High FIB-4 Index Research Articles

P2605Liver stiffness assessed by fibrosis-4 index; noninvasive marker using serum biomarkers is associated with right ventricular function and cardiovascular prognosis in HFpEF

Abstract Background Liver stiffness is reported to be associated with right atrial pressure and worse prognosis of heart failure. Fibrosis-4 (FIB4) index (age (years) × aspartate aminotransferase (IU/L)/platelet count (109/L) × square root of alanine aminotransferase (IU/L)) is known as a useful and simple marker for evaluating liver stiffness. However, the association between FIB4 index and prognosis in heart failure with preserved ejection fraction (HFpEF) was not elucidated. Purpose This study aimed to clarity the association between FIB4 index and right ventricular (RV) function and major adverse cardiac events (MACE) of HFpEF. Method From February 2012 to December 2015, 132 subjects diagnosed as HFpEF after hospitalization of acute decompensation were enrolled (79 years, 59 male). Subjects performed thoracic surgery or percutaneous coronary intervention within half a year and died before discharge were excluded. All subjects were measured FIB4 index and tricuspid annular plane systolic excursion (TAPSE) to assess RV function before discharge. In addition, patients were classified into two groups: high-(≥3.01, n=52) and low-FIB4 index groups (<3.01, n=80). MACE incidence during the follow-up period were compared between these groups. Results Patient with high-FIB4 index were older and higher level of blood pressure. There was no difference in prevalence rates of history of liver disease. In multivariate Linear regression analysis, FIB4 index was significantly association with TAPSE independently confounding factors. Kaplan-Meier analysis showed that patients with high-FIB4 index experienced more CV events during the 1734 days of follow-up (42.3% vs 26.2%, p=0.028) (figure). Kaplan-Meier curve freedom from MACE Conclusions FIB4 index is associated with RV dysfunction and a high risk of future CV event of HFpEF.

Fibrosis-4 index reflects right-sided filling pressure in patients with heart failure.

The fibrosis-4 index (FIB-4 index) is a marker of liver fibrosis. It has been reported that the FIB-4 index in compensated phase is associated with estimated right-sided filling pressure and poor prognosis in patients with heart failure. However, the relationship with invasively obtained right-sided cardiac pressures has been unclear. Hemodynamic status was evaluated by right heart catheterization in 189 heart failure patients who were in a clinically compensated phase between January 2015 and September 2017. Patients were assigned to two groups based on a median FIB-4 index of 2.15, then hemodynamic parameters and event rates were compared. Endpoint was defined as a composite of all-cause death, readmission for heart failure, or left ventricular-assist device implantation. Then, we also investigated correlations between the FIB-4 index and clinical factors, including hemodynamic parameters. Patients with a high FIB-4 index were significantly older (76 [IQR, 63-80] vs. 65 [IQR, 56-74] years, P < 0.001) and had higher right atrial pressure (RAP; 7 [IQR, 5-11] vs. 4 [IQR, 1-6] mmHg, P < 0.001) and pulmonary capillary wedge pressure (16 [IQR, 12-22] vs. 12 [IQR, 8-19] mmHg, P = 0.011) than those with a low FIB-4 index. The FIB-4 index correlated more strongly with parameters of right-sided than left-sided HF (RAP, R = 0.41, P < 0.001; inferior vena cava diameter, R = 0.44, P < 0.001; pulmonary capillary wedge pressure, R = 0.15, P = 0.038; brain natriuretic peptide, R = 0.14, P = 0.29). Multiple regression analysis showed that the FIB-4 index independently correlated with RAP. In conclusion, the FIB-4 index can non-invasively reflect right-sided filling pressure, which might explain why it is associated with a poor prognosis, among patients with heart failure.

The combination of the preoperative albumin-bilirubin grade and the fibrosis-4 index predicts the prognosis of patients with hepatocellular carcinoma after liver resection.

