosis (60%). The patients' most common volunteered concerns related to managing symptoms, emotional issues and disease. Most ranked 'developing liver cancer' (79%), 'losing ability to do daily tasks for yourself' (76%), 'fear of dying' (64%) and 'fear of the unknown' (64%) as priority concerns. Regarding the use of support services, 24% of patients had accessed a dietician, 20% a pharmacist and 18% a psychologist. From the HP' perspective, the patients' most significant challenges related to managing disease (65%) and symptoms (48%), access to healthcare (56%) and information/knowledge (48%)., Conclusions: Our findings demonstrate that cirrhosis (its symptoms, complications and treatment) is associated with significant concerns for patients. The discrepancies between the views of HP and patients suggest that we may not be measuring or addressing patients' needs appropriately., (© 2017 Royal Australasian College of Physicians.)

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: 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 (rs  = 0.47, rs  = 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., (© 2012 John Wiley & Sons A/S.)