Hepatitis C infection in African Americans: its natural history and histological progression

OBJECTIVE: The aim of this retrospective analysis was to determine the natural history of hepatitis C virus infection in African Americans versus non-African Americans by evaluating the clinical, virological, and histological findings. METHODS: We examined in a retrospective manner the demographics, mode of infection, virological features, and histological progression of HCV infection in African Americans versus non-African Americans. There were 355 patients who met criteria based on adequate liver biopsy specimens and exclusion of other hepatic diseases. RESULTS: African Americans (n = 112) were significantly more likely to be infected with genotype 1 virus (88%) than were non-African Americans (n = 243; 67%; p < or = 0.001). Baseline HCV RNA levels were similar, although baseline ALT values were significantly lower in African Americans (80.0 microl +/- 5.5 vs 112.1 microl +/- 6.2; p < or = 0.001). African Americans were significantly older at the time of presentation and were significantly more likely to be women (p < or = 0.02). In African Americans, there was a trend toward less cirrhosis (22% vs 30%; p < or = 0.1) and significantly less piecemeal necrosis on liver biopsy. Non-African Americans had significantly higher fibrosis scores, ALT values, and piecemeal necrosis ratings, and tended to progress more rapidly to cirrhosis. This difference in histological progression between the two groups was not explained by differences in alcohol consumption. CONCLUSION: The lower ALT, piecemeal necrosis scores, and slower progression of fibrosis in African Americans may reflect less immunological recognition of HCV-infected liver cells.     

Hepatitis C virus infection,microRNA and liver disease progression

Hepatitis C virus (HCV) is a global health problem with an estimated 170-200 million peoples (approximately 3% of world population) are chronically infected worldwide and new infections are predicted to be on rise in coming years. HCV infection remains categorized as a major risk factor for chronic hepatitis, liver cirrhosis and hepatocellular carcinoma worldwide. There has been considerable improvement in our understanding of virus life cycle since, the discovery of HCV two-decades ago. MicroRNAs (miRNAs) are important players in establishment of HCV infection and their propagation in infected hepatocytes. They target crucial host cellular factors needed for productive HCV replication and augmented cell growth. Very first anti-miRNA oligonucleotides, miravirsen has been tested in clinical trial and shown promising results as therapeutic agent in treatment against chronic HCV infection. Deregulated expression of miRNAs has been linked to the pathogenesis associated with HCV infection by controlling signaling pathways such as, proliferation, apoptosis and migration. Circulating miRNAs emerging as growing field in identification of biomarkers in disease progression and their potential as a means of communication between cells inside the liver is an exciting area of research in future. This review focuses on recent studies enforcing the contribution of miRNAs in HCV life cycle and coordinated regulation in HCV mediated liver disease progression.     

Hepatitis C virus quasi-species dynamics predict progression of fibrosis after liver transplantation

BACKGROUND: The dynamics of hepatitis C virus (HCV) quasi species in the E2 region may correlate with the course of infection after orthotopic liver transplantation (OLT). METHODS: Thirty-four patients who underwent transplantation for HCV-related cirrhosis were studied. Serum and liver samples were available before OLT and at 1 week, 4 months, and 1 year after OLT. Patients were divided into group 1 (Knodell/Ishak fibrosis stage [FS] at 1 year, <2) and group 2 (FS at 1 year, > or =2). Complexity was estimated by the number of bands in a single-strand conformational polymorphism assay, whereas diversity was measured by Shannon entropy (SE) and median mobility shift (MMS) values derived from the heteroduplex mobility assay. Diversity dynamics were measured at transmission (before OLT vs. 1 week after OLT) and after OLT (1 week after OLT vs. 1 year after OLT). RESULTS: Complexity was higher in group 1 patients than in group 2 patients before OLT (P<.02) and at 1 week after OLT (P<.04). Diversity decreased in group 1 at transmission, as measured by either SE (P<.01) or MMS (P<.04). However, diversity increased in this group after OLT, as measured by SE (P<.03) or MMS (P<.02). FS at 1 year after OLT correlated with transmission changes, as measured by SE (r=0.642, P<.0001) and MMS (r=0.443, P<.04), and with post-OLT changes (for SE: r=-0.583, P<.01; for MMS: r=-0.536, P<.01). CONCLUSIONS: HCV complexity and diversity in the E2 region correlated with the severity of recurrence of HCV infection after OLT. Increased diversity of quasi species at transmission correlated with a higher FS at 1 year. However, increased diversity of quasi species in the post-OLT period correlated with a lower FS at 1 year. The dynamics of HCV quasi species in patients who undergo transplantation are predictive of outcome.     

