High-grade Fibrosis Research Articles

Differentiation of nonalcoholic from alcoholic steatohepatitis: are routine laboratory markers useful?

Specific markers for differentiation of nonalcoholic (NASH) from alcoholic steatohepatitis (ASH) are lacking. We investigated the role of routine laboratory parameters in distinguishing NASH from ASH. Liver biopsies performed at our hospital over a 10-year period were reviewed, 95 patients with steatohepatitis identified and their data prior to biopsy reevaluated. The diagnosis NASH or ASH was assigned (other liver diseases excluded) on the basis of the biopsy and history of alcohol consumption (< 140 g/week). Logistic regression models were used for analysis. NASH was diagnosed in 58 patients (61%; 30 f) and ASH in 37 (39%; 9 f). High-grade fibrosis (59% vs. 19%, P < 0.0001) and an AST/ALT ratio > 1 (54.1% vs 20.7%, P = 0.0008) were more common in ASH. The MCV was elevated in 53% of ASH patients and normal in all NASH patients (P < 0.0001). Multivariate analysis identified the MCV (P = 0.0013), the AST/ALT ratio (P = 0.011) and sex (P = 0.0029) as relevant regressors (aROC = 0.92). The AST/ALT ratio (P < 0.0001) and age (P = 0.00049) were independent predictors of high-grade fibrosis. Differences in MCV were more marked in high-grade fibrosis. Higher MCVs and AST/ALT ratios in ASH reflect the severity of underlying liver disease and do not differentiate NASH from ASH. Instead, these biomarkers might prove useful in guiding selection of patients for liver biopsy and in targeting therapy.

13C‐methacetin breath test as a quantitative liver function test in patients with chronic hepatitis C infection: continuous automatic molecular correlation spectroscopy compared to isotopic ratio mass spectrometry

The (13)C-methacetin breath test (MBT) has been proposed for the non-invasive evaluation of hepatic microsomal activity. To test a new continuous breath analysis system (BreathID) in comparison with gold-standard isotopic ratio mass spectrometry (IRMS) in patients with chronic hepatitis C infection and to assess the diagnostic performance of these validation data compared with liver biopsy for the quantification of liver fibrosis. Fifty patients at different METAVIR stages received 75 mg of (13)C-methacetin. Breath isotopic ratio was analysed over 90 min by BreathID (one sample/3 min; BreathID) and IRMS (one sample/10 min). Results were expressed as delta over baseline [DOB (%)] at each time interval and maximal DOB [DOB(max)(%)]. A high linear association between both methods was observed (R(2) = 0.95, P < 0.001). For all DOB and DOB(max), the limits of agreement by Bland-Altman analysis were within the predefined maximal width of s.d. <2.5%. MBT parameters in patients with high-grade fibrosis were different from patients with low-grade fibrosis (P < 0.001). The MBT obtained by an easy to operate, automated BreathID provides results comparable with standard IRMS and differentiates fibrosis grades in patients with chronic hepatitis C infection.

From Trials to a Real Hospital Setting: Effectiveness of Pegylated Interferon-α-2b/Ribavirin Combination Therapy for Naïve Chronic Hepatitis C Patients

Registration trials regarding pegylated interferon treatment of hepatitis C have created great expectations for improved results, but there is little information on actual outcomes in everyday hospital practice. We aimed to define the effectiveness of this treatment in a hospital setting. Seventy-four naïve patients with hepatitis C treated with 12 kD-pegylated-interferon-alpha-2-b/ribavirin (PEG-IFN) were retrospectively analyzed in comparison with 54 patients treated with IFN-alpha-2-b/ribavirin (STANDARD IFN) and with results of three main registration trials. Overall sustained viral response rates were 46% in the STANDARD IFN group and 54% in PEG-IFN group, ranging from 48-61% in similar arms of the registration trials considered, although more of our patients presented comorbidity and high-grade fibrosis, and our dosages at outset of PEG-IFN were lower than optimal (mean 1.18 microg/kg BW). In our hospital setting, the effectiveness of PEG-IFN/ribavirin therapy appeared similar to that reported in large registration trials.

Treatment of hepatitis C virus genotype 4 with peginterferon alfa-2a: Impact of bilharziasis and fibrosis stage

