FibroMeter scores for the assessment of liver fibrosis in patients with autoimmune liver diseases.

INTRODUCTION AND OBJECTIVES: We assessed FibroMeter virus (FMvirus) and FibroMeter vibration-controlled transient elastography (FMVCTE) in 134 patients with autoimmune liver diseases [ALD, autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC)], in order to assess new potential non-invasive biomarkers of liver fibrosis in patients with ALD, as similar data are missing. PATIENTS AND METHODS: The following groups were included: group 1: n = 78 AIH; group 2: n = 56 PBC. FMvirus and FMVCTE were determined in all 134 patients who underwent liver biopsy and TE the same day with sera collection. In addition, APRI and FIB-4 scores were calculated. RESULTS: The AUCs for TE and FMVCTE were significantly better (0.809; p < 0.001 and 0.772; p = 0.001, respectively for AIH and 0.997; p < 0.001 and 1; p < 0.001, for PBC) than the other three markers in predicting ≥ F3 fibrosis irrespective of the biochemical activity. FMVCTE and TE had good diagnostic accuracy (75.6% and 73%, respectively) for predicting severe fibrosis in AIH and performed even better in PBC (94.6% and 96.4%, respectively). The cut-offs of TE and FMVCTE had the best sensitivity and specificity in predicting ≥ F3 fibrosis in both AIH and PBC. CONCLUSIONS: FMVCTE seems to detect severe fibrosis equally to TE in patients with ALD but with better specificity. Biochemical disease activity did not seem to affect their diagnostic accuracy in ALD and therefore, could be helpful for the assessment of fibrosis, especially if they are performed sequentially (first TE with the best sensitivity and then FMVCTE with the best specificity).

Assessment of biopsy proven liver fibrosis by two-dimensional shear wave elastography in patients with primary biliary cholangitis.

BACKGROUND: Two-dimensional shear-wave elastography (2D-SWE) is an ultrasound-based technique used to stage liver fibrosis by measuring liver stiffness (LS). The diagnostic performance of 2D-SWE for assessing liver fibrosis in patients with primary biliary cholangitis (PBC) has not been reported before. AIMS: To investigate the diagnostic performance of 2D-SWE for staging liver fibrosis in patients with PBC by using histologic analysis as a reference standard. METHODS: Patients with PBC who underwent liver biopsy and 2D-SWE were retrospectively collected. Liver fibrosis was staged according to the Scheuer scoring system. Areas under receiver operating characteristic curve (AUROC) was constructed to assess the accuracy of 2D-SWE and serum fibrosis models for staging liver fibrosis. RESULTS: The diagnostic performance characteristics were determined for 157 patients with PBC. The AUROCs of LS measured by 2D-SWE for significant fibrosis, severe fibrosis, and cirrhosis were 0.88, 0.97 and 0.99, respectively. The cutoff values of LS measured by 2D-SWE in discriminating significant fibrosis, severe fibrosis, and cirrhosis were 10.7 kPa, 12.2 kPa and 14.1 kPa, respectively. The diagnostic accuracy of 2D-SWE for staging liver fibrosis was 73.9%. CONCLUSIONS: 2D-SWE is an efficient noninvasive method for the assessment of liver fibrosis in patients with PBC.

Consensus guidelines: best practices for detection, assessment and management of suspected acute drug-induced liver injury occurring during clinical trials in adults with chronic cholestatic liver disease.

BACKGROUND: Improved knowledge of the molecular pathophysiology and immunopathogenesis of cholestatic liver diseases in recent years has led to an increased interest in developing novel therapies. Patients with cholestatic liver disease often require different approaches to assessment and management of suspected drug-induced liver injury (DILI) compared to those with healthy livers and those with parenchymal liver diseases. At present, there are no regulatory guidelines or society position papers, that systematically address best practices pertaining to detection of DILI in these patients. AIMS: To outline best practices for detection, assessment and management of suspected acute DILI during clinical trials in adults with the cholestatic liver diseases - Primary Biliary Cholangitis (PBC) and Primary Sclerosing Cholangitis (PSC). METHODS: This is one of the several papers developed by the IQ DILI Initiative, which is comprised of members from 16 pharmaceutical companies, in collaboration with DILI experts from academia and regulatory agencies. The contents are the result of an extensive literature review, as well as in-depth discussions among industry, regulatory and academic DILI experts, to achieve consensus recommendations on DILI-related issues occurring during clinical trials for cholestatic liver diseases. RESULTS: Recommended best practices are outlined pertaining to hepatic eligibility criteria, monitoring of liver tests, approach to a suspected DILI signal, and hepatic discontinuation rules. CONCLUSIONS: This paper provides a framework for the approach to detection, assessment and management of suspected acute DILI occurring during clinical trials in adults with cholestatic liver disease.

