Lower Fibrosis Stage Research Articles

Real-world results of direct-acting antivirals use for the treatment of chronic hepatitis C in old patients.

Old people with chronic hepatitis C (HCV) were considered a difficult-to-treat category with more frequent adverse events until recently. Interferon-free direct-acting antivirals (DAAs) improved treatment adherence and quality of life of old patients. In this study, we aimed at reporting the real-world efficacy and safety of DAAs, in addition to predictors of sustained virological response (SVR) in old chronic HCV population. This is a prospective observational intention-to-treat analysis that included old chronic hepatitis C genotype-4 patients (> 65years) treated in a single specialized viral hepatitis treatment center in Egypt. Treatment regimens were allocated according to national guidelines for treatment of hepatitis C. Primary outcome was undetectable HCV-RNA at 12-week post-treatment by PCR. Secondary outcomes were identification of predictors of SVR and assessment of safety related issues. Our study included 864 patients (64% females) with mean age of 67.7 ± 2.8years. Overall SVR rate was 98.9% while SVR rates for sofosbuvir/daclatasvir/ribavirin, paritaprevir/ombitasvir/ritonavir/ribavirin, sofosbuvir/daclatasvir, sofosbuvir/ledipasvir/ribavirin, sofosbuvir/simeprevir/daclatasvir/ribavirin, sofosbuvir/simeprevir, interferon/sofosbuvir/ribavirin and sofosbuvir/ribavirin were 100%, 100%, 100%, 100%, 100%, 99.3%, 98% and 94.2%, respectively. DAAs were well tolerated. None of the patients discontinued the treatment due to adverse effects. Higher albumin, higher platelet count, lower bilirubin and lower stage of fibrosis were among predictors of favourable response. Different DAAs regimens were safe and effective in old Egyptian patients with chronic HCV.

Real world experience with the all-oral interferon free regimen for the treatment of chronic hepatitis c virus infection in the Lebanese population.

The treatment of hepatitis C has dramatically improved since the introduction of the new Direct-Acting Antivirals (DAAs). The aim of this study is to assess the effectiveness and safety of all oral DAAs with or without ribavirin in the treatment of hepatitis C virus (HCV) in treatment naïve and experienced Lebanese population. We reviewed all cases approved for hepatitis C treatment with DAAs according to the Lebanese guidelines for treatment of HCV at the Ministry of Public Health from October 2015 till December 2016. Available data concerning age, sex, mode of transmission, genotype (GT) and subtype, fibrosis stage, previous treatment (if present), new DAAs treatment, and sustained virological response at week 12 (SVR12) were collected. During a period of 15 months (October 2015 to December 2016), 186 patients were treated with DAAs. 57% were male and the mean age was 54.3 years. The source of infection was unknown in 51% of cases and blood transfusion in 35.5% of cases. Genotype 1 was the most predominant genotype (45%), followed by GT4 (34%) and GT3 (12%). 71.6% of patients had advanced fibrosis before starting DAAs and 57% were cirrhotic. 42% of patients were treatment experienced (85% pegylated interferon and ribavirin). Different DAAs regimens were used according to the Lebanese guidelines for treatment of HCV: Ledipasvir/Sofosbuvir (38.7%), Sofosbuvir/Daclatasvir (16.1%), Sofosbuvir/Velpatasvir (1.6%), Sofosbuvir/RBV (7.5%), Ombitasvir/Paritaprevir/Ritonavir (17.5%) and Ombitasvir/Paritaprevir/Ritonavir -Dasabuvir (18.8%). Ribavirin was used in 51.6% of cases. SVR12 was achieved in 93% of patients (relapse in 4%, loss of follow up and/or severe adverse effect in 3%). SVR 12 was achieved in 93%, 96% and 94% of GT1, GT3 and GT4 cases respectively. SVR12 was seen in 91.3% of cirrhotic patients vs. 98.7% of F0-F3 patients. (p = 0.047). There was no difference in SVR12 between treatment naïve and experienced patients. Hepatocellular carcinoma developed in 5 patients (2.9%) during the study period. This is the first real world Lebanese data of HCV treatment with DAAs. The study population was significant for a large number of patients with cirrhotic (50%) and treatment experienced patients (42%). SVR12 was achieved in 93% of patients with no difference between treatment naïve and experienced patients. SVR12 was lower in patients with cirrhosis compared to patients with lower stage of fibrosis (91.3% vs. 98.7%).