To evaluate pegylated interferon alpha2a (PegIFN-alpha2a) in Egyptian patients with HCV genotype 4, and the impact of pretreatment viral load, co-existent bilharziasis and histological liver changes on response rate. A total of 73 naive patients (61 with history of bilharziasis) with compensated chronic HCV genotype 4 were enrolled into: group A (38 patients) who received 180 mg PegIFN-alpha2a subcutaneously once weekly for a year and group B (35 patients) received IFN alpha-2a 3 MU 3 times weekly. Ribavirin was added to each regimen at a dose of 1200 mg. Patients were followed for 72 wk and sustained response was assessed. Significant improvement in both end of treatment response (ETR) (P < 0.002) and sustained response (SR) (P < 0.05) was noted with pegylated interferon, where ETR was achieved in 29 (76.3%) and 14 patients (40%) in both groups respectively, and 25 patients in group A (65.8%) and 9 (25.7%) in group B could retain negative viraemia by the end of follow up period. Sustained virological response (SVR) showed a significant negative correlation with age and positive correlation with pretreatment inflammation in patients receiving PegIFN. Viral clearance after 3 mo of therapy was associated with high incidence of ETR and SR (P < 0.001), but without significant difference between both forms of interferon. Significant improvement in response was achieved in patients with high grade fibrosis (grade 3 and 4) with PegIFN-alpha2a, where SR was seen in 5 out of 13 patients in group A, but none in group B. There was no significant difference in response between bilharzial and non-bilharzial patients in both groups. In terms of safety and tolerability, neutropenia was the predominant side effect; both drugs were comparable. PegIFN-alpha2a combined with ribavirin results in improvement in sustained response in HCV genotype 4, irrespective of history of bilharzial infestation.

External Validation for Fibrosis Predicting Index in Hereditary Hemochromatosis

Gastroenterology, Mendaro Hospital (Castiella) Clinical Epidemiology, Donostia Hospital (Emparanza)

Duration of Hepatic Iron Exposure Increases the Risk of Significant Fibrosis in Hereditary Hemochromatosis: A New Role for Magnetic Resonance Imaging

Hepatic fibrosis is a complication of hereditary hemochromatosis. The aim of this study was to determine whether the product of the magnitude and duration of hepatic iron exposure is related to the risk of significant fibrosis. Receiver-operating characteristic curve analysis to determine the utility of hepatic iron concentration (HIC) and age in the diagnosis of low- or high-grade fibrosis was undertaken retrospectively in 60 subjects who had undergone liver biopsy for assessment of hereditary hemochromatosis. A prospective pilot study was then conducted in 10 additional subjects to evaluate utility of magnetic resonance imaging (MRI) measurements of HIC to predict fibrosis. Eighteen subjects had high-grade fibrosis while 42 subjects had low-grade fibrosis. Hepatic iron concentration alone was highly sensitive (100%) but of limited specificity (67%) in diagnosis of high-grade fibrosis. The product of [HIC x age] had a sensitivity and specificity of 100% and 86%, respectively, for diagnosis of high-grade fibrosis. Magnetic resonance imaging measurements also provided accurate assignment of subjects into fibrosis severity groups. Duration of exposure to iron is important in the development of hepatic fibrosis in hereditary hemochromatosis. The product of HIC and age is highly sensitive and specific for diagnosis of high-grade fibrosis and can be obtained using MRI.

External Beam Ionizing Radiation for Inhibition of Myointimal Hyperplasia after Dilatation and Anastomoses: Experimental Models and Results

In recent years there has been intensive research on the use of ionizing radiation for inhibition of intimal hyperplasia (IH). Results have clearly established that beta ionizing radiation delivered from an endoluminal source after angioplasty inhibits intimal restenosis. This effect has been confirmed by recent multicenter clinical trials in patients undergoing coronary dilatation. The purpose of this study was to determine if gamma radiation therapy delivered superficially from an external source also reduced smooth muscle cell proliferation in two animals models-the first involving experimentally induced restenosis and the second involving anastomosis between a prosthesis and artery. Ultimately we hope to develop a therapeutic application for patients undergoing peripheral anastomoses, especially in the lower extremities. Two different animal models were used in this two-stage study. The first-stage rabbit model (model 1) involved balloon injury of the aorta to validate the dose effect of external beam irradiation. The second-stage porcine model (model 2) involved aortic bypass followed by external beam irradiation of the distal anastomosis site. In model 1 a total of 56 rabbits were studied. They were divided into five groups including one control group in which external radiation was not applied after balloon injury and four test groups in which external radiation was applied in a single fraction on day 0 at four different doses: 10 grays, 15 grays, 20 grays, and 25 grays. In model 2, a total of 24 pigs underwent aortic bypass with a 6-mm PTFE graft followed by irradiation of the distal end-to-side anastomosis at a dose of 20 grays on day 0. In both models specimens were harvested after 6 weeks and studied histologically after staining with HES and orcein, histomorphometrically by measuring intimal hyperplasia, and immunohistochemically using actin and factor VIII/von Willebrand factor (F VIII/vWF). The zones of study on the anastomosis were separated into base of the artery to the tip and heel of the anastomosis and the edge of the arteriotomy. Measurements were compared using the Mann Whitney test. In the first-stage model designed to study IH in rabbits, mean intimal and medial thickness values and the intima-to-media ratio showed no difference between the control group and the groups irradiated at doses of 10 grays and 15 grays (p = 0.111, p = 0.405, and p = 0.14); (p = 0.301, p = 0.206, and p = 0.199). Conversely, there was a significant difference between the control group and the groups irradiated at 20 grays and 25 grays (p < 0.0001, p = 0.107 and p = 0.008; p = 0.008, p = 0.155, and p = 0.008). Histological examination demonstrated extensive changes in the wall with high-grade fibrosis after application of ionizing radiation. In the second-stage swine model, irradiation significantly inhibited development of IH at the level of anastomosis both at the base of the artery (p < 0.01) (tip 0.06 vs. 0.27 mm and heel 0.04 vs. 0.36) and at the level of the arteriotomy at the suture site (p < 0.001) (0.13 vs. 0.86 mm). Immunochemical analysis of the thickened zones showed a positive reaction of endothelial cells to smooth muscle actin and F VII/vWF. Like irradiation applied using an endoluminal source, superficial gamma ionizing radiation from an external source inhibits IH. Analysis of the dose effect showed that the overall dose must be between 15 and 20 grays. External radiation also reduces overall IH at the anastomosis between a prosthesis and artery. Although these experimental data are promising, further study will probably be necessary before attempting to undertake clinical trials using external beam radiation therapy for patients undergoing peripheral anastomoses.

