Progression Of Chronic Hepatitis Research Articles

Helicobacter infection and cirrhosis in hepatitis C virus carriage: is it an innocent bystander or a troublemaker?

Since it has been shown that Helicobacter hepaticus causes both chronic hepatitis and hepatocellular carcinoma (HCC) in mice, it is suggested that differences in the progression of chronic hepatitis C may be due to a cofactor stemming from co-infection by bacteria, especially Helicobacter pylori, and/or other Helicobacter species. An assessment was made of the prevalence of H. pylori infection in HCV-positive cirrhotic patients. The presence of Helicobacter species (spp). was evaluated in resected liver tissue from HCC patients. Serum anti-H. pylori IgG antibodies were determined in 70 males with a clinical and/or histological diagnosis of cirrhosis and HCV infection and in 310 age-matched male blood donors. The prevalences of H. pylori antibody were 77% (54/70) and 59% (183/310) (P 0.004). Primers identifying 26 Helicobacter species were used to determine the presence of the genomic 16S rRNA of this genus in liver tissue resected from 25 cirrhotic HCC patients. Genomic sequences corresponding to H. pylori and H. pullorum were identified in 23 of these 25 livers. Together, these findings support the proposal that H. pylori is implicated in the pathogenesis and progression of cirrhosis, particularly in HCV-infected individuals. Involvement of Helicobacter spp. in HCC also seems highly possible.

Steatosis is a determinant of fibrosis progression in chronic hepatitis C and is correlated both with body composition and viral factors

The knowledge of factors which induced progression of chronic hepatitis C (CHC) is of pr ima~ importance for cfinical, prognostic and therapeutic implications. The aim of this study was to evaluate the role of steatosis in the progression of liver fibrosis. 180 (median age, 49 yrs) consecutive untreated patients with biopsy-proven CHC and stable weight were enrolled. Excluded were patients with diabetes, dydipidemie, alcohol intake >30 g/d, genetic or antoimmune hepatic diseases, or HBV or HIV. Patients were evaluated for histological grading, staging, grading of steatosis (0-4) and hepatic ken, HCV genotype (InnoLipa), levels of viremia CoDNA), body mass index (BMI), waist circumference. O v e r ~ prevalence of steatosis was 41%. HCV genotypes were not correlated with fibrosis. Steatosis was more frequent in patients with genotype 3a (p 40% showed a higher HAI (6.2 vs 5.0; p<0.01), levels of yGT (p<0.0001) and ALT values (p<0.01). In conclusion our study indicates that steatosis is a determinant of fibrosis progression in CHC. Visceral obesity plays a role in the development of steatosis. HCV type 3a seems to have s direct effect on steatogenesis. (Supported by MURST). l P/C06/47 l

Hepatocellular carcinoma. Part 1. General considerations and diagnosis

Several aspects are revised on the subject hepatocellular carcinoma related to its incidence/prevalence, risk and prognostic factors, cellular proliferation, pathological aspects, progression of chronic hepatitis B and C to cirrhosis and hepatocellular carcinoma, natural course of hepatocellular carcinoma, some clinical data, morphological diagnosis with special emphasis on radiological findings as ultrasound, dynamic computed tomography and magnetic resonance imaging, color-power Doppler, tissue and contrast harmonic.

Natural history of hepatitis C

It is now widely accepted that 85% or more of individuals with acute hepatitis C virus (HCV) infection progress to chronic hepatitis, and chronic hepatitis C is a known risk factor for cirrhosis and hepatocellular carcinoma (HCC). However, there has been much controversy about the inevitability of developing cirrhosis and HCC and the time frames in which they are likely to occur. Natural history studies have provided varying estimates of the risk of progression in chronic hepatitis C. Part of this variation may be a result of viral-specific, host, and/or environmental factors, but much of it undoubtedly is a result of the difficulties of doing natural history studies in this disease: acute onset is rarely identified, chronic infection is often asymptomatic, and the duration of disease is prolonged. Three types of studies—prospective, retrospective, and retrospective-prospective (nonconcurrent prospective)—have attempted to determine the clinical outcomes of chronic HCV infection and have provided widely varying estimates. The combined population data indicate that the disease progresses slowly over approximately 30 years, on average. Approximately 20% of infected individuals will progress to fibrosis and cirrhosis. Of these, approximately 20% will progress to HCC. The likelihood of progression appears to be independent of genotype or viral load but increases with alcohol intake, male sex, age over 40 years at infection, and coinfection with human immunodeficiency virus (HIV) or hepatitis B virus (HBV). Results of ongoing nonconcurrent studies are needed to determine disease progression in the third, fourth, and fifth decades of infection and to better define the factors that affect progression.