Natural history of hepatic fibrosis progression in chronic hepatitis C virus infection in India

Background and Aim:  The rate of fibrosis progression per year can predict the time for the development of cirrhosis in chronic hepatitis C (CHC). We assessed the rate of fibrosis progression and the predictors of disease severity in Indian CHC patients.
Methods:  Of the 355 treatment-naïve, histologically-proven CHC patients, the precise duration of infection (from the time of exposure to HCV until liver biopsy) could be determined in 213 patients (age = 41.6 ± 14.7 years, male : female = 139 : 74, genotype 3 = 75%). The rate of fibrosis progression per year was calculated. The correlation of the advanced degree of fibrosis and age, duration of infection, age at the onset of infection, sex, mode of infection, hepatitis C virus (HCV) genotype, histological activity index (HAI), and the presence of diabetes mellitus were studied.
Results:  The median rate of fibrosis progression per year was 0.25 (0.0–1.5) fibrosis units. The fibrosis progression rate was higher in patients who acquired infection at > 30 years of age, those < 30 years (0.33 vs 0.15; P  < 0.001), and those who acquired HCV infection with a history of blood transfusion than with other modes of transmission (0.25 vs 0.19; P  = 0.04). The median time to progress to cirrhosis was 16 years. The multivariate analysis found that the HAI score (odds ratio [OR]= 14.03; P  < 0.001) and the duration of infection > 10 years (OR = 4.83; P  < 0.001) correlated with severe liver disease (fibrosis ≥ 3).
Conclusion:  The median rate of fibrosis progression per year in Indian CHC patients is 0.25 fibrosis units. A higher HAI and longer duration of infection are associated with a significant risk of advanced liver disease, and merit early therapeutic interventions.     

Hepatitis C and liver transplantation: fibrosis progression and treatment. Or how to improve management

Hepatitis C virus-related end-stage liver disease, alone or in combination with alcohol, has become the leading indication for liver transplantation in most transplant programs accounting for approximately half of transplants performed in European centers. Hepatitis C virus infection recurs virtually in every post-transplant patient. The natural history of hepatitis C after liver transplantation is variable. Progression of chronic hepatitis C virus is more aggressive after liver transplantation with a cumulative probability of developing graft cirrhosis estimated to reach 30% at 5 years. Approximately 10% of the patients with recurrent disease will die or require re-transplantation within 5 years post-transplantation. Several factors, including those related to the virus, the host, the environment and the donor, are probably implicated in the outcome. The immune status represents the main significant variable in influencing disease severity in hepatitis C virus-infected patients; with higher HCV viral load and the significant association described between the degree of immunosuppression and disease severity. Interventions to prevent, improve, or halt the recurrence of hepatitis C virus infection have been evaluated by multiple small studies worldwide with similar overall rates of virological clearance of approximately 9-30%. Current consensus recommends combination therapy with pegylated interferon and ribavirin for those patients with histological recurrence of hepatitis C virus infection and fibrosis. Therapy is adjusted to tolerance and rescued with granulocyte colony-stimulating factor and erythropoietin for bone marrow suppression. In this article we present a comprehensive review of post-transplant hepatitis C virus infection; in particular fibrosis progression and the major challenges according to treatment.     

Mild donor liver steatosis has no impact on hepatitis C virus fibrosis progression following liver transplantation.