Prevalence of hepatitis C and fibrosis stage per age group in Lebanese population

In Lebanon, hepatitis C virus (HCV) prevalence is estimated to 0.2% among all ages, with genotype 1 the most common genotype. The age distribution shows 2 peaks reflecting 2 probable mode of transmission of HCV in Lebanon: 20-39 years and more than 40 years. The burden of HCV-related complications on the health system in Lebanon is expected to increase in the upcoming years. The number and prevalence per age group and the fibrosis stage of HCV infections is required to better estimate the burden of the disease in Lebanon. We calculated the prevalence per age group. Concerning fibrosis stage, patients recently diagnosed with HCV and never been treated previously were included and were divided into three groups according to their age Concerning the prevalence by age group, the lowest was seen in the group less than 20 years and the highest in the population aged more than 60. Concerning the fibrosis by age group, the majority of patients less than 40 years had low fibrosis stage, while in the group of more than 60 years F3 and F4 represent respectively 15.07% and 68.49%. Female gender had more significant fibrosis and cirrhosis than male gender. There is an exponential increase of significant fibrosis with age In Lebanon, the highest prevalence of hepatitis C is seen in the age group more than 60 years. In the 2 age groups (40-59 years and >60 years), we noted an advanced fibrosis stage and the majority of patient more than 60 years were cirrhotic at the time of diagnosis, which can reflect the burden of the disease in these groups.

Prediction of high-stage liver fibrosis using ADC value on diffusion-weighted imaging and quantitative enhancement ratio at the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI at 1.5 T.

Background Recently, diffusion-weighted imaging (DWI) and quantitative enhancement ratio measured at the hepatobiliary phase (HBP) of Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) has been established as an effective method for evaluating liver fibrosis. Purpose To evaluate which is a more favorable surrogate marker in predicting high-stage liver fibrosis, apparently diffusion coefficient (ADC) value or quantitative enhancement ratio measured on HBP. Material and Methods Eighty-three patients with 99 surgically resected hepatic lesions were enrolled in this study. DWI was performed with b-values of 100 and 800 s/mm2. Regions of interest were set on ADC map, and the HBP of Gd-EOB-DTPA-enhanced MRI, to calculate ADC value, liver-to-muscle ratio (LMR), liver-to-spleen ratio (LSR), and contrast enhancement index (CEI) of liver. We compared these parameters between low-stage fibrosis (F0, F1, and F2) and high-stage fibrosis (F3 and F4). Receiver operating characteristic analysis was performed to compare the diagnostic performance when distinguishing low-stage fibrosis from high-stage fibrosis. Results LMR and CEI were significantly lower at high-stage fibrosis than at the low stage ( P < 0.01 and P = 0.04, respectively), whereas LSR did not show a significant difference ( P = 0.053). No significant difference was observed in diagnostic performance between LMR and CEI ( P = 0.185). The best sensitivity and specificity, when an LMR of 2.80 or higher was considered to be low-stage fibrosis, were 82.4% and 75.6%, respectively. ADC value showed no significant differences among fibrosis grades ( P = 0.320). Conclusion LMR and CEI were both adequate surrogate parameters to distinguish high-stage fibrosis from low-stage fibrosis.

A randomised controlled trial of losartan as an anti-fibrotic agent in non-alcoholic steatohepatitis.

IntroductionNon-alcoholic fatty liver disease (NAFLD) is a common liver disease worldwide. Experimental and small clinical trials have demonstrated that angiotensin II blockers (ARB) may be anti-fibrotic in the liver. The aim of this randomised controlled trial was to assess whether treatment with Losartan for 96 weeks slowed, halted or reversed the progression of fibrosis in patients with non-alcoholic steatohepatitis (NASH).MethodsDouble-blind randomised-controlled trial of Losartan 50 mg once a day versus placebo for 96 weeks in patients with histological evidence of NASH. The primary outcome for the study was change in histological fibrosis stage from pre-treatment to end-of-treatment.ResultsThe study planned to recruit 214 patients. However, recruitment was slower than expected, and after 45 patients were randomised (median age 55; 56% male; 60% diabetic; median fibrosis stage 2), enrolment was suspended. Thirty-two patients (15 losartan and 17 placebo) completed follow up period: one patient (6.7%) treated with losartan and 4 patients (23.5%) in the placebo group were “responders” (lower fibrosis stage at follow up compared with baseline). The major reason for slow recruitment was that 39% of potentially eligible patients were already taking an ARB or angiotensin converting enzyme inhibitor (ACEI), and 15% were taking other prohibited medications.ConclusionsDue to the widespread use of ACEI and ARB in patients with NASH this trial failed to recruit sufficient patients to determine whether losartan has anti-fibrotic effects in the liver.Trial registrationISRCTN 57849521

Low to moderate lifetime alcohol consumption is associated with less advanced stages of fibrosis in non-alcoholic fatty liver disease