There is little information regarding the use of a combination of the albumin-bilirubin (ALBI) grade and the fibrosis-4 index (FIB-4) in predicting hepatocellular carcinoma (HCC) patient outcomes after liver resection. In this study, we aimed to analyze the predictive ability of a combination of the ALBI grade and the FIB-4 score (ALBI-FIB-4) for HCC patients within the Milan criteria after liver resection. The data of HCC patients within the Milan criteria who underwent liver resection between 2011 and 2019 at our center were reviewed (n = 544). Patients with an FIB-4 index > 3.25 were considered to have a high FIB-4 index and were given a score of 1, whereas patients with an FIB-4 index ≤ 3.25 were considered to have a low FIB-4 index and were given a score of 0. The ALBI-FIB-4 score was a summary score that combined the ALBI grade and the score based on the FIB-4 index. During the follow-up period, 279 patients experienced recurrence, and 175 patients died. Multivariate analysis showed that tumor size, the presence of multiple tumors, the presence of microvascular invasion and the ALBI-FIB-4 score were four independent risk factors for both postoperative recurrence-free survival (RFS) and overall survival (OS). The 5-year RFS of patients with high ALBI-FIB-4 scores of 1, 2, and 3 were 55.0%, 44.2% and 35.3%, respectively (p = 0.004). The 5-year OS rates of patients with high ALBI-FIB-4 scores of 1, 2, and 3 were 72.9%, 66.4% and 54.8%, respectively (p = 0.011). The ALBI-FIB-4 score may be a surrogate marker for predicting the prognosis of patients with HCC after liver resection. A high ALBI-FIB-4 score was associated with a high incidence of postoperative recurrence and mortality.

Favorable impact of non-alcoholic fatty liver disease on the cerebral white matter hyperintensity in a neurologically healthy population.

Although non-alcoholic fatty liver disease (NAFLD) shares common cardiovascular risk factors with cerebral white matter hyperintensity (WMH), few studies have reported the association between NAFLD and WMH. The association between the presence of NAFLD with its severity and the volume of WMH was investigated. This cross-sectional study was conducted for 2460 subjects who voluntarily participated in health screening check-ups including brain magnetic resonance imaging and liver ultrasonography at the Health Promotion Center at Seoul National University Hospital from 2009 to 2013. Ultrasonography was used to detect the presence and severity of NAFLD combined with the NAFLD fibrosis score and the FIB-4 index. The volume of WMH was measured using a semi-automated quantification method by a trained neurologist. The prevalence of NAFLD was 36.5%, and the median volume of WMH in all the subjects was 1.1ml (interquartile range 0.2-2.7ml). The presence of NAFLD was associated with a smaller volume of WMH [β (standard error, SE) -0.051 (0.046); P=0.012]. Moderate to severe NAFLD was associated with a smaller volume of WMH than was non-NAFLD [β (SE) -0.067 (0.061); P=0.002]. The negative correlation observed between NAFLD severity and WMH volume was persistent only in those with low FIB-4 index and low NAFLD fibrosis scores, whereas there was a positive association in those with high FIB-4 index and NAFLD fibrosis scores. Non-alcoholic fatty liver disease, and its severity, showed a favorable association with WMH volume. However, its causality and mechanism should be evaluated in further relevantly designed studies.

Dynamic Evaluation of Liver Fibrosis to Assess the Risk of Hepatocellular Carcinoma in Patients With Chronic Hepatitis C Who Achieved Sustained Virologic Response.

