Algorithms for early detection of silent liver fibrosis in the primary care setting - a scoping review

Introduction Fatty liver disease affects almost 30% of the adult population worldwide. Most patients are asymptomatic, and there is not a linear relationship between exposure to risk factors and the risk of developing fibrosis. The combination of a very large, asymptomatic risk population where only a few percent will develop life-threatening liver disease is a growing diagnostic challenge for the health services. Accurate fibrosis assessment in primary care is limited by poor correlation with liver blood tests and low availability of elastography. Non-invasive tests are promising tools, but little is known about their diagnostic accuracy in low-risk populations. Areas covered A scoping review was conducted to identify articles that focused on the current use of biomarkers and algorithms in primary care for the detection of patients with fatty liver disease in need of referral for further work-up. Expert opinion Currently available algorithms for targeted screening for liver fibrosis perform better than the individual routine liver blood tests or liver ultrasonography. However, primary care physicians urgently need algorithms with even higher diagnostic accuracies than what is available today. The main limitation of the existing widely accessible algorithms, such as the FIB-4, is the large number of false-positive tests, resulting in overdiagnosis and futile referrals to secondary care.publishedVersio

2D shear wave liver elastography by aixplorer to detect portal hypertension in cirrhosis: an individual patient data meta-analysis

Background & Aims: Liver stiffness measured with 2-dimensional shear wave elas- tography by Supersonic Imagine (2DSWE-SSI) is well-established for fibrosis diagnos- tics, but non-conclusive for portal hypertension. Methods: We performed an individual patient data meta-analysis of 2DSWE-SSI to identify clinically significant portal hypertension (CSPH), severe portal hyperten- sion and large varices in cirrhosis patients, using hepatic venous pressure gradient and upper endoscopy as reference. We used meta-analytical integration of diagnos- tic accuracies with optimized rule-out (sensitivity-90%) and rule-in (specificity-90%) cut-offs. Results: Five studies from seven centres shared data on 519 patients. After exclu- sion, we included 328 patients. Eighty-nine (27%) were compensated and 286 (87%) had CSPH. 2DSWE-SSI < 14 kPa ruled out CSPH with a summary AUROC (sROC), sensitivity and specificity of 0.88, 91% and 37%, and correctly classified 85% of pa- tients, with minimal between-study heterogeneity. The false negative rate was 60%, of which decompensated patients accounted for 78%. 2DSWE-SSI ≥ 32 kPa ruled in CSPH with sROC, sensitivity, specificity and correct classifications of 0.83, 47%, 89% and 55%. In a subgroup analysis, the 14 kPa cut-off showed consistent sensitivity and higher specificity for patients with compensated cirrhosis, without ascites, viral 2 aetiology or BMI < 25 kg/m . 2DSWE-SSI ruled out severe portal hypertension and large varices with fewer correctly classified and lower sROC, and with minimal benefit for ruling in. Conclusion: Liver stiffness using 2-dimensional shear wave elastography below 14 kPa may be used to rule out clinically significant portal hypertension in cirrhosis patients, but this would need validation in populations of compensated liver disease. 2DSWE-SSI cannot predict varices needing treatment

Recent advances in alcohol-related liver disease (ALD): summary of a Gut roundtable meeting

Alcohol-related liver disease (ALD), which includes a range of disorders of different severity and is one of the most prevalent types of liver disease worldwide, has recently regained increased attention. Among other reasons, the realisation that any alcohol intake, regardless of type of beverage represents a health risk, and the new therapeutic strategies tested in recently published or undergoing clinical trials spur scientific interest in this area. In April 2019, Gut convened a round table panel of experts during the European Association for the Study of the Liver (EASL) International Liver Congress (ILC) in Vienna to discuss critical and up-to-date issues and clinical trial data regarding ALD, its epidemiology, diagnosis, management, pathomechanisms, possible future treatments and prevention. This paper summarises the discussion and its conclusions

The emergence of non-secretory multiple myeloma during the non-cytotoxic treatment of essential thrombocythemia: A case report