Histological, Immunohistochemical and clinical study of HEPATIC immune response in CHRONIC hepatitis C

The factors that determine persistence or clearance of hepatitis C virus (HCV) infection are poorly understood. Information in this area may lead to better understanding of the immune response against HCV infection. Such understanding can support the goal of development of a broad based cellular and humoral immune response to HCV which may be important for eradication of infection. In the present study, needle biopsy specimens from hepatitis C virus infected patients were prepared for histological, histopathological and immunohistochemical studies. Patient history, full clinical examination and biochemical investigations were recorded. Primary and secondary lymphoid follicles were evident in ABOUT 50% of the biopsies. Because CD4(+) T- helper (T-h) lymphocytes provide help for humoral immunity, these cells were demonstrated in the liver biopsies by immunohistochemical methods. Positive fluorescence representing CD3(+)/CD4(+) T-h was vigorous in liver residing lymph follicles. To test the possibility of T-h proliferation due to autoimmune reaction, the serum of patients was tested for the presence of antimitochondrial, antismooth muscle and antinuclear antibodies by immunohistochemical method. Analysis of the results eliminated the autoimmune response leaving the possibility of antiviral response. Histological examination indicated bile duct injury in areas occupied by secondary follicles. This may indicate that viral core proteins, with antigenic properties that elucidate immune response, may reach the portal area, in which the follicles are formed, via the bile canaliculi to the bile duct where antigen antibody complex is phagocytosed leading to bile duct injury. Unlike the case of patients who did not show follicles in their liver biopsy, those showing secondary follicles did not show liver cirrhosis or high grade fibrosis suggesting immune protection. Moreover, the incidence of secondary follicles in females was higher than males suggesting sex-dependent immune response. The present study calls for more investigation towards the understanding of the possible immunity and vaccination against virus C hepatitis which may lead to eradication of its infection.

Relationship between grade of fibrosis in pancreatic stump and postoperative pancreatic exocrine activity after pancreaticoduodenectomy: with special reference to insufficiency of pancreaticointestinal anastomosis.

Pancreaticoduodenectomy (PD) has become a standard operation for malignant and benign periampullary diseases. Although the operative mortality of PD has decreased to less than 4% in hospitals with many cases of PD, the leakage of pancreaticointestinal anastomosis (PIA) still carries a substantial risk of lethal outcome. The aim of this study was to evaluate the local factors that affect the incidence of PIA leakage by evaluation of exocrine function and fibrosis in the pancreatic remnant following PD. Twenty-eight patients (17 pancreatic disease, 8 bile duct cancers and 3 ampullary cancers) underwent PD with complete extracorporeal pancreatic juice drainage. The cut-end of the pancreatic remnant was histologically studied for its grade of fibrosis in comparison with the exocrine activity of the pancreatic remnant (EAPR) calculated by the value of the product of volume of drained pancreatic juice and its amylase activity. The influences of those factors and other clinicopathologic data on PIA outcome were evaluated. The histological grade of fibrosis in the pancreatic stump was inversely correlated with EAPR (rs=0.5848, p=0.0011). Three patients had major leakages and 6 had minor leakages of PIA; all the patients with leakages had biliary or ampullary diseases, but not pancreatic diseases. The incidence of leakage of PIA was significantly higher in the patients with high values of EAPR (p<0.05). None with EAPR less than 10(7) had PIA leakage. The incidence of PIA leakage in low-grade fibrosis of the pancreatic stump was significantly higher than that in high-grade fibrosis (p<0.05). Other clinicopathologic data did not influence the incidence of leakage of PIA. The degree of fibrosis in the pancreatic stump is significantly related to the EAPR and affects the development of PIA insufficiency as a local factor.