Liver fibrosis is an important risk factor for the development of hepatocellular carcinoma (HCC) after sustained virologic response (SVR) in patients with persistent hepatitis C virus (HCV) infection. However, as the degree of liver fibrosis changes following the eradication of HCV after SVR, it is unclear whether the prediction of HCC development based on liver fibrosis at baseline remains valid. In 522 patients who achieved SVR by interferon-based anti-HCV therapy, the Fibrosis-4 Index for Liver Fibrosis (FIB-4 index) was updated annually by recalculation based on laboratory values after SVR. The incidence of HCC was reassessed annually based on the updated FIB-4 index. The percentage of patients with mild liver fibrosis (FIB-4 index <1.45) increased annually after SVR, whereas the percentage of patients with advanced liver fibrosis (FIB-4 index ≥3.25) decreased. The incidences of HCC based on the FIB-4 index remained constant between the time of SVR and subsequent annual updates. No patients developed HCC after SVR if the FIB-4 index decreased to <1.45. The FIB-4 index retained its predictive ability for the risk of HCC when recalculated after SVR, despite the decrease in patients with high FIB-4 index values. Dynamic assessment of the FIB-4 index can be useful in the surveillance of HCC after SVR. Patients with a FIB-4 index <1.45 did not develop HCC even by the regression from advanced fibrosis after SVR. Further studies will be necessary to confirm these findings, which may result in a decrease in the number of patients in whom surveillance is required.

High Fib4 index in patients with suspected NASH is associated with elevation of chymase-dependent angiotensin II-forming activity in circulating mononuclear leucocytes.

Fatal hepatic disease is closely related to non-alcoholic fatty liver disease, especially non-alcoholic steatohepatitis (NASH). NASH is associated with cardiovascular events because it develops on the background of lifestyle-related diseases. Chymase-dependent angiotensin II-forming activity (dAIIFA) in circulating mononuclear leucocytes (CML) is a marker of local angiotensin II production and inflammation. This study investigated the association between CML chymase dAIIFA and NASH. Cardiovascular outpatients were recruited and the Fib4 index (F4I) was calculated. Patients with an F4I > 2.67 were classified into the high F4I group and these patients were strongly suspected to have NASH, while patients with an F4I < 1.30 were classified into the low F4I group. Patient background factors were compared between these groups. CML chymase dAIIFA was measured by ELISA using Nma/Dnp-modified angiotensin I. Among 499 patients, 16% were classified into the high F4I group. Compared with the low F4I group, the high F4I group had a significantly higher age, pancytopenia, more frequent diabetes mellitus, lower diastolic blood pressure, lower estimated glomerular filtration rate, higher brain natriuretic peptide, lower plasma aldosterone concentration, higher total AIIFA, higher CML chymase dAIIFA, and higher pulse wave velocity. Contrary to expectations, the body mass index, triglycerides, and low-density lipoprotein cholesterol were relatively low in the high F4I group. Many cardiovascular outpatients have a high F4I and can probably be categorized as NASH. The high F4I patients had few features of metabolic syndrome and were suspected to have elevated tissue chymase dAIIFA contributing to inflammation in the liver as well as in cardiovascular organs.

Liver Fibrosis is Associated with Loss of Skeletal Muscle Mass in Community-Dwelling Older Adults with No History of Liver Diseases

In this study, we aimed to examine the possible association between liver fibrosis and loss of skeletal muscle mass (SM) in community-dwelling older adults with no history of liver diseases. A total of 2,028 older adults (mean age, 69.8 ± 5.2 years) who had not received any treatment for liver diseases and had participated in a comprehensive health survey for community residents in Wakayama, Japan were included in this study. We carried out bioelectrical impedance analysis to estimate the SM of the whole body including the arms, legs, and trunk of the subjects. Liver fibrosis was evaluated by calculating the Fib4 index based on the subject's age, AST level, ALT level, and platelet counts. The subjects were divided into three groups according to cutoff values of the Fib4 index (low: <1.30, medium: 1.30-2.66, high: ≥2.67). The SM index (kg/m2) was the lowest among subjects in the high-Fib4-index category, followed by the medium- and low-Fib4-index categories. This dose-response reduction in the SM index was more pronounced among individuals with lower blood albumin level (low nutrition) and in those with more sedentary behavior (physical inactivity). Among the selected 262 subjects who underwent SM measurement twice with an interval of 3 years, the subjects with a high Fib4 index showed greater reduction in the SM index than those with medium and low Fib4 indices. Multiple regression analysis revealed that the Fib4 index was significantly associated with the SM index, independent of age, sex, albumin level, sedentary behavior, diabetes mellitus, alcohol intake, and smoking status. The present findings suggest that the potential progression of liver fibrosis is associated with the excessive loss of SM among apparently healthy older adults without any treatment for liver diseases.

