Hepatocyte steatosis in HCV patients promotes fibrosis by enhancing TGF-beta liver expression.

Aim: The objective of this study was to examine the relationship between TGF-beta expression in steatotic liver and the stage and yearly progression rate of fibrosis in chronic hepatitis C (CHC) patients. Methods: We examined 44 CHC fatty liver patients, using 76 non-steatotic CHC patients as controls. The stage of hepatic fibrosis was assessed on a score scale. TGF-beta expression was determined with the use of monoclonal serum and the ABC three-step method. Results: We demonstrated a positive correlation of steatosis with the stage of fibrosis (P < 0.05). No relationship of thiskind was found with the yearly progression rate of fibrosis (P > 0.09). In steatotic biopsies, TGF-beta expression index in portal spaces and lobules was found to be higher as compared to TGF-beta expression in biopsies without steatosis (P < 0.05). Conclusion: In CHC patients steatosis induces the development of fibrosis by elevating the hepatic expression of TGF-beta.     

Hepatic steatosis in chronic hepatitis B patients is associated with metabolic factors more than viral factors

Background and Aims:  Hepatic steatosis is commonly seen in chronic hepatitis C (CHC) patients. It has been reported to be associated with both metabolic factors and viral factors, and affects the severity of fibrosis in CHC. However, the relationship between hepatic steatosis and chronic hepatitis B (CHB) is unclear. The aims of this study were to investigate the frequency of hepatic steatosis in CHB patients, to identify the factors associated with its presence, and assess the relationship between the stage of steatosis and the severity of fibrosis.
Methods:  Medical records of 153 adult patients with CHB who had undergone a liver biopsy within the past 4 years were included in the study.
Results:  Body mass index (BMI) and age of CHB patients with steatosis was significantly higher than the patients without steatosis ( P  < 0.05), as determined by the univariate analysis. Steatosis was found to correlate with the BMI values and alanine aminotransferase (ALT) levels, and ALT levels were associated with hepatitis B virus (HBV)–DNA levels and histology activity index (HAI) scores, stages of fibrosis were associated with the HAI score and HBV–DNA, as determined by the multivariate analysis. In contrast, there was no significant association between advanced stages of fibrosis and steatosis.
Conclusion:  Our data indicate that hepatic steatosis is more frequently present in CHB patients than in the general population. We hypothesize that steatosis in CHB patients may be due to metabolic factors and the ability of HBV to indirectly facilitate the development of steatosis. In the present study, steatosis in CHB patients was not found to be associated with the severity of fibrosis.     

Expression of adiponectin and its receptors in livers of morbidly obese patients with non-alcoholic fatty liver disease

Background and Aim:  Obesity is one of the risk factors for non-alcoholic fatty liver disease (NAFLD) and a common disease that comprises simple steatosis and non-alcoholic steatohepatitis (NASH), and can eventually lead to liver cirrhosis. Adiponectin is an adipocyte-derived protein that has anti-obesity, antidiabetic and anti-inflammatory properties, and is considered to possess a hepatoprotective function. Its role in the development and progression of NAFLD in morbidly obese patients is unknown. In this study, we examined the expression levels of adiponectin and its receptors in liver biopsies of morbidly obese patients and then determined whether there was an association with the disease severity.
Methods:  Liver biopsies from 30 morbidly obese patients (18 NASH vs 12 steatosis) were analyzed. The needle core biopsies were subjected to routine histological examination and stained immunohistochemically for adiponectin, adiponectin receptor I (adipoRI) and receptor II (adipoRII).
Results:  The two groups were comparable with respect to body mass index, age and gender distribution. The expression of adiponectin decreased in liver biopsies with NASH as compared to those with simple steatosis (1.61 ± 0.70 vs 2.25 ± 0.75, P  = 0.028). Spearman's rank correlation coefficient analysis showed that the staining intensity of adiponectin negatively correlated with the grade of inflammation ( r  = −0.368, P  = 0.045) and stage of fibrosis ( r  = −0.380, P  = 0.038). There was no significant difference in expression of adipoRI and adipoRII between the two groups.
Conclusion:  These findings indicate that decreased liver adiponectin expression may play a role in the development and progression of NAFLD, from simple steatosis to NASH, in morbidly obese patients.     

