Histological Assessment Of Liver Fibrosis Research Articles

Protocol for the development of a core outcome set for clinical trials in primary sclerosing cholangitis

BackgroundPrimary sclerosing cholangitis (PSC) is a progressive immune-mediated liver disease, for which no medical therapy has been shown to slow disease progression. However, the horizon for new therapies is encouraging,...

Updates in the quantitative assessment of liver fibrosis for nonalcoholic fatty liver disease: Histological perspective.

Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) is a major cause of liver fibrosis and cirrhosis. Accurate assessment of liver fibrosis is important for predicting disease outcomes and assessing therapeutic response in clinical practice and clinical trials. Although noninvasive tests such as transient elastography and magnetic resonance elastography are preferred where possible, histological assessment of liver fibrosis via semiquantitative scoring systems remains the current gold standard. Collagen proportionate area provides more granularity by measuring the percentage of fibrosis on a continuous scale, but is limited by the absence of architectural input. Although not yet used in routine clinical practice, advances in second harmonic generation/two-photon excitation fluorescence (SHG/TPEF) microscopy imaging show great promise in characterising architectural features of fibrosis at the individual collagen fiber level. Quantification and calculation of different detailed variables of collagen fibers can be used to establish algorithm-based quantitative fibrosis scores (e.g., qFibrosis, q-FPs), which have been validated against fibrosis stage in NAFLD. Artificial intelligence is being explored to further refine and develop quantitative fibrosis scoring methods. SHG-microscopy shows promise as the new gold standard for the quantitative measurement of liver fibrosis. This has reaffirmed the pivotal role of the liver biopsy in fibrosis assessment in NAFLD, at least for the near-future. The ability of SHG-derived algorithms to intuitively detect subtle nuances in liver fibrosis changes over a continuous scale should be employed to redress the efficacy endpoint for fibrosis in NASH clinical trials; this approach may improve the outcomes of the trials evaluating therapeutic response to antifibrotic drugs.

Subgroup analysis of the predictive ability of aspartate aminotransferase to platelet ratio index (APRI) and fibrosis-4 (FIB-4) for assessing hepatic fibrosis among patients with chronic hepatitis C.

There are many laboratory indices to assess liver fibrosis. Aspartate aminotransferase to platelet ratio index (APRI) and fibrosis-4 (FIB-4) index have been used as well-known serum markers of liver fibrosis. With the increasing use of non-invasive fibrosis assessment, it is important to recognize the limitations of these tests. The factors influencing the diagnostic accuracy to evaluate liver fibrosis are not well-established. This study aimed to perform a subgroup analysis of the predictive ability of laboratory indices. Overall, 113 patients with chronic hepatitis C infection who underwent liver biopsy were retrospectively examined. The histological assessment of liver fibrosis was performed using the METAVIR scoring system, and the values of several laboratory tests were also evaluated on the same day. We categorized our study population by treatment status, body mass index (BMI), and age. The two laboratory indices APRI and FIB-4 index could predict advanced (F3-4) liver fibrosis and cirrhosis (F4), with the area under the receiver operating characteristic curve (AUROC)>0.8 and accuracy >70%. The AUROCs and accuracies were higher among patients with sustained virological response (SVR) than among those without SVR. A higher predictive ability was also observed among patients with BMI <25kg/m2. Age did not appear to affect liver fibrosis predictability. The laboratory indices APRI and FIB-4 index exhibit good diagnostic performance for determining advanced fibrosis and cirrhosis among patients with hepatitis C infection. The diagnostic accuracy appears better among patients with SVR and those with BMI <25kg/m2.

The histological assessment of liver fibrosis in grafts from extended criteria donors predicts the outcome after liver transplantation: A retrospective study

The use of extended criteria donors (ECD) in liver transplantation is increasing due to the organ shortage. Histological evaluation of the liver graft in the context of procurement is an important tool for extending the donor pool without affecting the quality of the transplanted organs. Macrovesicular steatosis is widely accepted as predictor of early allograft dysfunction (EAD), while other features, such as portal fibrosis, are poorly studied. To identify morphological features, other than macrovesicular steatosis, that may affect recipients' outcome. Between 2014 and 2016, 132 donors with extended criteria underwent pre-transplant liver biopsy during procurement. Histological variables of the graft, donors'/recipients' clinical data, EAD and patient/graft survival were registered. The recipients who received a graft with histological-proven portal fibrosis had a significant lower patient and graft survival in comparison to patients without fibrosis (P = 0.044 and P = 0.039, respectively). Donors' dyslipidemia was significantly associated with the occurrence of EAD (P = 0.021). When dyslipidemia was combined with histological liver fibrosis a 54.5% incidence of EAD was observed (P = 0.012). The histological assessment of liver fibrosis in pre-transplant biopsy of ECD grafts, together with donor's clinical data, provides important information on recipients' outcome.