Factors associated with advanced hepatic fibrosis in patients with various internal diseases: A multicenter community-based survey.

Advanced hepatic fibrosis can occur in patients with various diseases, including diabetes mellitus and hypertension. We aimed to investigate the prevalence and risk factors of advanced hepatic fibrosis in patients with various internal diseases. We performed a community-based survey in which 1012 patients were enrolled (mean age, 63.1 ± 10.8years; female/male, 505/507). Hepatic fibrosis was evaluated by Fib-4 index and patients were classified into high and low Fib-4 groups. Independent factors for the high Fib-4 group were analyzed using logistic regression and decision tree analysis. A high prevalence of high Fib-4 index was observed in patients with cardiovascular diseases; 37.1% of patients with hypertension belonged to the high Fib-4 group. Independent factors associated with the high Fib-4 group were BMI (OR 0.95, 95%CI 0.918-0.989, P < 0.01), male sex (OR 1.35, 95%CI 1.03-1.78, P < 0.05), and hypertension (OR 1.41, 95%CI 1.03-1.92, P < 0.05). In patients with hypertension, a decision tree algorithm revealed three profiles for Fib-4 index: 1) creatinine level < 0.76mg/dL (high Fib-4; 30.0%), 2) creatinine level ≥ 0.76mg/dL without sodium-glucose cotransporter 2 inhibitor (SGLT2i) treatment (high Fib-4; 48.2%), and 3) creatinine level ≥ 0.76mg/dL with SGLT2i treatment (high Fib-4; 23.5%). A high prevalence of advanced hepatic fibrosis was observed in patients with hypertension. Hypertension was an independent risk factor, and creatinine level and SGLT2i were divergence variables for advanced hepatic fibrosis. Thus, hypertension with chronic kidney injury may exacerbate hepatic fibrosis, while SGLT2i treatment may ameliorate hepatic fibrosis.

Association of coronary artery calcification with liver fibrosis in Japanese patients with non-alcoholic fatty liver disease.

Cardiovascular events are the leading cause of death among patients with non-alcoholic fatty liver disease (NAFLD), but their relationship remains unclear. This study examined the association between coronary atherosclerosis and liver fibrosis, represented by the coronary artery calcification (CAC) score and non-invasive fibrosis markers, respectively. Among 698 patients with chest pain or electrocardiographic abnormalities who underwent coronary computed tomography (CT) between April 2006 and March 2010, those with known liver disorders or history of emergency coronary angioplasty were excluded, leaving 366 patients for this study. Diagnosis of NAFLD was based on abdominal CT and history of alcohol consumption. Subjects with CAC of 100AU or more were categorized into the high-risk group for cardiovascular events. Patient records were examined for clinical parameters including CAC score and non-invasive fibrosis marker FIB-4 index. Ninety-four patients (25.7%) had NAFLD. In this group, univariate analysis identified old age, high diastolic blood pressure, high liver to spleen ratio and high FIB-4 index as risk factors for cardiovascular events and multivariate analysis identified age of 66years or older and FIB-4 index of 2.09 or more as the significant risk factors. For the observation period until August 2014, the cumulative proportion of PCI performance was significantly higher in patients with FIB-4 of 2.09 or more than those with FIB-4 of less than 2.09. The progression of arteriosclerosis and that of liver fibrosis may be associated in NAFLD patients. The FIB-4 index can be easily determined and thus can be a useful marker for predicting cardiovascular events in NAFLD patients.