Prediction of progressive liver fibrosis in hepatitis C infection by serum and tissue levels of transforming growth factor-β

Although many patients with chronic viral hepatitis C infection suffer from progressive liver disease, the rate of fibrosis progression is highly variable and some patients do not show any measurable progression. However, our ability to predict which patients progress is very limited. Since transforming growth factor-β (TGF-β) is a key mediator of liver fibrogenesis, we assessed the predictive role of TGF-β for fibrogenesis in chronic hepatitis C. We studied 39 patients with chronic hepatitis C in whom two liver biopsies were taken at least 12 months apart, and who did not receive therapy during this period. TGF-β was measured by bioassay and by ELISA in serum samples taken at the time of the first biopsies, and TGF-β was determined semiquantitatively by immunostaining of liver biopsy sections. Fibrosis was scored blinded in the biopsy samples by two pathologists independently. There was a close correlation between TGF-β serum levels and the rate of fibrosis progression. Patients with no progression of fibrosis had significantly lower (59 ng/mL ± 22) TGF-β serum levels than patients with progressive disease (115 ng/mL ± 20), and a TGF-β level below 75 ng/mL was predictive for stable disease. Immunohistology for TGF-β in biopsy samples was also predictive for progressive liver disease with fibrosis progression found in those patients displaying staining of hepatocytes and sinusoidal cells. No such correlation was found with other markers such as procollagen III peptide, viral load or transaminase levels. These results further support the role of TGF-β in liver fibrogenesis, and offer an opportunity to predict clinical disease progression, which may help in selecting patients who are in need of therapeutic interventions.     

Worsening of steatosis is an independent factor of fibrosis progression in untreated patients with chronic hepatitis C and paired liver biopsies

BACKGROUND AND AIMS: Steatosis, a frequent histological finding in patients with chronic hepatitis C (CHC), has been suggested to influence liver fibrosis progression. The aim of the present study was to evaluate in patients with CHC and paired liver biopsies the relationship between the evolution of steatosis and that of fibrosis between the two biopsies. METHODS: Ninety six patients were selected according to the following criteria: absence of treatment; absence of cirrhosis at initial biopsy; and serum hepatitis B surface antigen and human immunodeficiency virus antibody negativity. Degrees of necroinflammatory activity, fibrosis, and steatosis grades were assessed in the two biopsies. In addition to histological lesions, parameters studied included the source of infection, duration of infection, body mass index, alcohol intake, alanine aminotransferase levels, hepatitis C virus genotype, and viral load. RESULTS: The mean interval between the two biopsies was 48 (32) months. Steatosis was found in 54% of patients at first biopsy, and was severe in 9%. Worsening of steatosis was observed in 34% of patients, stability in 50%, and improvement in 16%. Worsening of steatosis was significantly associated with hepatic fibrosis progression in patients with (p=0.03) or without (p<0.03) steatosis at diagnosis. Overall, fibrosis progression was observed in 31% of patients and stability in 69%. In a univariate analysis, fibrosis progression was associated with male sex (p=0.05), worsening of histological activity (p=0.04), and worsening of steatosis (p=0.0003). In a multivariate analysis, the only factor independently associated with fibrosis progression was worsening of steatosis (worsening v improvement/stability: odds ratio 4.7 (95% confidence interval 1.3-10.8); p=0.0001). CONCLUSIONS: Our results suggest that in untreated patients with CHC and serial liver biopsies, fibrosis progression is strongly associated with worsening of steatosis.     

Hepatic steatosis in chronic hepatitis B and C: predictors, distribution and effect on fibrosis

BACKGROUND/AIMS: Chronic hepatitis B (CHB) and C (CHC) are commonly associated with hepatic steatosis. The aims of this study were to investigate predictors of hepatic steatosis, and their impact on inflammation and fibrosis in CHB and CHC. METHODS: Consecutive patients with either CHB or CHC who underwent a liver biopsy at The Alfred Hospital between April and September 2002 were included. Histological analysis of liver biopsies was performed by two hepatopathologists blinded to the clinical data. RESULTS: Ninety-one patients were analysed including 17 patients with CHB and 74 with CHC. CHC genotype 3, C-peptide, glucose and waist circumference were independent predictors of extent of Brunt steatosis grade, while CHC genotype 3, C-peptide and waist circumference were independent predictors of microvesicular steatosis grade. Alcohol intake and age were predictors of hepatic fibrosis. There was a trend toward a correlation between both Brunt steatosis and microvesicular steatosis grades and fibrosis progression rate in CHC genotype non-3. CONCLUSIONS: Hepatic steatosis is common in chronic hepatitis B and C, and is associated with waist circumference, glucose, C-peptide and chronic hepatitis C genotype 3. Steatosis grade appears to relate to hepatic fibrosis progression rate in chronic hepatitis C genotype non-3.     