Assessment of liver fibrosis in primary biliary cholangitis: Comparison between indirect serum markers and fibrosis morphometry.

BACKGROUND: The accuracy of non-invasive methods for the quantification of liver fibrosis in primary biliary cholangitis (PBC) is still debated. AIMS: To determine the histo-morphometric measurement of fibrotic tissue and to explore the possible association between indirect markers (APRI, FORNS, FIB-4, and Lok) and morphometry. METHODS: Retrospective analysis of medical data from patients with PBC, on whom needle liver biopsy was performed as part of the diagnostic assessment. One section of each biopsy stained with Sirius red was used for calculating the percentage of collagen. Quantitative measure of fibrotic tissue (fibrosis morphometry) was calculated as a percentage of collagen content by digital image analysis. Morphometry results were divided into four groups reflecting Ludwig's staging and compared with values for indirect serum markers. RESULTS: 50 PBC patients were enrolled (86% females, mean age 57 ± 12.30 years), 19 were Ludwig's stage I (38%), 14 stage II (28%), 12 stage III (24%), and five stage IV (10%). Morphometry results were significantly different among Ludwig stages (p<0.05). No significant differences were found for indirect serum markers. A significant correlation was found between morphometry results and indirect serum markers tested (p<0.05). CONCLUSION: In our cohort, the histo-morphometric values of fibrotic tissue increased progressively with Ludwig's stages of PBC, while non-invasive markers did not.

Noninvasive markers in the assessment and management of autoimmune liver diseases.

Historically, liver biopsy has been used to determine the etiology of liver disease, the degree of inflammation, the stage of liver fibrosis, and the response to treatments. In the last decade, the advent of noninvasive tests has improved the diagnosis and management of autoimmune liver diseases. For example, serum markers can identify hepatic inflammation, whereas ultrasound and MRI can diagnose liver fibrosis. Physicians now have a much larger repertoire of diagnostic tests to assess the liver parenchyma compared with liver biopsy alone. In some rare cases, noninvasive tests may provide an alternative to liver biopsy. In general, however, these noninvasive tests complement liver biopsy and provide quick, accurate, and reliable adjunctive data.

Acoustic radiation force impulse elastography for non-invasive assessment of disease stage in patients with primary biliary cirrhosis: A preliminary study.

AIM: To investigate the diagnostic performance of the acoustic radiation force impulse (ARFI) elastography for the assessment of primary biliary cirrhosis (PBC) stage. MATERIALS AND METHODS: Sixty-one patients with PBC in which liver biopsy and ARFI elastography measurements were performed in the same session were included in the study. The diagnostic performance of ARFI elastography for predicting the PBC stage was determined from the area under receiver operating characteristics (AUROC) curve analysis. RESULTS: ARFI elastography correlated significantly with histological stage (r = 0.74, p < 0.001) in patients with PBC. The AUROC of ARFI elastography for predicting histological stage equal to or higher than II, III, and equal to IV were 0.83, 0.93, and 0.91, respectively. The optimal cut-off values of ARFI elastography were 1.51 m/s, 1.79 m/s, and 2.01 m/s for PBC stage equal to or higher than II, III, and equal to IV, respectively. CONCLUSION: ARFI elastography is an acceptable and powerful technique for quantitative assessment of PBC stage.

Noninvasive elastography-based assessment of liver fibrosis progression and prognosis in primary biliary cirrhosis.