Background and aim: Moderate alcohol consumption has been associated with a lower risk of disease severity in non-alcoholic fatty liver disease (NAFLD). It is unclear if this reflects current or lifetime drinking, or can be attributed to confounders such as diet and exercise. We evaluated the impact of lifetime alcohol consumption on fibrosis severity in NAFLD.Methods: We prospectively enrolled 120 subjects with biopsy-proven NAFLD and through detailed questionnaires examined lifetime alcohol consumption, diet and physical activity. Main outcome measures were odds ratios (OR) for fibrosis stage, calculated through ordinal regression after adjustment for body mass index, diabetes mellitus type 2, smoking and age at biopsy. A biomarker for recent alcohol consumption, phosphatidyl ethanol (PEth) was sampled.Results: An increase in median weekly alcohol consumption to a maximum of 13 drinks per week was associated with lower fibrosis stage (adjusted OR for each incremental unit, 0.86; 95% CI, 0.76–0.97; p = .017). The lowest risk for fibrosis was found with the lowes`t odds seen in the top quartile of alcohol consumption (aOR 0.23; 95% CI 0.08–0.66; p = .006). Adding soft drink and coffee consumptions, and physical activity to the model did not change the estimates. Subjects with PEth ≥0.3 μmol/L had higher ORs for a higher fibrosis stage (aOR 2.77; 95% CI 1.01–7.59; p = .047).Conclusion: Lifetime alcohol consumption with up to 13 units per week is associated with lower fibrosis stage in NAFLD. Elevated PEth is associated with higher stages of fibrosis.

Histological severity and clinical outcomes of nonalcoholic fatty liver disease in nonobese patients.

Nonobese NAFLD patients tend to have less-severe disease and may have a better prognosis than obese patients. Hypertriglyceridemia and higher creatinine are the key factors associated with advanced liver disease in nonobese patients. (Hepatology 2017;65:54-64).

Acoustic radiation force impulse accuracy and the impact of hepatic steatosis on liver fibrosis staging.

The accuracy of Acoustic Radiation Force Impulse (ARFI) imaging has been validated in the setting of hepatitis C, however, the accuracy in the setting of fatty liver disease (FLD) has been less well-established. The aim of this study was to assess the accuracy of ARFI in the setting of hepatic steatosis. Patients with biopsy proven or sonographically diagnosed liver steatosis were assessed for ARFI trends including: inter-operator concordance, interquartile range, ARFI failure rate, relationship between ARFI velocity and steatosis severity, and concordance between biopsy and ARFI fibrosis scores. Three hundred and forty-nine patients were assessed (53 'biopsy' cohort and 296 'ultrasound' cohort), with 28 patients having biopsy on the same day as ARFI. Low stages of fibrosis (F0/1) were over-estimated by ARFI in 62% of cases with biopsy correlation (n=16, P<0.001), with ARFI offering increased accuracy in regard to higher-stage fibrosis (14/15 cases, 93%). In both the biopsy and ultrasound cohorts the failure rate and median inter-quartile range increased with increasing steatosis, and the inter-operator concordance remained good across all liver steatosis severities. In the setting of steatosis, ARFI is very sensitive in detecting, and accurate in diagnosing, higher stages of fibrosis regardless of steatosis severity. It tends to overestimate the fibrosis category in lower stages of fibrosis. The present study does not show conclusively if the presence of steatosis or its severity independently alters ARFI measurements.

PTH-101 Accuracy of Transient Elastography in Predicting Histological Fibrosis Severity in Treated Autoimmune Hepatitis?: Abstract PTH-101 Table 1

Introduction The role of transient elastography (TE) or Fibroscan in assessing severity of liver fibrosis has been validated against liver biopsy in chronic hepatitis B and C and in NAFLD. There are few studies assessing its role in autoimmune hepatitis (AIH). Four preliminary studies have reported data on the role of Fibroscan in AIH. In these, most patients had recently started treatment and thus, still had active disease. Minimal data on transaminases was provided. We aimed to assess the accuracy of Fibroscan in predicting histological fibrosis severity in patients who had achieved biochemical remission (normal transaminases) and were undergoing follow-up liver biopsy to confirm histological remission as per our Unit’s clinical policy. Methods Between 1/12/13 and 31/12/15 36 same-day Fibroscan and liver biopsy were performed in 32 patients with AIH (1999 International Group criteria; 25 female, age 56 (17–78) years who had achieved biochemical remission (normal serum ALT and globulins) after 2.7 (2.1–24.9) years treatments. No patient had ascites, extrahepatic cholestasis or congestive cardiac failure based on clinical and laboratory evaluation. Fibroscan was performed in fasted patients using the Echosens machine (M or XL probe used as needed) by trained operators. We assessed how accurately the liver stiffness evaluation (LSE) score on Fibroscan could predict Ishak fibrosis stage on biopsy (assessed independently by AKD). Results The ALT was 21 (9–99), normal value Conclusion In this study, Fibroscan showed good accuracy in excluding, but lower accuracy in predicting Ishak fibrosis stage of 4 or more. Accuracy was improved if a valid scan was obtained. Fibroscan was less accurate in predicting lower fibrosis stages. A combination of methods of assessing liver fibrosis may be necessary in some patients. Disclosure of Interest None Declared