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.     

Assessment of hepatic steatosis and hepatic tissue blood flow by xenon computed tomography in nonalcoholic steatohepatitis

Aim:  The diagnosis of non-alcoholic steatohepatitis (NASH) can be difficult using blood tests and imaging studies. Histological diagnosis by liver biopsy remains the gold standard of NASH diagnosis. There is an urgent need to develop and validate simple, reproducible, noninvasive tests to accurately assess NASH stage and grade. We assess the usefulness of xenon computed tomography (Xe-CT), as a non-invasive method of quantitatively and visually determining hepatic tissue blood flows (TBFs), and xenon solubility (λ value) simultaneously with TBF, in the evaluation of NASH pathophysiology.
Methods:  Histological severity of fatty changes and severity of fibrosis based on Brunt's classification were determined in 38 NASH patients. We evaluated correlations between the grade of fatty changes and λ value, and correlations between the stage of fibrosis and TBFs.
Results:  The λ value showed significant positive correlations with both grade of steatosis ( r  = 0.813, P  < 0.001) and each 10% range of histological fatty infiltration ( r  = 0.926, P  < 0.001). A significant negative correlation was seen between λ value and the liver : spleen ratio ( r  = −0.835, P  < 0.001). Portal venous tissue blood flow and total hepatic tissue blood flow showed significant negative correlations with the progression of fibrosis ( r  = −0.465, P  < 0.01; r  = −0.433, P  < 0.01, respectively). Total hepatic tissue blood flow tended to decrease with progressing grade of steatosis.
Conclusion:  Xe-CT offers a convenient and objective method for evaluating fatty infiltration and changes in blood flow in the entire liver, and appears useful for detailed evaluation of patients with NASH.     

Kinetics of serum cytokines reflect changes in the severity of chronic hepatitis C presenting minimal fibrosis

Our aims were to measure the kinetics of serum tumour necrosis alpha (TNF-α) and transforming growth factor beta (TGF-β) levels as markers of progression of disease in nontreated chronic hepatitis C virus (HCV)-infected patients with minimal or no fibrosis and minimal histology activity index (HAI) scores. Our study group consisted of 56 patients diagnosed with minimal (1) or no fibrosis (0) and minimal HAI (0–1) on their first biopsy as defined by Knodell and METAVIR scores. We compared their initial (entry of study) cytokine levels with a group of 103 HCV controls with minimal (0–1) to mild fibrosis (0–3) and mild HAI (5.5). Serum TNF-α and TGF-β levels were measured by enzyme-linked-immunosorbent-assay. A significant difference was seen in TNF-α levels at baseline in the study group vs. controls. Regardless of their HAI, there was a correlation between TGF-β and degree of fibrosis. As shown by their biopsies, during the 3 years (from entry to follow up), many of the patients that initially had minimal fibrosis progressed to higher degree of fibrosis. This progression is paralleled by an increase in TGF-β levels when comparing initial and follow-up levels. In conclusion, serum TNF-α reflects the progression of inflammation as seen in liver biopsies and TGF-β reflects the degree of fibrosis in HCV patients.     

Prevalence and risk factors of hepatic steatosis and its impact on liver injury in Chinese patients with chronic hepatitis B infection

Background and Aims:  The clinical significance of hepatic steatosis in chronic hepatitis B infection (CHB) is unclear. The aims of this study were thus to investigate the prevalence and risk factors for hepatic steatosis in patients with CHB and its relationship with liver injury.
Methods:  Consecutive patients with biopsy-proven CHB at Hangzhou Sixth People's Hospital between January 2005 and June 2007 were included. Patients co-infected with other viruses or suffering from liver disease of any other cause were excluded. Liver steatosis, necroinflammation and fibrosis were assessed by both Brunt and Scheuer classifications.
Results:  A total of 1915 patients (1497 men) with a mean age of 31 ± 9.5 years were analyzed. Hepatic steatosis was present in 260 (14%) patients. The steatosis involved < 33% of hepatocytes in 90% of cases, and was more frequent among men than women (15% vs 8%, P  < 0.001). Two-thirds (178 of 260) of patients with steatosis were hepatitis B e antigen (HBeAg)-positive, but there was no correlation with either serum HBeAg status or hepatitis B virus DNA titer. Degree of inflammation and fibrosis were more mild among those with steatosis than those without. Multivariate analysis showed that steatosis was independently associated with body mass index, serum triglyceride, apolipoprotein B, uric acid, and fasting blood glucose. However, fibrosis was only independently associated with age and inflammatory grade, and the latter associated with viral load and fibrosis stage.
Conclusions:  Hepatic steatosis is common in CHB, it is associated with metabolic factors not viral ones, and does not appear to affect the severity of liver disease.     