Introduction. The emergence of multiple myeloma as a second malignancy in patients with essential thrombocythemia is extremely rare. Several cases have been published so far, pointing out the impact of a cytotoxic effect during treatment of essential thrombocythemia on the development of multiple myeloma. Case presentation. We report the case of a 52-year-old Caucasian man who presented to our hospital because of leukocytosis, a slightly decreased hemoglobin level and thrombocytosis. After a complete hematological work-up, essential thrombocythemia was diagnosed. The patient was included in a multicenter clinical study, treated with anagrelide and his platelet counts were maintained in the normal range for more than 3 years. A sudden drop in his hemoglobin level with normal leukocyte and platelet count occurred at the same time as a back pain. Magnetic resonance imaging of his spine revealed the existence of a pathological fracture of Th4, the collapse of the upper edge of Th7 and osteolytic lesions of multiple thoracic vertebrae. Repeated hematological examinations, including bone biopsy with immunohistochemistry, disclosed diagnosis of multiple myeloma of the non-secretory type. Conclusions: To the best of our knowledge this is the first published case in which multiple myeloma developed during the treatment of essential thrombocythemia with the non-cytotoxic drug anagrelide. Our attempts to find a common origin for the coexistence of multiple myeloma and essential thrombocythemia have not confirmed the genetic basis of their appearance. Further studies are needed to determine the biological impact of this coexistence

A Dynamic Aspartate-to-Alanine Aminotransferase Ratio Provides Valid Predictions of Incident Severe Liver Disease

The aspartate-to-alanine aminotransferase ratio (AAR) is associated with liver fibrosis, but its predictive performance is suboptimal. We hypothesized that the association between AAR and liver disease depends on absolute transaminase levels and developed and validated a model to predict liver-related outcomes in the general population. A Cox regression model based on age, AAR, and alanine aminotransferase (ALT) level (dynamic AAR [dAAR]) using restricted cubic splines was developed in Finnish population-based health-examination surveys (FINRISK, 2002-2012; n = 18,067) with linked registry data for incident liver-related hospitalizations, hepatocellular carcinoma, or liver death. The model was externally validated for liver-related outcomes in a Swedish population cohort (Swedish Apolipoprotein Mortality Risk [AMORIS] subcohort; n = 126,941) and for predicting outcomes and/or prevalent fibrosis/cirrhosis in biopsied patients with nonalcoholic fatty liver disease (NAFLD), chronic hepatitis C, or alcohol-related liver disease (ALD). The dynamic AAR model predicted liver-related outcomes both overall (optimism-corrected C-statistic, 0.81) and in subgroup analyses of the FINRISK cohort and identified persons with >10% risk for liver-related outcomes within 10 years. In independent cohorts, the C-statistic for predicting liver-related outcomes up to a 10-year follow-up was 0.72 in the AMORIS cohort, 0.81 in NAFLD, and 0.75 in ALD. Area-under-the-curve (AUC) for detecting prevalent cirrhosis was 0.80-0.83 in NAFLD, 0.80 in hepatitis C, but only 0.71 in ALD. In ALD, model performance improved when using aspartate aminotransferase instead of ALT in the model (C-statistic, 0.84 for outcome; AUC, 0.82 for prevalent cirrhosis). Conclusion: A dAAR score provides prospective predictions for the risk of incident severe liver outcomes in the general population and helps detect advanced liver fibrosis/cirrhosis. The dAAR score could potentially be used for screening the unselected general population and as a trigger for further liver evaluations.Peer reviewe

Real-world evidence on non-invasive tests and associated cut-offs used to assess fibrosis in routine clinical practice

Background & Aims: Non-invasive tests (NITs) offer a practical solution for advanced fibrosis identification in non-alcoholic fatty liver disease (NAFLD). Despite increasing implementation, their use is not standardised, which can lead to inconsistent interpretation and risk stratification. We aimed to assess the types of NITs and the corresponding cut-offs used in a range of healthcare settings. Methods: A survey was distributed to a convenience sample of liver health experts who participated in a global NAFLD consensus statement. Respondents provided information on the NITs used in their clinic with the corresponding cut-offs and those used in established care pathways in their areas. Results: There were 35 respondents from 24 countries, 89% of whom practised in tertiary level settings. A total of 14 different NITs were used, and each respondent reported using at least one (median = 3). Of the respondents, 80% reported using FIB-4 and liver stiffness by vibration-controlled transient elastography (Fibroscan®), followed by the NAFLD fibrosis score (49%). For FIB-4, 71% of respondents used a low cut-off of <1.3 (range <1.0 to <1.45) and 21% reported using age-specific cut-offs. For Fibroscan®, 21% of respondents used a single liver stiffness cut-off: 8 kPa in 50%, while the rest used 7.2 kPa, 7.8 kPa and 8.7 kPa. Among the 63% of respondents who used lower and upper liver stiffness cut-offs, there were variations in both values (7.5 to >20 kPa, respectively). Conclusions: The cut-offs used for the same NITs for NAFLD risk stratification vary between clinicians. As cut-offs impact test performance, these findings underscore the heterogeneity in risk-assessment and support the importance of establishing consistent guidelines on the standardised use of NITs in NAFLD management. Lay summary: Owing to the high prevalence of non-alcoholic fatty liver disease (NAFLD) in the general population it is important to identify those who have more advanced stages of liver fibrosis, so that they can be properly treated. Noninvasive tests (NITs) provide a practical way to assess fibrosis risk in patients. However, we found that the cut-offs used for the same NITs vary between clinicians. As cut-offs impact test performance, these findings highlight the importance of establishing consistent guidelines on the standardised use of NITs to optimise clinical management of NAFLD