Histogram analysis of noncancerous liver parenchyma on gadoxetic acid-enhanced MRI: predictive value for liver function and pathology.

To clarify whether the heterogeneity of hepatic parenchyma in the hepatobiliary phase on gadoxetic acid-magnetic resonance (MR) imaging is correlated with liver damage. We retrospectively examined the cases of 98 patients with or without chronic liver disease who underwent gadoxetic acid-enhanced 3T MR imaging before a hepatectomy between December 2010 and October 2014. For the evaluation of the heterogeneity of the signal intensity in the hepatobiliary phase, we placed the region of interest on the hepatic parenchyma, and the skewness and kurtosis were calculated using ImageJ software. A discriminant analysis was performed to examine the routine preoperative laboratory test results including indocyanine green retention at 15min (ICG-R15), necro-inflammation grade, and liver fibrosis stage according to the METAVIR system: A0/1 (n=69) and A2 (n=29); F0/1 (n=47), F2/3 (n=31), and F4 (n=20). The combination of skewness and kurtosis could discriminate the high ICG-R15 (>20) and low (<20) groups (lambda; 0.925, p=0.025), necro-inflammatory grade (lambda; 0.926, p=0.026), and fibrosis stage (lambda; 0.752, p<0.0001) with statistical significance. The difference between the patients with normal values and those with an abnormal platelet count or aspartate transaminase level was also detectable (lambda; 0.901, p<0.007, and lambda; 0.864, p=0.001, respectively). Histogram analyses of the hepatobiliary phase of gadoxetic acid-enhanced MR imaging have potential as a biomarker for the assessment of liver function, liver fibrosis, and necro-inflammation.

Evaluation of Dual Therapy in Real Life Setting in Treatment-Naïve Turkish Patients with HCV Infection: A Multicenter, Retrospective Study.

Before the introduction of direct-acting antivirals in the treatment of chronic hepatitis C patients, the combination of peginterferon alpha and ribavirin was the standard therapy. Observational studies that investigated sustained virological response (SVR) rates by these drugs yielded different outcomes. The goal of the study was to demonstrate real life data concerning SVR rate achieved by peginterferon alpha plus ribavirin in patients who were treatment-naïve. A multicenter, retrospective observational study. The study was conducted retrospectively on 1214 treatment naïve-patients, being treated with peginterferon alpha-2a or 2b plus ribavirin in respect of the current guidelines between 2005 and 2013. The patients' data were collected from 22 centers via a standard form, which has been prepared for this study. The data included demographic and clinical characteristics (gender, age, body weight, initial Hepatitis C virus RNA (HCV RNA) level, disease staging) as well as course of treatment (duration of treatment, outcomes, discontinuations and adverse events). Renal insufficiency, decompensated liver disease, history of transplantation, immunosuppressive therapy or autoimmune liver disease were exclusion criteria for the study. Treatment efficacy was assessed according to the patient's demographic characteristics, baseline viral load, genotype, and fibrosis scores. The mean age of the patients was 50.74 (±0.64) years. Most of them were infected with genotype 1 (91.8%). SVR was achieved in 761 (62.7%) patients. SVR rate was 59.1% in genotype 1, 89.4% in genotype 2, 93.8% in genotype 3, and 33.3% in genotype 4 patients. Patients with lower viral load yielded higher SVR (65.8% vs. 58.4%, p=0.09). SVR rates according to histologic severity were found to be 69.3%, 66.3%, 59.9%, 47.3%, and 45.5% in patients with fibrosis stage 0, 1, 2, 3 and 4, respectively. The predictors of SVR were male gender, genotype 2/3, age less than 45 years, low fibrosis stage, low baseline viral load and presence of early virological response. SVR rates to each peginterferon were found to be similar in genotype 1/4 although SVR rates were found to be higher for peginterferon alpha-2b in patients with genotype 2/3. The number of patients who failed to complete treatment due to adverse effects was 33 (2.7%). The number of patients failed to complete treatment due to adverse effects was 33 (2.7%). Our findings showed that the rate of SVR to dual therapy was higher in treatment-naïve Turkish patients than that reported in randomized controlled trials. Also peginterferon alpha-2a and alpha-2b were found to be similar in terms of SVR in genotype 1 patients.