Pathophysiology and Treatment of Hepatitis C Infection

The pathophysiology and treatment of hepatitis C infection, formerly known as non-A, non-B hepatitis, are discussed. The worldwide prevalence is approximately 1%. The majority of patients infected with hepatitis C virus will develop chronic infection, leading to cirrhosis in a significant percentage. Transmission of hepatitis C is primarily through parenteral routes. Those who use intravenous drugs or received blood transfusions prior to 1992 comprise the major risk groups for the infection. The progression of chronic hepatitis C infection is insidious with possible progression to an inflammatory hepatitis developing within 5–10 years, cirrhosis in 10–20 years, and hepatocellular carcinoma in 20–30 years. Combination therapy with interferon alpha-2b and ribavirin is currently the treatment of choice. Therapy for hepatitis C continues to evolve with newer forms of interferon and HCV antivirals under development.

Factors predicting progression to cirrhosis and hepatocellular carcinoma in patients with transfusion-associated hepatitis C virus infection.

The clinical progression of chronic hepatitis C is not uniform throughout the entire period of infection and is more rapid in patients with advanced histologic disease. Our study was designed to identify factors contributing to progression to cirrhosis and hepatocellular carcinoma by taking the entire period of infection into consideration. Two hundred thirteen patients with transfusion-associated hepatitis type C chronic liver disease were included in this study. They did not have either a history of antiviral therapy or any other potential causes of chronic liver disease except for transfusion. Hepatitis C virus genotype 1b was detected in 144 (68%) patients, followed by 2a in 51 (24%), 2b in 11 (5%), 1a in 4 (2%), and coinfection with 1b and 2a in 3 (1%). The log-rank test in the Kaplan-Meier method revealed that the cumulative percentage of cirrhosis-free or hepatocellular carcinoma-free patients became significantly lower as the transfusion age went up. Patient age at the time of transfusion was the only independent factor related to disease progression in multivariate analysis using Cox's proportional hazards model. Thus age at transfusion should be taken into consideration in designing the optimal follow-up schedule and therapy in patients with posttransfusion-associated chronic hepatitis C.

Modeling the impact of interferon alfa treatment on liver fibrosis progression in chronic hepatitis C: A dynamic view

Background & Aims: Impact of hepatitis C treatment has never taken into account the dynamics of fibrosis progression. This study assessed the impact of interferon on liver fibrosis progression in patients with chronic hepatitis C according to 3-month aminotransferase activity response. Methods: We recruited 287 patients, 185 treated and 102 control, with paired biopsy specimens. Before follow-up, the fibrosis progression rate per year was estimated as the ratio between fibrosis stage in METAVIR units (1 U, 1 stage; 4 U, cirrhosis) and the duration of infection. During follow-up, fibrosis progression was assessed by the observed difference between stages divided by duration between biopsies. Results: The median fibrosis progression rate in treated patients decreased compared with the rate before treatment from 0.103 F METAVIR U/yr (95% confidence interval [CI], 0.087–0.120) to 0.000 (95% CI, 0.000–0.000; P ≤ 0.0001). Among 91 treated responders, fibrosis stage worsened in 19 (22%), compared with 21 (22%) of 94 treated nonresponders and 57 of 102 controls (56%; P ≤ 0.0001 compared with treated patients), and improved in 26 (29%), 17 (18%), and 8 (8%; P = 0.0002 compared with 29% and P = 0.03 compared with 18%), respectively. These observed differences persisted after genotype, viremia, sex, age at infection, duration of infection, and alcohol consumption were taken into account. Conclusions: Interferon treatment changes the natural fibrosis progression rate in patients with chronic hepatitis C independently of genotype and early response. GASTROENTEROLOGY 1999;116:378-386

Clinical implication of vascular cell adhesion molecule-1 and very late activation antigen-4 interaction, and matrix metalloproteinase-2 production in patients with liver disease.