UNLABELLED: The development of liver fibrosis markers in primary biliary cirrhosis (PBC) is needed to facilitate the assessment of its progression and the effectiveness of new therapies. Here, we investigated the potential usefulness of transient elastography (TE) in the noninvasive evaluation of liver fibrosis stage and disease progression in PBC. We performed, first, a prospective performance analysis of TE for the diagnosis of METAVIR fibrosis stages in a diagnostic cohort of 103 patients and, second, a retrospective longitudinal analysis of repeated examinations in a monitoring cohort of 150 patients followed-up for up to 5 years. All patients were treated with ursodeoxycholic acid. Diagnostic thresholds of liver stiffness in discriminating fibrosis stages ≥ F1, ≥ F2, ≥ F3, and =F4 were 7.1, 8.8, 10.7, and 16.9 kPa, respectively. TE showed high performance and was significantly superior to biochemical markers (e.g., aspartate aminotransferase [AST]/platelet ratio, FIB-4, hyaluronic acid, AST/alanine aminotransferase ratio, and Mayo score) in diagnosing significant fibrosis, severe fibrosis, or cirrhosis. Analysis of the monitoring cohort data set using generalized linear models showed the following: (1) an overall progression rate of 0.48 ± 0.21 kPa/year (P = 0.02) and (2) no significant progression in patients with F0-F1, F2, or F3 stages, but a significant increase (4.06 ± 0.72 kPa/year; P < 0.0001) in cirrhotic patients. A cut-off value of 2.1 kPa/year was associated with an 8.4-fold increased risk of liver decompensations, liver transplantations, or deaths (P < 0.0001, Cox regression analysis). CONCLUSION: TE is one of the best current surrogate markers of liver fibrosis in PBC. Over a 5-year period, on-treatment liver stiffness appears stable in most noncirrhotic PBC patients, whereas it significantly increases in patients with cirrhosis. Progression of liver stiffness in PBC is predictive of poor outcome.

Assessment of liver fibrosis and steatosis in PBC with FibroScan, MRI, MR-spectroscopy, and serum markers.

BACKGROUND: In recent years noninvasive methods have been evaluated for the assessment of liver fibrosis predominantly in patients with viral hepatitis. In this study, transient elastography (FibroScan), magnetic resonance imaging (MRI), magnetic resonance (MR)-spectroscopy, and serum markers were compared in patients with primary biliary cirrhosis (PBC) for the assessment of liver fibrosis and steatosis. METHODS: Forty-five patients with PBC and histologic assessment of liver fibrosis received transient elastography and examinations for serum markers of fibrosis and steatosis. In addition, 41 out of 45 patients received contrast-enhanced MRI and 38 out of 45 patients received proton MR-spectroscopy. RESULTS: The adjusted accuracy (area under the receiver operating characteristic) for the diagnosis of histologic-stage > or = II for FibroScan, MRI-contrast enhancement and Forns index was 80%, 83%, and 69%, and for the diagnosis of liver cirrhosis 95%, 91%, and 94%, respectively. No correlation of histologic-stage was observed for FibroTest and AST to platelet ratio index. Histologic steatosis significantly correlated with body mass index (r=0.46), the SteatoTest (r=0.39), homeostasis model assessment of insulin resistance (r=0.46), and MR-spectroscopy (r=-0.76). The accuracy for the diagnosis of histologic steatosis was best with MR-spectroscopy (88%). CONCLUSIONS: Contrast-enhanced MRI and FibroScan can be used with comparable results for the assessment of liver fibrosis in patients with PBC and seem to supplement each other. MR-spectroscopy represents the best method for highly accurate noninvasive measurement of liver steatosis.

Biochemical markers for non-invasive assessment of disease stage in patients with primary biliary cirrhosis.

AIM: To evaluate different biochemical markers and their ratios in the assessment of primary biliary cirrhosis (PBC) stages. METHODS: This study included 112 patients with PBC who underwent a complete clinical investigation. We analyzed the correlation (Spearman's test) between ten biochemical markers and their ratios with different stages of PBC. The discriminative values were compared using areas under receiver operating characteristic (ROC) curves. RESULTS: The mean age of patients included in the study was 53.88 +/- 10.59 years, including 104 females and 8 males. We found a statistically significant correlation between PBC stage and Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) to platelet ratio (APRI), ALT/platelet count, AST/ALT, ALT/AST and ALT/Cholesterol ratios, with the values of Spearman's rho of 0.338, 0.476, 0.404, 0.356, 0.351 and 0.325, respectively. The best sensitivity and specificity was shown for AST/ALT, with an area under ROC of 0.660. CONCLUSION: Biochemical markers and their ratios do correlate with different sensitivity to and specificity of PBC disease stage. The use of biochemical markers and their ratios in clinical evaluation of PBC patients may reduce, but not eliminate, the need for liver biopsy.