Hyaluronic acid, transforming growth factor-β1 and hepatic fibrosis in patients with chronic hepatitis C virus and human immunodeficiency virus co-infection

Summary.  Chronic hepatitis C virus (HCV) infection follows an accelerated course in patients co-infected with human immunodeficiency virus (HIV); establishing the extent of liver fibrosis is crucial for disease staging and determining treatment strategy in these patients. The utility of noninvasive markers of fibrosis as alternatives to liver biopsy has not been well-studied in these patients. We evaluated the predictive value of serum transforming growth factor-beta1 (TGF-β1) and hyaluronic acid (HA) levels for determining the extent of liver fibrosis. Liver biopsies and blood samples were collected from 69 consecutive patients (74% male; median age, 41 years) between May 2005 and November 2006. Serum TGF-β1 and HA were analysed using commercial kits. Aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transpeptidase levels were elevated in 81%, 70% and 60% of patients, respectively. Fifty-three patients (90%) were on highly active antiretroviral therapy and the median CD4-positive cell count was 422 cells/μL. The extent of fibrosis according to Scheuer's scoring was 32% F0 (no fibrosis), 16.5% F1, 16.5% F2, 26% F3 and 7% F4 (cirrhosis). Mean serum TGF-β1 was 36.1 ± 14.4 ng/mL; mean serum HA was 75.2 ± 85.0 μg/L. Serum HA was positively associated and significantly correlated with the stage of fibrosis ( r  =   0.56; P  <   0.05). The area under the curve for discriminating mild (F0–F2) from significant (F3–F4) fibrosis in receiver operating analysis using HA was 0.83 (sensitivity, 87%; specificity, 70%). These data suggest that HA is clinically useful for predicting liver fibrosis and cirrhosis in patients co-infected with HCV/HIV. However, serum TGF-β1 was not predictive of histological damage in co-infected individuals treated with HAART.     

Overweight and obesity, hepatic steatosis, and progression of chronic hepatitis C: a retrospective study on a large cohort of patients in the United States

BACKGROUND: Hepatic steatosis has been associated with chronic hepatitis C (CHC), but its prevalence, risk factors, and clinical significance remain to be determined. AIMS: The present study determined the frequency of, and risk factors for hepatic steatosis and its association with activity and progression of CHC in a large cohort of U.S. patients. METHODS: This is a retrospective study that utilized systematic chart review and statistical analyzes to investigate 324 U.S. patients with CHC from a university medical center and a regional VA medical center. RESULTS: The frequency of hepatic steatosis was 66.0%. We demonstrated that not only being obese, but also overweight (i.e. body mass index > or =25 kg/m(2)) was independently associated with hepatic steatosis. In our cohort of patients with CHC, hepatic steatosis, especially grade II/III steatosis, was significantly associated with elevated aspartate aminotransferase at entry, persistently elevated alanine aminotransferase, and stage III/IV fibrosis. Grade II/III steatosis, was significantly associated with a higher histology activity index as well. Multivariate analysis indicated that steatosis, especially grade II/III steatosis, was independently associated with stage III/IV fibrosis. CONCLUSIONS: Being overweight/obese serves as an independent risk factor for hepatic steatosis in U.S. patients with CHC. Steatosis accelerates activity and progression of CHC, and is independently associated with stage III/IV hepatic fibrosis in these patients.     