High FIB-4 index as an independent risk factor of prevalent chronic kidney disease in patients with nonalcoholic fatty liver disease

Growing evidence suggests that non-alcoholic fatty liver disease (NAFLD) is linked to an increased risk for chronic kidney disease (CKD); liver fibrosis with biopsy-proven NAFLD has also been shown to associate with an increased risk of CKD. This study compares the diagnostic performance of simple noninvasive tests in identifying prevalent CKD among individuals with ultrasonography-diagnosed NAFLD. A total of 755 with ultrasonography-diagnosed NAFLD were included. Estimated glomerular filtration rate and noninvasive markers for hepatic fibrosis: aspartate transaminase to alanine transaminase ratio (AAR), aspartate transaminase to platelet ratio index (APRI), FIB-4 score, NAFLD fibrosis score (NFS) and BARD score were assessed. Binary logistic regression to generate a propensity score and receiver operating characteristic curves were developed for each of the noninvasive markers for predicting CKD, and the area under the receiver operating characteristic curve was greatest for FIB-4 score (0.750), followed by NFS (0.710), AAR (0.594), APRI (0.587), and BARD score (0.561). A cut-off value of 1.100 for FIB-4 score gave a sensitivity of 68.85% and a specificity of 71.07% for predicting CKD. The positive predictive value and negative predictive value were 37.50 and 90.05%, respectively. In multiple logistic regression analysis, only FIB-4 score ≧1.100 (OR 2.660, 95% CI 1.201-5.889; p = .016), older age, higher diastolic blood pressure and higher uric acid were independent predictors of CKD. High noninvasive fibrosis score is associated with an increased risk of prevalent CKD; the FIB-4 is the better predictor. With a cut-off value of 1.100 for FIB-4, it is useful in excluding the presence of CKD in patients with NAFLD.

Predictive value of FIB-4 versus fibrotest, APRI, FIBROINDEX and FORNS to noninvasively estimate fibrosis in hepatitis C

Reply: We thank Dr. Adler's group for their interesting results which confirm the accuracy of the FIB-4 index for delineating significant (requiring therapy) and nonsignificant fibrosis in chronic hepatitis C (HCV), in HCV monoinfection as well as in human immunodeficiency virus (HIV)-HCV coinfection.1 Adler et al. included in their analysis a broad population of patients, some of them with chronic hepatitis B (HBV) infection and alcoholic liver disease. Our results in chronic hepatitis B (work submitted) suggest that the FIB-4 index is robust to diagnose nil-to-moderate fibrosis, providing therefore an interesting first-line evaluation. The comparison of the FIB-4 index with liver biopsies performed the same day in 138 patients allowed the correct identification of patients with nil-to-moderate fibrosis (METAVIR F0-F2) with an area under the receiving operating characteristic curve of 0.81 (confidence interval 95% 0.74-0.88) (P < 0.001). Interestingly, the longer the length of the liver biopsy, the higher was the AUROC increasing from 0.81 to 0.91. The FIB-4 score was less accurate for assessing the diagnosis of severe fibrosis (METAVIR F3-F4). The high number of African patients included in our study could explain at least in part these results: most discordant patients with a high FIB-4 index and nil-to-moderate fibrosis had a low platelet count, possibly following chronic malarial infection. In alcohol-related liver disease (ALD), our analysis of the FIB-4 index in 160 patients is disappointing and confirmed the idea that existing diagnostic tests based on aminotransferase level and platelet count are not suitable for the determination of fibrosis stage in patients with ALD (work submitted). This point could receive several nonexclusive explanations: alcohol is well known to induce a higher AST/ALT ratio than other causes of liver diseases; the level of aminotransferases is classically lower in ALD and this has been related to pyridoxal phosphate deficiency; platelet count is affected by the acute toxicity of ethanol on thrombopoiesis and its correlation to portal hypertension is therefore poor in that context. All these alcohol-related variations clearly make an impact on the FIB-4 index which includes AST, ALT, GGT and the platelet count. The accuracy and the low cost of the FIB-4 index should make the FIB-4 index, with the fibroscan, a first line noninvasive biochemical marker and should be added to the recommendations of the Haute Autorité de Santé.2 Anais Vallet-Pichard M.D.*, Vincent Mallet M.D., Ph.D.*, Stanislas Pol M.D., Ph.D.*, * Université Paris Descartes; INSERM U.567; APHP, Hôpital Cochin, Unité d'hépatologie Paris, France.