Smoking and increased severity of hepatic fibrosis in primary biliary cirrhosis: A cross validated retrospective assessment.

An epidemiological association between cigarette smoking and primary biliary cirrhosis (PBC) has been demonstrated. Our aim was to determine the relationship between smoking and severity of liver fibrosis at presentation in patients with PBC. All patients with PBC seen at the three major teaching hospitals of Case Western Reserve University between October 1998 and December 2005 were identified. Data obtained at the time of the first evaluation leading to the PBC diagnosis on 97 patients were collected. The cumulative number of cigarette packs smoked per year (pack-years) was calculated. Advanced histological disease was defined as Ludwig stages 3 or 4. Analyses were performed to determine associations between advanced histological disease, smoking and other variables related to liver fibrosis. Smoking history was more common (P = .0008) in patients with advanced histological disease at presentation compared to those with early disease. Among smokers, mean lifetime tobacco consumption was higher (P = .04) in cases with advanced histological disease at presentation (30 pack-years) compared to cases with early disease (17 pack-years). Logistic regression demonstrated a significant association between a lifetime tobacco consumption of > or =10 pack-years and advanced histological disease at presentation (OR = 13.3). The association remained significant after adjusting for age, gender, and alcohol intake. The validity of these results was corroborated by cross-validation in an independent confirmatory set of 172 patients with PBC. In conclusion, smoking may accelerate the progression of PBC. This could be induced by exposure to chemicals in cigarette smoke.

Assessment of biliary fibrosis by transient elastography in patients with PBC and PSC.

Noninvasive measurement of liver stiffness with transient elastography has been recently validated for the evaluation of hepatic fibrosis in chronic hepatitis C. The current study assessed the diagnostic performance of liver stiffness measurement (LSM) for the determination of fibrosis stage in chronic cholestatic diseases. One hundred one patients with primary biliary cirrhosis (PBC, n=73) or primary sclerosing cholangitis (PSC, n=28) were prospectively enrolled in a multicenter study. All patients underwent liver biopsy (LB) and LSM. Histological and fibrosis stages were assessed on LB by two pathologists. LSM was performed by transient elastography. Efficiency of LSM for the determination of histological and fibrosis stages were determined by a receiver operating characteristics (ROC) curve analysis. Analysis failed in six patients (5.9%) because of unsuitable LB (n=4) or LSM (n=2). Stiffness values ranged from 2.8 to 69.1 kPa (median, 7.8 kPa). LSM was correlated to both fibrosis (Spearman's rho= 0.84, P < .0001) and histological (0.79, P < .0001) stages. These correlations were still found when PBC and PSC patients were analyzed separately. Areas under ROC curves were 0.92 for fibrosis stage (F) > or =2, 0.95 for F > or =3 and 0.96 for F=4. Optimal stiffness cutoff values of 7.3, 9.8, and 17.3 kPa showed F > or =2, F > or =3 and F=4, respectively. LSM and serum hyaluronic acid level were independent parameters associated with extensive fibrosis on LB. In conclusion, transient elastography is a simple and reliable noninvasive means for assessing biliary fibrosis. It should be a promising tool to assess antifibrotic therapies in PBC or PSC.

Tests for the proportional intensity assumption based on the score process.

Proportional intensity models are widely used for describing the relationship between the intensity of a counting process and associated covariates. A basic assumption in this model is the proportionality, that each covariate has a multiplicative effect on the intensity. We present and study tests for this assumption based on a score process which is equivalent to cumulative sums of the Schoenfeld residuals. Tests within principle power against any type of departure from proportionality can be constructed based on this score process. Among the tests studied, in particular an Anderson-Darling type test turns out to be very useful by having good power properties against general alternatives. A simulation study comparing various tests for proportionality indicates that this test seems to be a good choice for an omnibus test for proportionality.