Correlation of hepatic steatosis with body mass index, serum ferritin level and hepatic fibrosis in Japanese patients with chronic hepatitis C

Aims:  The present study was aimed at determining the predictors of hepatic steatosis and fibrosis in Japanese patients with chronic hepatitis C.
Methods:  The relationship between the degrees of hepatic steatosis or fibrosis and several clinical parameters was evaluated using univariate and multivariate analyses.
Results:  Steatosis was observed in 117 out of 184 patients (64%), including 45 patients (25%) with grade 1 (<10% of hepatocytes affected), 56 patients (30%) with grade 2 (10–30%), 12 patients (7%) with grade 3 (30–50%), and four patients (2%) with grade 4 (>50%). In the multivariate analysis, body mass index (BMI) ( P  =   0.0038) and serum ferritin ( P  <   0.0001) were selected as independent predictors of hepatic steatosis. Six of the 184 patients (3%) had stage 0 fibrosis (no fibrosis), 87 patients (47%) had stage 1, 55 patients (30%) had stage 2 and 36 patients (20%) had stage 3. In the multivariate analysis, platelet count ( P  =   0.0012), aspartate aminotransferase (AST) ( P  =   0.0219), hyaluronic acid ( P  <   0.0001) and the grade of steatosis ( P  =   0.0008) were selected as independent predictors of hepatic fibrosis.
Conclusion:  Obesity and iron storage, as evaluated by BMI and serum ferritin level, respectively, have important roles in the pathogenesis of hepatic steatosis, which is a factor responsible for the development of hepatic fibrosis in Japanese patients with chronic hepatitis C.     

Lipid peroxidation in hepatic steatosis in humans is associated with hepatic fibrosis and occurs predominately in acinar zone 3

BACKGROUND AND AIMS: Hepatic steatosis has been shown to be associated with lipid peroxidation and hepatic fibrosis in a variety of liver diseases including non-alcoholic fatty liver disease. However, the lobular distribution of lipid peroxidation associated with hepatic steatosis, and the influence of hepatic iron stores on this are unknown. The aim of this study was to assess the distribution of lipid peroxidation in association with these factors, and the relationship of this to the fibrogenic cascade. METHODS: Liver biopsies from 39 patients with varying degrees of hepatic steatosis were assessed for evidence of lipid peroxidation (malondialdehyde adducts), hepatic iron, inflammation, fibrosis, hepatic stellate cell activation (alpha-smooth muscle actin and TGF-beta expression) and collagen type I synthesis (procollagen alpha1 (I) mRNA). RESULTS: Lipid peroxidation occurred in and adjacent to fat-laden hepatocytes and was maximal in acinar zone 3. Fibrosis was associated with steatosis (P < 0.04), lipid peroxidation (P < 0.05) and hepatic iron stores (P < 0.02). Multivariate logistic regression analysis confirmed the association between steatosis and lipid peroxidation within zone 3 hepatocytes (P < 0.05), while for hepatic iron, lipid peroxidation was seen within sinusoidal cells (P < 0.05), particularly in zone 1 (P < 0.02). Steatosis was also associated with acinar inflammation (P < 0.005). alpha-Smooth muscle actin expression was present in association with both lipid peroxidation and fibrosis. Although the effects of steatosis and iron on lipid peroxidation and fibrosis were additive, there was no evidence of a specific synergistic interaction between them. CONCLUSIONS: These observations support a model where steatosis exerts an effect on fibrosis through lipid peroxidation, particularly in zone 3 hepatocytes.     

The impact of hepatic steatosis on the natural history of chronic hepatitis C infection

Summary.  Since patients with hepatitis C virus (HCV) often have hepatic steatosis, this retrospective analysis aimed to assess whether steatosis influences fibrosis progression. We studied 112 HCV RNA positive subjects (median age 44, IQR 39–51 years), who had two liver biopsies performed (median biopsy interval 50, 34–74 months). Fibrosis was staged using the Ishak method and steatosis by the Kleiner system (<5% steatosis = S0, 5–33% = S1, 33–66% = S2, and >66% = S3). The subjects were untreated because they had mild fibrosis ( n =  59), declined therapy ( n =  48), or had co-existing disease precluding treatment ( n  =   5). On first liver biopsy, 60 (54%) had S0, 34 (30%) had S1, 12 (11%) had S2, and 6 (5%) had S3. Steatosis was associated with genotype 3, odds ratio 4.8 (95% CI 1.3–16.7, P =  0.02). Twenty-three patients (21%) had disease progression on the second biopsy, defined as an increase in Ishak score by ≥1 stage. On univariate analysis, fibrosis progression was associated with older age ( P =  0.004), higher AST ( P =  0.04), and steatosis ( P =  0.005) but on multivariate analysis, only baseline steatosis was significant, odds ratio 14.3 (2.1–111.1, P =  0.006). Kaplan-Meier analysis demonstrated that steatosis impacted on time to progression to both significant fibrosis (Ishak ≥F3) and cirrhosis (Ishak F5-6) ( P =  0.001 and P =  0.049, respectively). The finding that steatosis was significantly associated with fibrosis progression indicates that, independent of baseline fibrosis stage, patients should be considered for anti-viral treatment if steatosis is present. Furthermore, strategies to reduce steatosis may have a beneficial effect on fibrosis progression and, therefore, patient outcome.     