The Role Of Non-Invasive Methods In Evaluating Liver Fibrosis Of Patients With Non-Alcoholic Steatohepatitis

Objectives: Liver biopsy is the gold standard for diagnosing the extent of fibrosis in NAFLD/NASH; however, it is invasive with the risk of serious complications. This study aimed to validate the diagnostic usefulness of FIB4, NAFLD Fibrosis Score (NFS), FibroScan and ARFI in assessing liver ?brosis in patients with NAFLD/NASH. Patients and Methods: The study was carried out on 101 patients with NASH. All patients underwent a liver biopsy for histological assessment of liver fibrosis and non-invasive methods for assessment of liver fibrosis including FIB4, NFS, FibroScan, and ARFI. Cut-off values along with the diagnostic accuracy of these methods were determined by receiver-operating characteristic (ROC) curves. Results: Histological liver fibrosis was evaluated by Metavir scoring (F0: 10 cases; F1: 47 cases; F2: 24 cases; F3: 17 cases; and F4: 3 cases). Liver stiffness determined by FIB4, NFS, FibroScan, and ARFI were significantly correlated with the fibrosis stages (Spearman rho: 0.32; 0.51; 0.56 and 0.54; p<0.05, respectively). AUROC of FIB4, NFS, FibroScan and ARFI for diagnosing ≥ F3 were 0.6, 0.8, 0.8, and 0.9, respectively. FibroScan, ARFI v/s NFS were more accurate than FIB4 for diagnosing ≥ F3 (p<0.05). Among those, NFS had the highest sensitivity for diagnoses of ≥ F3. The specificity values of NFS, ARFI and TE were greater than 80% for diagnosing ≥ F3. Conclusions: Liver stiffness determined by these methods had significantly correlated with the fibrosis stages. FibroScan and ARFI had more accurate than NFS and FIB4 in diagnosis of advanced fibrosis. NFS was the best method for screening advanced fibrosis (≥ F3) in patients with NASH.

IVER FIBROSIS EVALUATION BY ACOUSTIC RADIATION FORCE IMPULSE IMAGING AND&amp;NBSP; THE ASPARTATE AMINOTRANSFERASE TO PLATELET RATIO INDEX IN CHRONIC HEPATIC DISEASE