To clarify the role of adhesion molecule in liver cell injury. The serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), and the expression of VCAM-1 and its ligand, very late activation antigen-4 (VLA-4), were examined in patients with various liver diseases. In addition, the presence of matrix metalloproteinase-2 (MMP-2) was investigated because the release of MMP-2 is thought to be mediated by VLA-4-positive cells. sVCAM-1 and MMP-2 were measured by ELISA assay, and VCAM-1 and VLA-4 were studied by immuno-histological methods. In acute hepatitis (AH) patients, the serum level of sVCAM-1 was significantly elevated compared with that in other cohorts. VCAM-1 was expressed on sinusoidal lining cells but not on hepatocytes. In patients with chronic liver disease, sVCAM-1 levels rose in concert with the progression of chronic hepatitis (CH), and VCAM-1 was also expressed. VLA-4 was detected in both mononuclear cells and Kupffer cells in AH livers, but mainly in Kupffer cells in patients with CH. In AH patients, MMP-2 levels were similar to those in control subjects, but in CH and liver cirrhosis patients, MMP-2 level was elevated in association with CH progression. The immune response through the VCAM-1 and VLA-4 pathways is important in hepatocyte injury, especially in AH patients, to attach VLA-4-positive mononuclear cells to VCAM-1-positive sinusoidal lining cells. The distribution of VLA-4-positive cells differs between AH and CH patients. VLA-4-positive Kupffer cells in chronic liver diseases might be involved in the progression of CH, perhaps through the mechanism of upregulation of MMP-2 production.

Texture Analysis of Laparoscopic Images in Chronic Liver Disease.

Determination of the site of progression of chronic liver disease is important for prognosis. In the present study we used texture analysis to quantitatively assess progression based on the appearance of the surface of the liver during laparoscopy. A total of 34 chronic liver disease patients who underwent laparoscopic examinations over a 2-year period were enrolled in this study. Their laparoscopic photographs were classified into a chronic hepatitis or a liver cirrhosis group, and image analysis was performed with intraoperative photographs of laparotomy patients without associated liver disease serving as the normal control group. The photographs of the 3 groups were input into a digital image processorr (NEXUS6400) by a film scanner, and the image data obtained were analyzed by the gray level difference method, the run length method, and fractal number. Significant differences were observed between the quantitative values in the three groups by each of these methods, but it was not possible to evaluate fine changes at the liver surface occurring during the progression of chronic hepatitis to liver cirrhosis.

Risk factors associated with fibrosis progression in chronic hepatitis C: Role of alcohol consumption and age at infection

Risk factors associated with fibrosis progression in chronic hepatitis C: Role of alcohol consumption and age at infection

Progression of type C chronic hepatitis to liver cirrhosis and hepatocellular carcinoma--its relationship to alcohol drinking and the age of transfusion.

Alcohol drinking has been reported to be an important factor that modulates the development and prognosis of chronic hepatitis B; however, little is known about an interrelationship between alcohol intake and the progression of chronic hepatitis C to liver cirrhosis (LC) and hepatocellular carcinoma (HCC). We attempted to clarify this interrelationship in patients with hepatitis C and history of blood transfusion. Thirty LC and 85 HCC patients were enrolled. In patients with LC, no significant correlation was observed between the amount of alcohol intake and the period from transfusion to diagnosis. The period from transfusion to diagnosis in HCC patients with alcohol intake > or = 46 g/day and < 46 g/day were 26 +/- 6 and 31 +/- 9 years, respectively, resulting in a significant difference (p < 0.05). The period from transfusion to diagnosis of LC and/or HCC showed significant negative correlation with the age of transfusion (r = 0.82, Y = -0.67X + 48.0, p < 0.01; r = 0.76, Y = -0.70X + 54.1, p < 0.001, respectively). This correlation was also observed in patients with HCC, regardless of the amount of alcohol intake. In conclusion, these data suggest that alcohol drinking might be an important factor that promotes an occurrence of HCC in patients with hepatitis C, and that hepatitis C virus infection in the elderly promotes development of liver disease via LC to HCC.