Insulin resistance and diabetes increase fibrosis in the liver of patients with genotype 1 HCV infection

OBJECTIVES: Metabolic factors may affect the course of chronic hepatitis C (CHC). Insulin resistance (IR) determines steatosis, but its direct role in affecting progression of hepatic fibrosis is less clear. We aimed to assess whether increasing degrees of IR, up to overt diabetes, are linked to steatosis and higher stages of fibrosis in patients with CHC resulting from genotype 1 HCV (G1-HCV).
METHODS: Two hundred one consecutive patients with G1-HCV infection were evaluated by liver biopsy and anthropometric and metabolic measurements, including IR, by the homeostasis model assessment (HOMA). Nondiabetic patients were defined as insulin resistant if HOMA-IR was >2.7. All biopsies were scored by one pathologist for staging and grading (Scheuer), and graded for steatosis.
RESULTS: Ninety-six patients were noninsulin resistant (group 1), 76 were insulin resistant without diabetes (group 2), and 29 were diabetic (group 3). At multivariate analysis, fibrosis of ≥3 was independently associated with high necroinflammatory activity (odds ratio [OR] 2.994, 95% confidence interval [CI] 1.422–6.098), low platelets (OR 0.994, 95% CI 0.981–0.999), low cholesterol (OR 0.987, 95% CI 0.976–0.998), high ferritin (OR 1.002, 95% CI 1.001–1.004), and a high prevalence of IR (OR 2.692, 95% CI 1.463–4.954). Diabetic patients were twice as likely to have severe fibrosis (60%) than those with IR but no diabetes (30%) ( P = 0.006). The degree of steatosis and that of fibrosis were weakly associated with each other ( P = 0.42).
CONCLUSIONS: In subjects with CHC resulting from G1-HCV, IR and overt diabetes are major determinants of advanced fibrosis, regardless of the degree of steatosis, mainly in the presence of severe necroinflammation.     

The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies

BACKGROUND/AIMS: The histological course of nonalcoholic fatty liver disease (NAFLD) remains undescribed. Therefore, we examined the liver histology of NAFLD patients who had undergone sequential liver biopsies. METHODS: Data on 103 patients who underwent serial liver biopsies in the absence of effective treatment were reviewed, and biopsies scored in a blind fashion. RESULTS: Mean interval between biopsies was 3.2+/-3.0 years (range 0.7-21.3). Fibrosis stage apparently progressed in 37%, remained stable in 34% and regressed in 29%. Severity of steatosis, inflammation, hepatocyte ballooning and Mallory's hyaline improved significantly. Aminotransferases decreased significantly between biopsies, paralleling improvement in steatosis and inflammatory features but not fibrosis stage. The rate of fibrosis change ranged from -2.05 to 1.7 stages/year. By multivariate analysis, diabetes (P = 0.007) and low initial fibrosis stage (P < 0.001) were associated with higher rate of fibrosis progression, as was higher body mass index (P = 0.008) when cirrhotics were excluded. CONCLUSIONS: Fibrosis in NAFLD progresses slowly over time with considerable variability in the rate of changes among patients. Changes of aminotransferases do not parallel changes in fibrosis stage. Diabetic patients with elevated BMI and low fibrosis stage are at risk for higher rates of fibrosis progression.     