Background/Objectives: Acoustic radiation force impulse (ARFI) is a novel non-invasive technology for the assessment of liver fibrosis. Some studies previously reported that ARFI is a promising method for assessing liver fibrosis. Aspartaste aminotransferase (AST) to platelet ratio index (APRI) has been proposed as an easily determined and quite accurate noninvasive marker of liver fibrosis. This study aimed to explore the value of liver fibrosis assessment by ARFI, APRI and their combination in patients with chronic hepatic disease. Patients and Methods: The study was carried out on 119 patients with chronic hepatitis B, C, alcoholic liver disease and NASH. All of patients underwent a liver biopsy for histological assessment of liver fibrosis, ARFI elastography and calculate APRI. Cut-off values were determined using receiver-operating characteristic (ROC) curves. The corresponding cut-off values, sensitivities (Se), specificities (Sp), positive predict value (PPV) and negative predict value (NPV) were calculated and compared. In addition, the correlation of liver fibrosis stages with SWV and APRI were also tested to evaluate significant data. Results: Histological liver fibrosis was evaluated by Metavir scoring; F0: 9 cases, F1: 57 cases, F2: 23 cases, F3: 19 cases and F4: 11 case. SWV correlated significantly with the fibrosis stage (Spearman rho: 0.69, p = &lt;0.0001). The areas under the ROC curves (AUROC) were 0.86 (95% CI: 0.79-0.93) for ≥F2 and 0.88 (0.80-0.96) ≥ F3. The cut-off values of SWV were as follows: ≥1.29 m/s for ≥F2 (Se 79.25%, Sp 89.36%, PPV 85.7% and NPV 84.3%), ≥ 1.36 m/s for ≥F3 (Se 96.67%, Sp 86.52%, PPV 70.7%, NPV 98.7%). APRI correlated with the fibrosis stage (Spearman rho: 0.35, p = 0.0001). AUROC were 0.7 (95% CI: 0.56-0.79) for ≥F2 and 0.7 (0.85-0.81) ≥ F3. The cut-off values of APRI were as follows: ≥0.569 for ≥F2 (Se 50.94%, Sp 88.33%, PPV 71.1% and NPV 67.9%), ≥ 1.163 for ≥F3 (Se 40%, Sp 96.63%, PPV 80%, NPV 82.7%). When both methods were taken into consideration, for predicting F ≥2, we obtained 45.3% Se, 100% Sp, 100% PPV, 69.5% NPV and 0,73 AUROC, while for predicting F ≥3 we obtained 40% Se, 98.9% Sp, 92.3% PPV, 83% NPV and 0.7 AUROC. When ARFI and APRI results agreed, F ≥2 was confirmed by liver biopsy in 45% of cases and F ≥3 in 43.3% of cases. Conclusions: Increasing SWV and APRI correlate with high degree of liver fibrosis. ARFI has a good accuracy with high specificities and NPV for prediction of significant and advanced fibrosis. APRI has a quite good accuracy with high specificities for prediction of significant and advanced fibrosis and high NPV for prediction of advanced fibrosis. The specificities and PPV of the combined tests were better than ARFI or APRI alone for predicting significant and advanced liver fibrosis. When these two methods are concordant in significant or advanced fibrosis, liver biopsy can be avoided. The methods should be employed routinely in the workup of patients with chronic liver disease to evaluate the presence of significant and advanced liver fibrosis. Key words: liver fibrosis, liver stiffness, chronic hepatic disease, acoustic radiation force impulse imaging (ARFI), the aspartate aminotransferase to platelet ratio index (APRI)

ASSESSING THE ROLE OF ACOUSTIC RADIATION FORCE IMPULSE IMAGING TO PREDICT THE STAGING OF LIVER FIBROSIS IN PATIENTS WITH NONALCOHOLIC STEATOHEPATITIS

Background/Objectives: Acoustic radiation force impulse (ARFI) is a novel non-invasive technology for the assessment of stages of liver fibrosis in chronic hepatic disease. Some studies previously reported that ARFI is a promising method for assessing liver fibrosis in patients with NAFLD/NASH. This study aimed to validate the diagnostic usefulness of ARFI for prediction of staging of liver fibrosis in patients with NASH. Patients and Methods: The study was carried out on 51 patients with NASH. All of patients underwent a liver biopsy for histological assessment of liver fibrosis and ARFI elastography. Cut-off values were determined using receiver-operating characteristic (ROC) curves. Results: Histological liver fibrosis was evaluated by Metavir scoring; F0: 8 cases, F1: 29 cases, F2: 10 cases and F3: 4 cases. ARFI quantification correlated significantly with the fibrosis stage (Spearman rho: 0.44, p &lt;0.05). The areas under the ROC curves (AUROC) were 0.75 (95% confidence intervals: 0.60-0.90) for ≥F2 and 0.78 (0.53-0.99) for F3. The cut-off values of the shear wave velocity (SWV) were as follows: ≥1.29 m/s for ≥F2 (sensitivity 64.3%, specificity 83.8%, PPV 60% and NPV 86.1%), ≥ 1.38 m/s for F3 (sensitivity 75%, specificity 89.4%, PPV 57.5%, NPV 97.7%). Conclusions: Increasing ARFI velocities correlate with high degree of liver fibrosis. ARFI has quite good accuracy and high specificity, NPV for prediction of significant and advanced fibrosis in patients with NASH. The method should be employed routinely in the workup of patients with NASH to exclude the presence of significant and advanced liver fibrosis. Key words: liver fibrosis, liver stiffness, non-alcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), acoustic radiation force impulse imaging (ARFI).