Evaluation of APRI and FIB-4 scoring systems for non-invasive assessment of hepatic fibrosis in chronic hepatitis B patients

While the gold standard in the assessment of liver fibrosis remains liver biopsy, non-invasive methods have been increasingly used for chronic hepatitis B (CHB). This study aimed to evaluate the performance of two commonly used non-invasive scoring systems (aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis index based on four factors (FIB-4)) to predict fibrosis stage in CHB patients. Demographic, histologic and clinical laboratory data from two trials investigating tenofovir disoproxil fumarate in CHB were analyzed. Predicted fibrosis stage, based on established scales and cut-off values for APRI and FIB-4 scores, was compared with Ishak scores obtained from liver biopsy at baseline and at 240 week follow-up. In the 575 patients with a baseline liver biopsy, APRI and FIB-4 scores correlated with Ishak stage (p<0.01); however extensive overlap in the distribution of both scores across Ishak stages prevented accurate determination of fibrosis. The majority (81-89%) of patients with advanced fibrosis or cirrhosis were missed by the scores. Similarly, 71% patients without fibrosis were misclassified as having clinically significant fibrosis. APRI and FIB-4 scores at week 240 tended to be low and underestimate fibrosis stage in the patients with liver biopsies after 240 weeks of therapy. APRI or FIB-4 reduction did not correlate with fibrosis regression after 240 weeks of antiviral therapy. APRI and FIB-4 scores are not suitable for use in clinical practice in CHB patients for assessment of hepatic fibrosis according to Ishak stage, especially in gauging improvements in liver fibrosis following therapy.

Usefulness of Cytokeratin-18M65 in Diagnosing Non-Alcoholic Steatohepatitis in Japanese Population

Objective: The aim of this study was to evaluate cytokeratin-18M65 (CK-18M65) for distinguishing between simple steatosis (SS) and non-alcoholic steatohepatitis (NASH) against healthy individuals (HIs) in Japanese population. Methods: The serum from 24 HIs, 21 patients with SS and 20 patients with NASH were examined. Serum CK-18M65 was measured by enzyme-linked immunosorbent assay. Results: Aspartate aminotransferase was significantly different between NASH patients and HIs with p < 0.0001 (SS patients and HIs: p < 0.0001), as was alanine aminotransferase between NASH patients and HIs with p < 0.0001 (SS patients and HIs: p < 0.0001). Serum CK-18M65 increased in a stepwise fashion in HIs and also in SS and NASH patients. Multivariate logistic regression analysis revealed that NASH could be diagnosed with the use of CK-18M65 alone (p = 0.0285, OR 1.0038, 95% CI 1.0004-1.0073). At the optimal cut-off level of 548 U/l, CK-18M65 had an AUC value of 0.7369, 60.00% sensitivity and 85.70% specificity. In patients with NASH, no significant difference was observed between low fibrosis (Stage 0-1, 794.30 ± 454.41, n = 10) and high fibrosis (Stage 2-3, 809.70 ± 641.43, n = 10; p = 0.5967) and between slight steatosis (<33%, 512.89 ± 229.65, n = 9) and moderate steatosis (≥33%, 655.13 ± 480.78, n = 32) in patients with non-alcoholic fatty liver disease (NAFLD; p = 0.7647) with the use of CK-18M65. Conclusion: Serum CK-18M65 distinguished NASH from SS, but could not assess the severity of steatosis in NAFLD patients or the grade of fibrosis in NASH patients in Japanese population.

Macrophage activation marker soluble CD163 and non-alcoholic fatty liver disease in morbidly obese patients undergoing bariatric surgery.