Primary biliary cirrhosis: incidence and predictive factors of cirrhosis development in ursodiol-treated patients.

BACKGROUND & AIMS: Ursodeoxycholic acid (UDCA) slows the progression of primary biliary cirrhosis (PBC). However, some UDCA-treated patients escape and progress toward cirrhosis and end-stage disease. This study aimed to assess the incidence of cirrhosis in UDCA-treated patients with PBC and to determine the predictive factors of cirrhosis development under this treatment. METHODS: A Markov model was used to describe the progression toward cirrhosis in 183 UDCA-treated patients with PBC. A total of 254 pairs of liver biopsy specimens collected during 655 patient-years were studied. RESULTS: The incidence of cirrhosis after 5 years of UDCA treatment was 4%, 12%, and 59% among patients followed-up from stages I, II, and III, respectively. At 10 years, the incidence was 17%, 27%, and 76%, respectively. The median time for developing cirrhosis from stages I, II, and III was 25 years, 20 years, and 4 years, respectively. The independent predictive factors of cirrhosis development were serum bilirubin greater than 17 mumol/L, serum albumin less than 38 g/L, and moderate to severe lymphocytic piecemeal necrosis. CONCLUSIONS: This study provides new data about the time course of PBC under UDCA and constitutes a rationale for the design and evaluation of clinical trials aimed to assess the efficacy of drugs associated with UDCA.

Time course of histological progression in primary sclerosing cholangitis.

OBJECTIVE: The aim of this study was to determine the time course over which patients with primary sclerosing cholangitis (PSC) progress through the histological stages of the disease. METHODS: One hundred seven patients with PSC who had at least two liver biopsies were identified. The stage information from two consecutive biopsies formed one observation and a continuous time Markov model was used to describe the rate of progression between biopsies. RESULTS: Three hundred seven liver biopsies were performed in the 107 patients giving a total of 200 observations. At 1 yr, 42% of patients in stage II disease progress, 66% at 2 yr, and 93% at 5 yr; whereas 14% of patients in stage III progress at 1 yr, 25% at 2 yr, and 52% at 5 yr. The frequency of progression of stage I disease could not be determined because of the small number of patients in stage I. Regression of histological stage was observed in 30 of 200 total observations (15%), and in 30 of 85 observations (35%) in which there was a change in stage. CONCLUSIONS: These data regarding histological progression in PSC may be potentially helpful in determining the number of patients and length of time necessary to appreciate a treatment effect in clinical trials. However, the high degree of sampling variability in PSC may restrict the usefulness of serial liver biopsies as a means of evaluating treatment efficacy.

Non-invasive assessment of bone density in primary biliary cirrhosis.

BACKGROUND/AIMS: Low bone mass is an important complication of primary biliary cirrhosis (PBC), resulting in an increased risk of fractures and reduced mobility. In the present study, we sought to determine the frequency of low bone mass in PBC, and its relationship to disease severity and non-invasive markers of bone turnover. METHODS: In 36 women with PBC, bone mineral density of the lumbar spine and hip was assessed by dual emission X-ray absorptiometry. Serum and urinary markers of bone turnover were compared with those from age- and sex-matched controls. RESULTS: Spinal osteopenia (T score, -1.5 to -2.5) was present in 15 of the 36 patients (42%), while six others (16%) had established osteoporosis (T < -2.5). Osteopenia of the femoral neck was found in 17 patients (47%), and osteoporosis in five (14%). The severity of liver disease, as determined by Mayo Clinic R score and histological stage, correlated negatively with both regional bone mineral density and total bone mineral content expressed as a ratio to lean body mass. There was a strong positive correlation between serum levels of the procollagen degradation peptides, PICP and PIIINP (r = 0.65, P < 0.001), and both peptides correlated significantly (P < 0.001) with histological stage and Mayo Clinic R score. Fasting urinary pyridinoline and deoxypyridinoline to creatinine ratios were also significantly raised. CONCLUSIONS: Low bone mass in PBC correlates positively with disease severity, and is associated with a net increase in bone resorption, as assessed by urinary collagen cross-link excretion. These markers of bone turnover may be of value in controlled clinical trials aimed at improving bone mass in PBC.

Localisation and semiquantitative assessment of hepatic procollagen mRNA in primary biliary cirrhosis.