Transient elastography with a new probe for obese patients for non-invasive staging of non-alcoholic steatohepatitis

Transient elastography (TE) has shown promising results for the staging of liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) with the limitation that 25% of obese patients cannot be examined with the standard TE probe. The aim of this study was to evaluate a new XL probe for obese patients for the staging of liver fibrosis in NAFLD/NASH. Fifty patients with NAFLD/NASH and histological assessment of liver fibrosis were included in the study. All patients received TE with the standard probe (M probe) and the new XL probe, and the results were compared with liver histology. The diagnostic accuracy expressed as the area under the ROC curve for TE measurements with the M probe and the XL probe was 0.80 and 0.82 for the diagnosis of significant fibrosis, and 0.91 and 0.95 for the diagnosis of liver cirrhosis, respectively. Eighty-three percent of the patients who could not be measured with the M probe could be measured using the XL probe. Transient elastography using the XL probe for obese patients can be performed with comparable diagnostic accuracy to the standard probe and enables the examination of significantly more obese patients.

Evaluation of acoustic radiation force impulse elastography for fibrosis staging of chronic liver disease: a pilot study

Acoustic radiation force impulse (ARFI) is a new technology integrated into conventional B-mode ultrasonography. ARFI is used to evaluate tissue stiffness in several organs, but this method has not been applied for liver fibrosis. The aim of this study was to determine whether ARFI elastography is useful for the evaluation of liver fibrosis. This study enrolled 55 consecutive patients with chronic liver disease who underwent a liver biopsy for histological assessment of liver fibrosis by the Metavir scoring system. Liver stiffness of the 55 patients and 25 healthy volunteers was evaluated by ARFI elastography and was expressed as the shear wave velocity. Cut-off values were determined using receiver-operating characteristic (ROC) curves. Histological liver fibrosis was evaluated by Metavir scoring; F0: six cases, F1: 14 cases, F2: nine cases, F3: nine cases and F4: 17 cases. Liver stiffness determined by ARFI elastography was correlated with histological liver fibrosis (P<0.0001). The areas under the ROC curves were 0.94 (95% confidence intervals, 0.87-0.99) for F2-F4, 0.94 (0.88-0.99) for F3-F4 and 0.96 (0.91-1.01) for F4. The cut-off values of the shear wave velocity were as follows: >1.34 m/s for F2-F4 (sensitivity 91.4%, specificity 80%); >1.44 m/s for F3-F4 (sensitivity 96.2%, specificity 79.3%); and >1.80 m/s for F4 (sensitivity 94.1%, specificity 86.8%). Ultrasonic ARFI elastography is a novel, non-invasive and reliable method for the assessment of liver fibrosis in patients with chronic liver disease.

Real-Time Tissue Elastography Versus FibroScan for Noninvasive Assessment of Liver Fibrosis in Chronic Liver Disease

Transient elastography (FibroScan, [TE]) and serum fibrosis markers such as the FibroTest (FT) are established methods for the noninvasive staging of liver fibrosis. A study using real-time elastography (HI-RTE), which is integrated in a conventional ultrasound system, was recently published with comparable results to transient elastography. The aim of the present study was to validate real-time elastography using the formulas calculated in previous studies and to compare the results to transient elastography and FibroTest for the noninvasive assessment of liver fibrosis. One hundred and thirty-four patients with chronic liver disease and either histological assessment of liver fibrosis (n = 112) or proven liver cirrhosis (n = 22) were included in the study. All patients received TE, HI-RTE, and biochemical evaluation on the same day as presentation. The calculation of the elasticity score of real-time elastography was performed in accordance with the two previously published studies. The Spearman correlation coefficient between transient elastography, real-time elastography and FibroTest with the histological Chevallier score was statistically significant with 0.78, 0.34, and 0.67, respectively (p < 0.01). The diagnostic accuracy expressed as areas under ROC curves was 0.84, 0.69 and 0.85 for the diagnosis of significant fibrosis (F > or = 2), and 0.97, 0.65, and 0.83 for the diagnosis of cirrhosis, respectively. Real-time elastography in its present form cannot replace transient elastography for noninvasive assessment of liver fibrosis.