Macrophages play an important role in non-alcoholic fatty liver disease (NAFLD). Soluble CD163 (sCD163) is a specific marker of macrophage activation. We aimed to measure sCD163 in morbidly obese patients with varying degrees of NAFLD before and after bariatric surgery (BS). Demographic, clinical, and biochemical data, and plasma sCD163 measured by enzyme-linked immunosorbent assay, of 196 patients were collected preoperatively and 3, 6, and 12 months after BS leading to significant weight loss. Peroperative liver biopsies were assessed for the NAFLD Activity Score (NAS), Kleiner fibrosis score, and the fatty liver inhibition of progression (FLIP) algorithm. In a subset, CD163 immunohistochemistry and real-time quantitative polymerase chain reaction for CD163 mRNA were performed. sCD163 was higher in patients with NAS ≥ 5 compared with those with NAS < 5 (2.4(2.0-3.1) vs 1.9(1.5-2.3) mg/L, P < 0.001) and in patients with bridging fibrosis (F ≥ 3) compared with lower fibrosis stages (2.6(2.0-4.9) vs 2.0(1.5-2.4) mg/L, P = 0.001). Preoperative sCD163 was independently associated with both the NAS (P = 0.002) and the fibrosis score (P = 0.024). sCD163 decreased after BS and was greatly reduced after 12 months, more rapidly so in patients with NAS ≥ 5 (P < 0.001) and non-alcoholic steatohepatitis (NASH) according to the FLIP algorithm (P = 0.03). Immunohistochemistry showed CD163-positive macrophages aligning fat-laden hepatocytes and forming microgranulomas in patients with NASH. CD163 mRNA expression did not vary with NAS. sCD163 increased in parallel with the severity of NAFLD in morbid obesity, indicating macrophage activation. BS reduced sCD163 even in patients with severe liver injury and fibrosis, suggesting full reversibility of macrophage activation associated with improved insulin sensitivity.

Evaluation of area-based collagen scoring by nonlinear microscopy in chronic hepatitis C-induced liver fibrosis.

In this paper we analyze a fibrosis scoring method based on measurement of the fibrillar collagen area from second harmonic generation (SHG) microscopy images of unstained histological slices from human liver biopsies. The study is conducted on a cohort of one hundred chronic hepatitis C patients with intermediate to strong Metavir and Ishak stages of liver fibrosis. We highlight a key parameter of our scoring method to discriminate between high and low fibrosis stages. Moreover, according to the intensity histograms of the SHG images and simple mathematical arguments, we show that our area-based method is equivalent to an intensity-based method, despite saturation of the images. Finally we propose an improvement of our scoring method using very simple image processing tools.

Favorable Results of Allo-HSCT from MRD in Patients with Myelofibrosis

Introduction: Myelofibrosis (MF), chronic myeloid malignancy associated with shortened survival, in majority of patients develops de novo as Primary MF, but also polycythemia vera (PV) or essential thrombocythemia (ET) may progress into post-PV or post-ET MF. Although management of MF includes several treatment options, the only potentially curative treatment approach in MF is allogeneic hematopoietic stem cell transplantation (allo-HSCT). Aim of this study was to evaluate the results of allo-HSCT in patients with MF treated in Katowice, Poland.Material and Methods: 27 pts (14 male and 13 female) with median age 51 years (range 21–63) were treated with allo-HCT due to PMF (20), post-PV (4) or post-ET (3) MF. 11,7,11,26 and 41% of pts had DIPSS 0,1,2,3 and 4, respectively. Median bone marrow cellularity was 70% (10-100%), fibrosis was collagen-type (14 pts including 2 with osteosclerosis), reticulin (10) or it was not specified (3). Splenomegaly was present in all pts: 13-20 cm (14 pts), > 20 cm (13 pts). JAK2V617F point mutation was present in 18 pts. Karyotype was available in 14 pts: in 9 normal, in 5 with variable abnormalities. Median time from diagnosis to allo-HCT was 1.5 (0.4–9.5) years. 16 pts (59.3%) received cells from HLA-matched related donor (MRD), 11 pts (40.7%) from unrelated donor: 10/10 (9) or 9/10 (2) HLA-A,B,C,DR,DQ alleles matched. Reduced intensity conditioning (RIC) was used in 26 pts, 1 patient received myeloablative conditioning (MC). Sources of stem cells were: peripheral blood (21), bone marrow (4) and both (2). All pts but one had chronic phase of MF at time of transplantation.Results: 14/27 (52%) pts are alive at median 3.4 (0.4-5.4) years after allo-HSCT: 11/16(69%) from MRD and 3/11(27%) from MUD, p=0.032. Graft failure, graft loss or PRCA were observed in 3, 5 and 1 pt, respectively. Absolute neutrophil count >0.5×109/L and platelet count >50×109/L were achieved at median 16 and 28 days, respectively. 12/27 (44%) pts reached complete blood count of Hb>10 g/dl, Plt>100 G/l and WBC>3.5 G/l; 11 of them (92%) are alive. 6/27 (22%) pts remained either RBC or PLT transfusions dependent post-transplant; 3 of them (50%) died. 9/27 (33%) pts remained both RBC and PLT transfusion dependent and all of them died. JAK2V617F mutation was completely eradicated in 11/16 evaluated previously positive patients (69%), decreased in 4 (25%) and stable in 1(6%) pt. Acute graft-versus-host disease (aGVHD) III-IV developed in 5/27 (19%) and extensive chronic GVHD in 5/19 (26%) pts. Relapse occurred in 4 pts and was treated with subsequent second transplant (in 1 pt thereafter by 3-rd allo-HSCT). Spleen length decreased at median by 5 (0.3-9.2) cm. Out of 7 pts with initial collagen fibrosis who were evaluated post-transplant, 1 had no fibrosis, 5 reticulin type and only in 1 pt collagen fibrosis was stable. Out of 3 pts with initial reticulin fibrosis it disappeared in 2 and progressed to collagen type in 1. Causes of death were GVHD (5 pts: 3 aGVHD, 2 cGVHD) and pancytopenia with either infection (7 pts) or CNS hemorrhage (1 pt).Conclusions: Allo-HSCT, the only curative treatment of myelofibrosis, provides chance of long survival, regression of the disease (lower stage of fibrosis, JAK2V617F eradication) and improved quality of life (transfusion independency, decreased splenomegaly). Transfusion independency may indicate good outcome. Favorable results are observed after allo-HSCT from MRD. DisclosuresNo relevant conflicts of interest to declare.