BACKGROUND: This study examines the impact of donor liver macrovesicular steatosis on recurrence of hepatitis C virus (HCV) disease after liver transplantation. METHODS: Between 1998 and 2004, 113 patients underwent liver transplantation for HCV-related cirrhosis. Time to histologic recurrence (fibrosis score >or=2) was the primary endpoint of the study. Recurrence was graded according to the system of Ludwig and Batts. A Cox's proportional hazard regression model was used to analyse the association between donor liver steatosis and HCV recurrence. RESULTS: Recurrence-free survival for patients who received steatotic grafts was 82% and 47% at 1 and 4 years, respectively, and 81% and 52% for patients who received a non-steatotic liver. Donor macrovesicular steatosis (5-45%) was found to have no impact on HCV recurrence (P=0.47). Donor age (P=0.02) and cold ischaemia time (P=0.01) were found to increase the relative risk of HCV recurrence. The estimated risk of HCV recurrence increased by 23% for every 10-year increase in donor age. Similarly the risk of recurrence increased by 13% for every 1-h increase in cold ischaemia time. CONCLUSION: Mild-moderate donor liver macrovesicular steatosis has no impact on HCV recurrence after liver transplantation for HCV-related cirrhosis. Cold ischaemia time and donor age increased the likelihood of HCV recurrence.     

Hepatitis C and pulmonary fibrosis: Hepatitis C and pulmonary fibrosis

Background

Hepatitis C virus (HCV) is a hepatotropic and lymphotropic virus that causes hepatic and extrahepatic disease. Emerging clinical data suggest that chronic HCV infection can lead to many direct and indirect effects on the lung.

Objectives

This article discusses evidence on the relationship between HCV infection and pulmonary fibrosis to increase knowledge on this topic among clinicians and scientists and highlights the need for further study.

Methods

We searched the MEDLINE, ISI WEB OF KNOWLEDGE, OVID, ELSEVIER, and MDCONSULT databases and top respiratory journals, such as the American Journal of Respiratory and Critical Care, Chest, and Thorax for articles in English using the following keywords: hepatitis C, HCV infection, IPF, pulmonary fibrosis, and interstitial pneumonitis. We reviewed the reference lists of all identified studies.

Results

The evidence for a pathogenetic link between pulmonary fibrosis and HCV is: the higher frequency of HCV markers in IPF patients, an increase in lymphocyte and neutrophil numbers in bronchoalveolar lavage of chronic HCV infection patients, and the development of IPF in HCV-related chronic hepatitis that is treated with interferon. There is a discrepancy between studies on the frequency of HCV in IPF patients, which might be attributed to geographical differences of in the prevalence of HCV infection, selection bias in choosing the control group, and the HCV genome.

Conclusions

BAL studies in HCV infection are associated with increased counts of lymphocytes and neutrophils in BAL fluid. These studies show that HCV infection is associated with nonspecific pulmonary inflammatory reactions that are not compatible with IPF but that it can lead to pulmonary fibrosis. The other factor is interferon therapy. Interstitial pneumonia and sarcoidosis are well-documented complications of IFN therapy. More extensive cohort studies should be conducted to confirm an actual causal relationship between HCV infection and pulmonary fibrosis.     

Hepatitis C virus infection in patients with haematological diseases: evidence for the association with erythrocytes transfusion and liver disease

We analysed hepatitis C virus risk factors in 131 consecutive patients with haematological malignancies (17.6% anti-HCV positive), 42 with connective tissue diseases (30.9% anti-HCV positive) and 1071 (1.1% anti-HCV positive) new blood donors. Anti-HCV was associated with elevated serum ALT levels (P = 0.0001) and with red cells (P = 0.045), but not with platelets and plasma transfusions. HCV presence in immunocomplexes immunoadhering on the erythrocytes might explain the association between HCV infection and red cell transfusion. However, other risk factors have to be implicated in haematological malignancies to explain the high anti-HCV prevalence in patients who did not receive blood products.     

Risk factors for liver fibrosis progression in patients with chronic hepatitis C

The major hepatological consequence of HCV infection is the progression to cirrhosis and its potential complications. Several factors have been clearly shown to be associated with fibrosis progression rate: duration of infection, age, male sex, consumption of alcohol, HIV coinfection and low CD4 count. As age and duration of infection increases, the risk of fibrosis increases and the impact of treatment (IFN) decreases. In conclusion, fibrosis progression has a progressive acceleration, sex, age and consumption of alcohol are strongly involved in this progression; the possibility to assess with non-aggressive biochemical markers the fibrosis stage will probably allow in the future to identify other factors related to fibrosis progression.     