Expression of angiotensin-converting enzyme 2 in CCL4-induced rat liver fibrosis

The renin angiotensin system (RAS) plays a major role in liver fibrosis. A novel homologue of angiotensin converting enzyme, ACE2, was identified as a negative regulator of RAS as it degrades Ang II to Ang1-7. We investigated in vivo the expression of ACE2 in liver fibrosis. We evaluated the relationship between biochemical variables and liver tissue expression of ACE2, the correlation between a histological assessment of liver fibrosis and liver tissue expression of ACE2. Male SD rats were randomly divided into a CCL4 group which received injections of CCL4 and the control group which received injections of olive oil. Liver pathology was examined by H&E and Sirius red staining, and real-time PCR was performed to determine the gene expression levels of ACE2 and ACE. Real-time PCR analysis revealed that ACE2 mRNA was higher at the two-, four-, and six-week time points, respectively (p<0.01). Similarly, hepatic ACE mRNA was significantly increased after CCL4 injection. There was a significant correlation between ACE and ACE2 gene expression (r=0.750, P<0.001). ACE2 gene expression strongly correlated with ALT (r=0.669, P<0.0001) and AST levels (r=0.815, P<0.0001). There was a significant correlation between circulating ACE2 and histological scores of liver fibrosis. ACE2 and ACE gene expression correlated with the ISHAK score (r=0.850, P<0.001; r=0.806, P<0.001). There was a significant relationship between ACE2 gene expression and the degree of liver fibrosis. ACE2 plays a crucial role in liver fibrogenesis.

Identification of Chronic Hepatitis B Patients without Significant Liver Fibrosis by a Simple Noninvasive Predictive Model

Histological assessment of liver fibrosis is important in the management of chronic hepatitis B (CHB) infection but poorly accepted by patients because of its invasiveness. The aim of this study was to develop a noninvasive model to assess liver fibrosis in CHB patients using clinical and routine laboratory data. This was a retrospective study on 235 treatment-naive viremic CHB patients. Univariate analysis of data from the training cohort (n = 150) followed by multivariate logistic regression were performed to identify independent predictors of significant fibrosis and generate predictive models. The models were validated with the remaining patients or validation cohort (n = 85) and by receiver operating characteristics (ROC) analysis. Body mass index (BMI), platelet count, serum albumin, and total bilirubin levels were identified as independent predictors of bridging fibrosis or cirrhosis (Ishak stage 3-6). ROC analysis was performed using the predictive probabilities derived from the regression models. The area under the ROC curve of the best model was 0.803 (95% CI: 0.729-0.878) for the training cohort, 0.765 (95% CI: 0.644-0.885) for the validation cohort, and 0.791 (95% CI: 0.728-0.854) for the entire cohort. Using the low cut-off probability of 0.15, significant fibrosis could be excluded in 83 patients of the total patient population (negative predictive value 0.92). Our noninvasive model comprising BMI and three routine laboratory tests was accurate in predicting absence of significant fibrosis. Application of this model could provide useful additional information on the stage of disease, guide future management decisions, and potentially decrease the need for liver biopsy in some CHB patients.

Quantitative assessment of fibrosis in liver biopsies from patients with chronic hepatitis B

Accurate histological assessment of liver fibrosis is essential in the management of chronic hepatitis B (CHB). Although semi-quantitative scoring systems describe well the pathological patterns of hepatic structure, they produce fibrosis evaluation that is not very precise. Image analysis or morphometry has the theoretical advantage of providing truly quantitative data. The present study aimed at validating a new image analysis system, Bioquant Nova Prime, in estimating collagen content in liver biopsy samples from patients with CHB. The biopsies were stained with picrosirius red and the areas of collagen were measured. The results were correlated with laboratory parameters and Ishak modified histological scores. Discriminative reliability of morphometry was determined using receiver operating characteristics (ROC) analysis. There was excellent interobserver agreement (r=0.84-0.94, P<0.01) in the morphometric analysis. Significant correlations between the quantitative morphometric data and the semi-quantitative score (Spearman's r=0.68-0.78, P<0.001) were also demonstrated. Excellent discriminative power of morphometry in differentiating mild from advanced fibrosis and cirrhosis from absence of cirrhosis was shown by the ROC analysis. Our results validated the use of Bioquant Nova Prime in estimating collagen content in liver biopsies. We showed that morphometry is a sensitive method of liver fibrosis quantification in CHB and complements semi-quantitative histological scoring system. This tool, with its reliable intraassay variability, could be of special value in assessing histological response to treatment after anti-viral or anti-fibrotic therapy.