IL-34 and macrophage colony-stimulating factor are overexpressed in hepatitis C virus fibrosis and induce profibrotic macrophages that promote collagen synthesis by hepatic stellate cells.

Chronic hepatitis C virus (HCV) infection is characterized by progressive hepatic fibrosis, a process dependent on monocyte recruitment and accumulation into the liver. The mediators expressed in chronically injured liver that control the differentiation of human monocytes into profibrotic macrophages (Mφ) remain poorly defined. We report that chronically HCV-infected patients with high fibrosis stages have higher serum levels of macrophage colony-stimulating factor (M-CSF) and interleukin (IL)-34 than HCV-infected patients with lower fibrosis stages and healthy subjects. Immunohistochemistry reveals an intense expression of IL-34 and M-CSF by hepatocytes around liver lesions. In addition, HCV infection and inflammatory cytokines enhance the in vitro production of IL-34 and M-CSF by hepatocytes. We next analyzed the acquisition of profibrotic properties by Mφ generated with M-CSF (M-CSF-Mφ) or IL-34 (IL-34-Mφ). M-CSF and IL-34 up-regulate the expression, by differentiating monocytes, of chemokine (C-C motif) ligand (CCL)2, CCL4, C-C chemokine receptor (CCR)1, and CCR5, which are involved in monocyte recruitment/Mφ accumulation in liver lesions. M-CSF-Mφ and IL-34-Mφ also express the hepatic stellate cell (HSC) activators, platelet-derived growth factor, transforming growth factor beta, and galectin-3. IL-34-Mφ and M-CSF-Mφ induce type I collagen synthesis by HSCs, the main collagen-producing cells in liver fibrosis. IL-13, whose expression correlates with the fibrosis stage in HCV-infected patients, decreases the expression of the collagenase, matrix metalloproteinase 1, by IL-34-Mφ and M-CSF-Mφ, thereby enhancing collagen synthesis. By inhibiting the production of interferon-gamma (IFN-γ) by activated natural killer cells, IL-34-Mφ and M-CSF-Mφ prevent the IFN-γ-induced killing of HSCs. These results identify M-CSF and IL-34 as potent profibrotic factors in HCV liver fibrosis.

Peginterferon alfa-2a and peginterferon alfa-2b combined with ribavirin in patients with genotype 1 chronic hepatitis C: Results of a prospective single-centre study

PurposeThis prospective, randomized, single-centre study compared peginterferons alfa-2a and alfa-2b, combined with ribavirin, in treating patients infected with hepatitis C virus (HCV) genotype 1. Material/methodsHundred-and-one patients received 48 weeks of open-label treatment with peginterferon alfa-2a (180μg/week) and 111 patients received peginterferon alfa-2b (1.5μg/kg/week). All patients received the same dose of ribavirin 1000/1200mg/day, depending on weight. The primary efficacy endpoint was sustained virologic response (SVR), defined as undetectable HCV RNA (<50IU/mL) 24 weeks after the end of treatment. ResultsEarly virologic response (EVR), defined as at least 2log10IU/mL reduction of viral load at 12 weeks, was more common in patients treated with peginterferon alfa-2a (88% vs. 74.8%; p=0.04). However, the difference in SVR was not statistically significant (49.5% vs. 44.1%; p=0.43). ConclusionsPeginterferon alfa-2a treated patients were also more likely to be HCV RNA negative at the end of treatment (67.3% vs. 57.7%), but this difference did not reach statistical significance. Multivariate logistic regression analysis found that SVR was associated with low fibrosis stage (F1–2 by Scheuer; p=0.001) and low serum HCV RNA level (<400,000IU/L; p=0.023). While both forms of peginterferon showed similar efficacy as measured by SVR, use of peginterferon alfa-2b could lower the number of patients receiving unnecessary treatment beyond 12 weeks.