BACKGROUND: Chronic liver disease is characterised by excessive deposition of collagen and other extracellular matrix proteins, produced mainly, but not exclusively, by activated hepatic stellate cells in the perisinusoidal space. In primary biliary cirrhosis (PBC) fibrosis is concentrated mainly around the portal tracts. AIMS: To examine the hypothesis that, in addition to hepatic stellate cells, portal tract fibroblasts might play a significant role in the deposition of collagen in PBC. METHODS: Fifty liver biopsy specimens from patients with PBC were studied. An in situ hybridisation technique was adapted to localise and measure semiquantitatively type I procollagen mRNA in formalin fixed, paraffin wax embedded sections, using an 35S labelled cRNA probe specific for the alpha 1 chain of rat type I procollagen. Hepatic fibrogenic activity was also assessed using serum type III procollagen peptide (PIIINP). RESULTS: In PBC, type I procollagen gene expression was significantly increased. Signal was localised mainly in and around inflamed portal tracts, to cells which had the appearances of portal fibroblasts. Signal activity in these cells correlated with the degree of portal fibrosis and inflammation and also with serum PIIINP concentrations. CONCLUSIONS: Results are consistent with the hypothesis that the excessive extracellular matrix, deposited within the liver in PBC, is synthesised not only by hepatic stellate cells but also by portal tract fibroblasts. The semiquantitative assessment of procollagen mRNA in liver biopsy specimens may provide a useful method of evaluating the rate of synthesis of collagen and therefore disease activity in patients with PBC.

Time course of histological progression in primary biliary cirrhosis.

Histological staging is used for stratification and assessment of treatment efficacy in therapeutic trials for primary biliary cirrhosis (PBC). Knowledge of the rate of progression of the histological changes would be helpful in the design (duration) and conduct of clinical trials. The histological stages were recorded for liver biopsies performed annually on 222 patients during a randomized, placebo-controlled clinical trial in which therapy with D-penicillamine (DPCA) was shown to be ineffective. These data were analyzed using a Markov model to describe the time course of histological progression in PBC. At study entry, 15 patients were stage I, 56 were stage II, 96 were stage III, and 55 were stage IV. Histological progression was observed after 1 year in 41%, 43%, and 35% of the patients, and after 2 years in 62%, 62%, and 50% of the patients who were stage I, stage II, and stage III at entry, respectively. After 4 years biopsies showed cirrhosis in 31% and 50% of the patients in stage I and stage II at entry, respectively. A minority (20%) of the precirrhotic patients showed histological stability; sustained histological regression was rarely observed (2%). Our data suggest that a majority of patients with PBC will progress histologically within 2 years. The distribution of histological stages over time may be helpful in determining the number of patients and length of time necessary to appreciate a treatment effect on histological progression in clinical trials for PBC.

Semiquantitative assessment of cholestasis and lymphocytic piecemeal necrosis in primary biliary cirrhosis: a histologic and immunohistochemical study.

Histologic activity of chronic cholestasis and lymphocytic piecemeal necrosis, a characteristic finding of chronic active hepatitis, was examined semiquantitatively in 157 liver biopsy specimens from 122 patients with primary biliary cirrhosis (PBC). Although both of these lesions were usually admixed variably in a single liver specimen, semiquantitative assessment made it possible to classify liver biopsy specimens into four groups: group A, no or minimum cholestatic or hepatitic changes (58 specimens); group B, predominantly cholestatic changes (37 specimens); and group C, predominantly hepatitic changes (54 specimens). Only eight specimens fell into group D, prominent cholestatic as well as hepatitic changes. Serial liver biopsies of specimens within groups B and C showed a persistence of group B- and C-type pathologies, while liver biopsies of group A specimens frequently changed to group B or C. Immunohistochemical studies illustrated that lymphocytic piecemeal necrosis mainly consisted of activated T lymphocytes as seen in chronic active hepatitis. Our data suggest that either of two hepatic parenchymal lesions predominates and persists in each liver biopsy specimen. A high cholestatic score appeared to relate to poor prognoses of the patients and also to the degree of cirrhotic transformation. This grouping system may be valuable in the clinicopathologic assessment of PBC, when it is combined with ordinary staging.