Transforming growth factor-β1 gene polymorphisms are associated with progression of liver fibrosis in Caucasians with chronic hepatitis C infection

AIM: Considerable attention is focused on polymorphisms in the gene encoding transforming growth factor-β1 (TGF-β1), a multifunctional cytokine that is in turn a potent growth inhibitor involved in wound healing and differentiation. In humans, it promotes the pathogenesis of organ fibrosis, atherosclerosis, cancer, autoimmune and inflammatory diseases, keloid disease, and hypertrophic scarring. Forth is reason, much emphasis has been placed on studies elucidating the impact of TGF-131 and its gene variationsf or the susceptibility and pathogenesis of these diseases. Unfortunately, some studies have serious limitations. METHODS: We have recently described a high-throughput method for investigation the Arg25Pro polymorphism of human TGF-β1 gene and showed that the frequency of the Pro25 allele is significantly associated with hepatic fibrogenesis. In this report, we describe two novel Light Cycler (LC) techniques that facilitate the examination of the two other known alterations in the coding region of TGF-β1. We investigated whether these polymorphisms contribute to hepatitis-induced progression of fibrogenesis in Chinese and Caucasians. RESULTS: In the Chinese ancestry, the gene polymorphisms at codons 25 and 263 were not found and the genetic variant at codon 10 is unlikely to confer susceptibility to hepatic fibrosis. Contrarily, in Caucasians TGF-β1 allelic variations are more frequent and the presence of prolines     

Steatosis and progression of fibrosis in untreated patients with chronic hepatitis C infection

Hepatic steatosis is common in patients with chronic hepatitis C (CHC) and is reported to be a risk factor for progression of fibrosis. The aims of this study were to evaluate the interactions between hepatic steatosis and fibrosis in a well-defined cohort of patients with CHC. The computerized pathology database at the National Institutes of Health Clinical Center was searched for patients with CHC who had undergone liver biopsy between 1980 and 2003. Biopsies were scored for necroinflammation using a modified histology activity index, fibrosis using the Ishak system, and steatosis as either none (<5% of cells), mild (5%-25%), or moderate-to-severe (>25%). Four hundred ninety-four patients were identified. The mean age was 44 +/- 9.8 years; 60% were male, 80% Caucasian, and 65% were infected with genotype 1. Steatosis was mild in 31% and moderate to severe in 9% of patients. In univariate analysis, steatosis was associated with increased age, body weight, body mass index (BMI), alanine aminotransferase (ALT) levels, histological necroinflammatory activity, and fibrosis. However, in multivariate analysis, steatosis was associated only with increased age, BMI, and ALT levels and not with fibrosis. One hundred thirty-six patients had 2 liver biopsies separated by 0.5 to 17 years. Worsening of fibrosis occurred in 40% of patients and correlated independently with increasing age, periportal necroinflammation, and ALT elevations but not with steatosis. In conclusion, in this cohort of patients with CHC, steatosis was associated with older age, higher BMI, and higher serum ALT levels but not with the presence of or subsequent progression of fibrosis.     

Keratin variants associate with progression of fibrosis during chronic hepatitis C infection

Keratins 8 and 18 (K8/K18) protect the liver from various forms of injury. Studies of liver explants from a large cohort of U.S. patients showed that K8/K18 mutations confer a risk to developing end-stage liver diseases, though which diseases are preferentially involved is unknown. We tested the hypothesis that K8/K18 variants are associated with chronic hepatitis C (CHC) and that their presence correlates with progression of fibrosis. Genomic DNA was isolated from peripheral blood of a well-characterized German cohort of 329 patients with CHC infection. Exonic regions were PCR-amplified and analyzed using denaturing high-performance liquid chromatography and DNA sequencing. Our findings showed: (1) amino acid altering keratin heterozygous variants in 24 of 329 CHC patients (7.3%) and non-coding heterozygous variants in 26 patients (7.8%), and (2) 3 new exonic K8 variants (T26R/G55A/A359T); 6 novel non-coding variants and one K18 coding variant (K18 S230T; 2 patients). The most common variants were K8 R341H (10 patients), K8 G62C (6 patients) and K8 I63V (4 patients). A novel and exclusive association of an intronic KRT8 IVS7+10delC deletion in all 10 patients with K8 R341H was observed. Notably, there was a significant association of exonic, but not of intronic K8 variants with increased fibrosis. In conclusion, previously described and novel K8 variants are present in a German population and collectively associate with progression of fibrosis in CHC infection. The unique 100% segregation of the most common K8 variant, R341H, with an intronic deletion suggests that one of these two genetic changes might lead to the other.