Sa1036 Hepatic Fibrosis After Small-for-Size Liver Transplantation in Rats: Possible Role of TGFβ/SMAD Signaling

this study, we explored whether concomitant medication altered the risk of hepatic fibrosis in NAFLD. Specifically, we sought to ascertain the association between RAS blocking agents (angiotensin converting enzyme blocker or angiotensin II receptor blocker) and severity of hepatic fibrosis in NAFLD patients with hypertension. Methods: This study cohort consisted of 259 hypertensive patients with biopsy proven NAFLD prospectively followed up in hepatology outpatient clinics in Cleveland, OH. Clinical data including demographics, anthropometry, medical history, medication history, biochemical and liver biopsy findings were evaluated. Patients with and without RAS blocker use were compared in relation to liver fibrosis stage. Utilizing electronic medical records, risk factors for advanced fibrosis were explored, in particular, the association between commonly used medications and advanced fibrosis. Independent risk factors for advanced fibrosis were ascertained using binary regression. Results: The mean age of the cohort was 52.2 years and mean BMI was 37.33 kg/m2. Females, diabetics and patients with advanced fibrosis comprised 64.9%, 60.2% and 35.9% of the cohort respectively. Patients treated with RAS blockers had significantly less ballooning (1.05 vs. 1.33, p=0.002) and lower fibrosis stage (1.64 vs. 2.24, p=0.001) on liver biopsy compared to patients not treated with RAS blockers. Compared to patients without advanced fibrosis, patients with advanced fibrosis were older (54.6 vs. 50.9 years, p=0.014), more often diabetic (76.3 vs. 50.9%, p=0.000), had more ballooning on histology (1.57 vs. 0.93, p=0.000), more likely to be on insulin (22.6 vs. 11.5%, p=0.018), and sulfonylureas (29.0 vs. 15.8%, p=0.011) while less likely to be on RAS blockers (49.5 vs. 70.3%, p=0.001). On multivariate analysis, grade of ballooning had an independent positive association with advanced fibrosis (OR 7.539; 95%CI 3.402-16.706, p=0.000) while usage of RAS blockers had a negative association with advanced fibrosis (OR 0.293; 95%CI 0.1090.787, p=0.015). Conclusion: Hypertensive patients with NAFLD treated with RAS blockers had less advanced hepatic fibrosis, suggesting a beneficial role for angiotensin blockers to protect against NASH fibrosis. Prospective clinical trials are warranted to explore this association in greater detail.

A Study of CC-Chemokine Receptor 5 (CCR5) Polymorphism on the Outcome of HCV Therapy in Egyptian Patients

Background:Chronic hepatitis C virus (HCV) infection is a globally serious public health issue.Objectives:In this study, we investigated CC chemokine receptor 5 (CCR5-59029) polymorphism which is considered an important component of the immune system in determining the outcome of HCV infection. Its critical role as a marker in response to interferon therapy of HCV infection is also investigated besides its effect on other clinical patient factors.Patients and Methods:This study was conducted on 82 Egyptian patients with chronic Hepatitis C Virus (HCV) infection who received PEG-INF + Ribavirin treatment for 48 weeks. The study was also conducted on 50 healthy controls (with negative results for HCV antibody and RNA PCR). Full history of patients in this study was recorded. Clinical and histological examinations, qualitative HCV nested RT-PCR, quantitative real –time PCR, and genotyping of HCV RNA genome were performed. CCR5-59029 polymorphism with nucleotide substitution from G to A was amplified. The amplicons were digested with restriction endonuclease Bsp 1286I, and produced RFLPs of the CCR5 genotypes were determined.Results:The present study showed a significant association between the functional SNP of CCR5 gene and the viral response to interferon in chronic HCV Egyptian patients. It was shown that the higher fibrosis stages (F2-F4) had significant association with nonresponse to treatment compared to the lower fibrosis stages (F0-F1) (95% confidence: 5.497 - 55.074, P = 0.0001). In addition, worse liver activity grade (A2-A3) had a very highly significant association with non-responder HCV patients compared to those with better liver activity grade (A1) (95% confidence: 2.242 - 20.974, P = 0.0007). Most importantly HCV patients with G allele had a high significant association with nonresponse to treatment, higher fibrosis stages and worse liver activity grades, while the A allele had a high significant association with sustained response, low fibrosis stages and relatively better liver activity grade (95% confidence: 3.347 - 15.036, P = 0.0001).Conclusions:SNPs within the CCR5 gene should be considered as an important factor used in combination with other host gene SNPs when developing a mathematical model for anticipating response to HCV therapy.