LiverScreen project: study protocol for screening for liver fibrosis in the general population in European countries

Background: The development of liver cirrhosis is usually an asymptomatic process until late stages when complications occur. The potential reversibility of the disease is dependent on early diagnosis of liver fibrosis and timely targeted treatment. Recently, the use of non-invasive tools has been suggested for screening of liver fibrosis, especially in subjects with risk factors for chronic liver disease. Nevertheless, large population-based studies with cost-effectiveness analyses are still lacking to support the widespread use of such tools. The aim of this study is to investigate whether non-invasive liver stiffness measurement in the general population is useful to identify subjects with asymptomatic, advanced chronic liver disease. Methods: This study aims to include 30,000 subjects from eight European countries. Subjects from the general population aged ≥ 40 years without known liver disease will be invited to participate in the study either through phone calls/letters or through their primary care center. In the first study visit, subjects will undergo bloodwork as well as hepatic fat quantification and liver stiffness measurement (LSM) by vibration-controlled transient elastography. If LSM is ≥ 8 kPa and/or if ALT levels are ≥1.5 x upper limit of normal, subjects will be referred to hospital for further evaluation and consideration of liver biopsy. The primary outcome is the percentage of subjects with LSM ≥ 8kPa. In addition, a health economic evaluation will be performed to assess the cost-effectiveness and budget impact of such an intervention. The project is funded by the European Commission H2020 program. Discussion: This study comes at an especially important time, as the burden of chronic liver diseases is expected to increase in the coming years. There is consequently an urgent need to change our current approach, from diagnosing the disease late when the impact of interventions may be limited to diagnosing the disease earlier, when the patient is asymptomatic and free of complications, and the disease potentially reversible. Ultimately, the LiverScreen study will serve as a basis from which diagnostic pathways can be developed and adapted to the specific socio-economic and healthcare conditions in each country

Low Accuracy of FIB-4 and NAFLD Fibrosis Scores for Screening for Liver Fibrosis in the Population

Background & AimsFibrosis-4 (FIB-4) and the nonalcoholic fatty liver disease fibrosis score (NFS) are the 2 most popular noninvasive blood-based serum tests proposed for widespread fibrosis screening. We therefore aimed to describe the accuracy of FIB-4 and NFS to detect elevated liver stiffness as an indicator of hepatic fibrosis in low-prevalence populations.MethodsThis study included a total of 5129 patients with concomitant measurement of FIB-4, NFS, and liver stiffness measurement (LSM) by Fibroscan (Echosens, France) from 5 independent population-based cohorts from Spain, Hong Kong, Denmark, England, and France; 3979 participants from the general population and 1150 from at-risk cohorts due to alcohol, diabetes, or obesity. We correlated LSM with FIB-4 and NFS, and calculated pre- and post-test predictive values of FIB-4 and NFS to detect elevated LSM at 8 kPa and 12 kPa cutoffs. The mean age was 53 ± 12 years, the mean body mass index was 27 ± 5 kg/m2, and 2439 (57%) were women. One in 10 patients (552; 11%) had liver stiffness ≥8 kPa, but 239 of those (43%) had a normal FIB-4, and 171 (31%) had normal NFS. The proportion of false-negatives was higher in at-risk patients than the general population. FIB-4 was false-negative in 11% of diabetic subjects, compared with 2.5% false-negatives with NFS. Waist circumference outperformed FIB-4 and NFS for detecting LSM ≥8 kPa in the general population. Almost one-third (28%–29%) of elevated FIB-4/NFS were false-positive in both the general population and at-risk cohorts.ConclusionsFIB-4 and NFS are suboptimal for screening purposes due to a high risk of overdiagnosis and a non-negligible percentage of false-negatives, especially in patients with risk factors for chronic liver disease. Waist circumference emerged as a potential first step to identify patients at risk for liver fibrosis in the general population