Combination of oxidative stress and steatosis is a risk factor for fibrosis in alcohol-drinking patients with chronic hepatitis C

BACKGROUND AND AIMS: Alcohol and HCV have been shown to interact in stimulating hepatic oxidative damage. Thus, we investigated the contribution of oxidative mechanisms in the progression of chronic hepatitis C (CHC) in alcohol consumers. METHODS: An increased IgG reactivity against lipid peroxidation-derived antigens was used as the marker for alcohol-induced oxidative damage in 125 CHC patients. RESULTS: Alcohol intake significantly increased the frequency of the subjects with elevated lipid peroxidation-related IgG. However, no association was evident between oxidative stress markers and the severity of steatosis, necroinflammation, or fibrosis. Multivariate analysis revealed that age (P= 0.014) and hepatic iron content (P= 0.034) were the only independent predictors of fibrosis in these patients. However, the risk of fibrosis in the subjects with both steatosis and oxidative stress-induced immune responses was 6- (OR 6.2, 95% CI 1.2-31.0) and 14-fold (OR 14.6, 95% CI 3.1-68.1) higher than in the subjects with steatosis alone or without steatosis, respectively. Multivariate analysis confirmed that the combination of steatosis and oxidative stress (P= 0.045) was, together with age (P= 0.021) and hepatic iron content (P= 0.027), an independent risk factor for fibrosis in CHC patients with alcohol intake. CONCLUSIONS: These results demonstrate that oxidative stress interacts with steatosis to promote the progression of CHC in alcohol-consuming patients.     

8-Hydroxy-2'-deoxy-guanosine is a risk factor for development of hepatocellular carcinoma in patients with chronic hepatitis C virus infection

Background and Aim:  Increased production of reactive oxygen species, which cause oxidative DNA damage, is considered to be related to hepatocarcinogenesis. 8-Hydroxy-2'-deoxy-guanosine (8-OHdG) is a useful marker of DNA damage induced by oxidative stress. The aim of this study was to determine whether expression of 8-OHdG is a risk factor for the development of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV) infection.
Methods:  The expression of 8-OHdG in liver biopsy specimens was assessed immunohistochemically. In total, 104 patients with chronic HCV infection who were diagnosed on liver biopsy between January 1987 and December 2002 were studied retrospectively. Univariate and multivariate analyses using age, gender, habitual drinking, tobacco exposure, diabetes mellitus, serum alanine aminotransferase level, HCV genotype, hepatic fibrosis, inflammation, steatosis, and 8-OHdG expression in liver biopsy specimens were conducted to identify factors related to the development of HCC.
Results:  On multivariate analysis, 8-OHdG and fibrosis were independent and significant risk factors for HCC development (relative risk, 2.48; P  = 0.023; relative risk, 5.35; P  = 0.001, respectively). Furthermore, the cumulative incidence rate of HCC in 39 patients with high 8-OHdG expression levels was significantly greater than that in 65 patients with low 8-OHdG expression levels ( P  = 0.043). In addition, liver 8-OHdG expression was correlated with hepatic inflammation.
Conclusions:  8-OHdG is a risk factor for the development of HCC in patients with chronic HCV infection. Patients with chronic HCV who express 8-OHdG should be monitored carefully for the development of HCC.     

Visceral adipose tissue area is an independent risk factor for hepatic steatosis

Background and Aim:  Recent data indicate that hepatic steatosis is associated with insulin resistance, dyslipidemia and obesity (especially central body fat distribution). There have been few studies on the correlation between biopsy-proven hepatic steatosis and the above factors in a disease-free population. The aim of the present study was to evaluate the relation between hepatic steatosis assessed by biopsy and clinical characteristics including regional fat distribution measured by computed tomography (CT) in living liver donors.
Methods:  Laboratory data, liver/spleen Hounsfield ratio (L/S ratio), regional fat distribution by CT and liver status by biopsy were evaluated retrospectively in a total of 177 living liver donors without a history of alcohol intake.
Results:  The unpaired t -test showed that age, triglycerides (TG), high density lipoprotein, total cholesterol, alanine aminotransferase, body mass index, L/S ratio, visceral adipose tissue area (VAT) and subcutaneous adipose tissue area (SAT) were associated with hepatic steatosis. In the multiple logistic regression analysis, VAT (odds ratio 1.031, 95% CI 1.013–1.048, P  < 0.01) and TG (odds ratio 1.012, 95% CI 1.004–1.020, P  < 0.01) were independent risk factors of hepatic steatosis. Subgroup analysis also showed that VAT was an independent risk factor in men (odds ratio 1.022, 95% CI 1.003–1.041, P  < 0.05) and women (odds ratio 1.086, 95% CI 1.010–1.168, P  < 0.05).
Conclusion:  Our results suggest that visceral abdominal adiposity is correlated with hepatic steatosis in healthy living liver donors.