Hemosiderin deposition in portal endothelial cells: A novel hepatic hemosiderosis frequent in chronic viral hepatitis B and C

We have recently noted a hitherto undescribed hepatic hemosiderosis confined to endothelial cells of the portal tract in chronic viral hepatitis. In this study, this lesion was surveyed in 156 liver biopsy specimens from patients with chronic hepatitis C and in 21 liver biopsy specimens from patients with chronic hepatitis B. As controls, we examined 110 liver biopsy specimens from patients with primary biliary cirrhosis (PBC), 36 from patients with alcoholic liver injury, nine from patients with autoinunune hepatitis (AIH), and five from patients with primary hemochromatosis. Hemosiderin deposition was found in the endothelial cells of venous vessels in portal tracts regardless of the presence or degree of hemosiderin deposition in hepatic parenchyma. This phenomenon was observed in 65 of 156 cases (42%) of chronic hepatitis C and in eight of 21 (38%) cases of chronic hepatitis B. In controls, this lesion was frequent in AIH (78%), but infrequent in PBC (8.1%) and alcoholic liver injury (11%). The incidence of this lesion showed significant differences between chronic hepatitis C, B, and AIH, and between PBC and alcoholic liver injury. There was a positive correlation between the progression of disease and the incidence of this feature in chronic viral hepatitis; the incidence was 18.3% and 11.1% in milder chronic hepatitis C and B, respectively, and 61.2% and 58.3%, respectively, in more severe cases. However, this correlation was not evident in either PBC or alcoholic liver injury. This hemosiderin deposition was positively correlated with the degree of piecemeal necrosis in chronic hepatitis C, and to a lesser degree, the positive correlation was shown in chronic hepatitis B. These findings suggest that the progression of chronic hepatitis and the piecemeal necrosis in chronic hepatitis C and B, followed by the release of hepatocellular iron to portal and periportal areas, are directly or indirectly responsible for endothelial hemosiderosis. Further studies focusing on this peculiar phenomenon in relation to choice of therapy and evaluation of chronicity of viral hepatitis are encouraged.

Significance of sublobular hepatic necrosis in the progression of chronic hepatitis C.

The clinical characteristics of hepatitis C virus associated chronic liver diseases (C-LD) in 17 patients were compared with hepatitis B virus associated diseases (B-LD) in 47 patients, by analysing the histological findings of the liver and the change in serum alanine aminotransferase (ALT) level. The persistence of the moderate abnormality in ALT (> 100 IU/L) for longer than 1 year was more frequently seen in the C-LD group (P < 0.01), although the severe exacerbation of the disease with ALT higher than 500 IU/L was more frequent in the B-LD group (P < 0.01). The patients with the histological finding of sublobular hepatic necrosis (SN) in the C-LD group progressed to advanced stages more frequently than those with SN in the B-LD group (P < 0.05). Furthermore, nine of 10 patients with SN in C-LD finally progressed to hepatocellular carcinoma (HCC) in 52 +/- 23 months, whereas three of 16 with SN in B-LD developed HCC in 81 +/- 34 months. Although the morphological features of SN in C-LD and B-LD were almost the same, SN in C-LD seemed to be a more significant diagnostic condition for the progression to liver cirrhosis or HCC. The patients with SN in the C-LD group should be closely followed for the early detection of HCC, although further study with a greater number of patients is necessary.

Change of hepatitis B virus DNA distribution associated with the progression of chronic hepatitis.

Hepatitis B virus (HBV) DNA was detected by in situ hybridization in 53 out of 74 liver specimens from patients with chronic HBV infection. The distribution of HBV DNA was classified into three patterns: diffuse (HBV DNA distributed diffusely, within the section of specimen), lobular (HBV DNA was present in 1/3-2/3 of the section) and spotty. All three specimens from asymptomatic HBV carriers showed the diffuse pattern. In the advanced stage of liver disease (chronic active hepatitis with severe activity and liver cirrhosis), a decreased number of specimens showed the diffuse pattern, whereas the number of specimens with the lobular pattern increased. From these data, we conclude that HBV may replicate diffusely in the liver in the early stage of chronic liver disease, and the site of HBV replication becomes localized in the advanced stage of the disease. The main target cells of immunocytes may be hepatocytes undergoing HBV replication, because HVB DNA was frequently detected in areas of focal, piecemeal and bridging hepatic necrosis.

Detection of HBV infectivity by spot hybridization in HBeAg-negative chronic carriers: HBV DNA in sera from asymptomatic and symptomatic subjects.

DNA of hepatitis B virus (HBV DNA) in sera from HBeAg-positive carriers is now the most important and reliable marker of infectivity, but its significance in the progression of chronic hepatitis in anti-HBe carrier status is still under discussion. In this study, viral DNA was tested by a simplified spot hybridization method in sera of 206 HBeAg-negative Italian subjects. In a group of 153 HBsAg carriers, we found that 15.6% of anti-HBe-positive and 10.5% of anti-HBe-negative samples contained viral DNA. No HBV DNA was revealed in 38 HBsAg-negative nor in 15 anti-HBs-positive subjects with different serological markers of HBV. Viral DNA in sera of HBeAg-negative patients with severe chronic liver disease was correlated with increased alaninetransferase activity and IgM anti-HBc. Thus the presence of HBV DNA in these sera not only predicts which subjects are potentially infectious but also indicates chronic progression of hepatitis. Finally, viral DNA extracted from Dane particles of nine anti-HBe-positive sera was characterized by the Southern blot technique. The hybridization pattern shows bands indicating the presence of replicative intermediates.

Hepatic hemodynamics in patients with chronic hepatitis or cirrhosis as assessed by organ-reflectance spectrophotometry

Hepatic hemodynamics in patients with chronic liver disease has been studied by reflectance spectrophotometry of the liver in situ during peritoneoscopy. An organ-reflectance spectrophotometer used in this study was equipped with a branched optic fiber bundle, which coupled the liver surface with the spectrophotometer. The spectrophotometry could measure qualitatively and quantitatively the absorption of hemoglobin in the liver in situ, thus estimating the regional hepatic tissue blood hemoglobin concentration and the saturation level of hemoglobin in the regional tissue blood. The analysis of 42 cases has shown that the estimated regional hepatic tissue blood hemoglobin concentration and saturation level of hemoglobin decreased in most cirrhotic livers, suggesting that even in cirrhotic livers the hepatic oxygen extraction increased, concomitant with a decrease in the regional hepatic tissue blood hemoglobin concentration. The hepatic blood hemoglobin concentration estimated on the surface layer of the liver was positively correlated with the regional hepatic blood flow measured by radioisotope clearance technique. The estimated hepatic blood hemoglobin concentration was also correlated positively with serum albumin level and prothrombin time, and negatively correlated with plasma retention of indocyanine green at 15 min. It is concluded that the hepatic tissue blood hemoglobin concentration decreases significantly with progress of chronic hepatitis to cirrhosis. This decrease in hepatic blood hemoglobin concentration and flow is concomitant with a decrease in metabolic functions, which is not compensated by an increased hepatic oxygen extraction.

Experimental study on the development of liver cell carcinoma. Role of histamine in chronic liver injury.

Role of autotallergic mechanism on the chronicity of liver diseases with special reference to histamine, which is said to be one of the chemical media tors and plays a large part in antigen antibody reaction, was investigated experimentally.Under the administration of homologous liver antigen with histamine to rabbits, liver injury closely resembling chronic active hepatitis could be de veloped, which progressed into liver cirrhosis with pseudolobulus formation. This result may indicate that the progression of chronic hepatitis into liver cirrhosis can be regarded as one process. Estrogen promotes antigen anti body reaction and plays a large part in prolongation and aggregation of liver diseases. Furthermore, liver cell carcinoma was demonstrated in one animal and epithelial hyperplasia of bile ductules in two animals. This fact may sug gest that chronic hepatitis changes into malignant tumor and perpetual anti genic stimulation has a large role in the development and progression of malignant tumor and role of histamine should never be ignored.