Impact of Hepatic Steatosis on Natural History of Chronic HCV Infection
Fatty Liver/Treatment
Hepatic Steatosis (Fatty Liver Disease) Steatosis = fatty changes .
Hepatic steatosis ( Fatty Liver ) is a recognized feature of Chronic Hepatitis C CHC
How Many Untreated Patients Were In The Study ? ,/
In this retrospective analysis of a cohort of 112 untreated patients, the prevalence of steatosis (Fatty Liver ) was 46% on index liver biopsy, which is comparable to the 50% prevalence reported in a large meta-analysis.
What Factors Parallel With Fatty Liver Disease ? Genotype 3 /
Several factors were found to correlate with steatosis on the first biopsy by univariate analysis including male sex, raised γGT and fibrosis, but only infection with HCV genotype 3 was identified as being independently associated on multivariate analysis. This observation is consistent with previous reports that have examined the relationship between hepatic steatosis and HCV genotype.[19,22–24]
Genotype 1 and other factors .
The mechanisms responsible for steatosis appear to be dependent on HCV genotype; with metabolic features, e.g. obesity, diabetes mellitus and elevated body mass index, appearing to account for the increased levels of hepatic steatosis in genotype 1. /. In such cases, it is believed that insulin resistance plays a major role, leading to adipocyte lipolysis and an increase in circulating free fatty acids, which together with inhibition of hepatic lipid oxidation and export lead to triglyceride deposition in the liver.[8,9,25,26]
Fatty Liver In Genotype 3 Is A Direct Action To The Virus
In contrast, steatosis in patients with genotype 3 appears to occur as a direct action of the virus infection.[19,22] Furthermore, successful eradication of the virus using combination therapy with peginterferon and ribavirin, leads to a diminution of the extent of steatosis among patients infected with genotype 3 but not in those infected with other genotypes.[24,27]
Fatty Liver And Progression Of LIver Fibrosis : The Controversy
The association between hepatic steatosis and progression of liver fibrosis is a source of controversy, as some studies have implicated steatosis as a factor in fibrosis progression,[16,19,27] whereas others have found no correlation.[28,29] Many studies have been criticized for using cross-sectional analysis to examine the relationship with steatosis and fibrosis, when neither the duration of steatosis nor duration of infection was well documented l Therefore, we performed a longitudinal study on 112 patients who had undergone two liver biopsies separated by an average of 4.17 years. Worsening of fibrosis occurred in 21% of patients and on univariate analysis several factors were found to correlate with an increase in fibrosis. . However, using multivariate linear regression analysis only the presence of steatosis on the first biopsy was independently associated with fibrosis progression both to significant fibrosis (Ishak F ≥ 3) and cirrhosis (Ishak F5–6). This finding confirms reports by other groups[16,19,27] and a recent meta-analysis[21] that steatosis is associated with fibrosis progression. The confidence intervals for steatosis and fibrosis progression were extremely broad. . This problem may have been compounded by the small numbers of patients in each steatosis and Ishak Fibrosis group. Steatosis groups were collapsed to a binary variable to allow a simple analysis to be performed to determine if it was associated with fibrosis progression. A further explanation accounting for differences in fibrosis stage between liver biopsies may be sampling error, indeed, the problems of sampling error from liver biopsy in CHC are well documented.[32] .
Progression of Fibrosis In Genotype 1 and 3 .
Although we found that HCV genotype 3 was associated with steatosis, we did not demonstrate an association between this and any other specific genotype and fibrosis progression. / However, this was not unexpected as other studies have presented conflicting evidence, some suggesting an association with genotype 3 and fibrosis progression,[20,31,33] whereas others support a role only for genotype 1.[21,27]
.
The mechanism by which steatosis may lead to worsening fibrosis is not understood. The factors implicated include the impact of oxidative stress, insulin resistance, and an increased susceptibility to apoptosis leading to worsening fibrosis[34] because of its associated with activation of hepatic stellate cells.[35] Evidence in favour of the latter mechanism comes from the observation that caspase activity, which regulates apoptosis,[36] correlates with steatosis activity and is increased in CHC.
.
Our study could be criticized because of the absence of data on quantitative HCV RNA levels and the patient's body mass index. However, these parameters have been extensively studied before and many authorities accept a correlation between genotype 3 HCV RNA level and steatosis,[19,22] and the greater impact of metabolic factors on the development of steatosis in patients with HCV genotype 1.[37–40] In the absence of body mass index data and information regarding insulin resistance, it was not possible to gain further insights into their contribution to steatosis in this study.
. Steatosis Diminishes as Fibrosis Worsens in Chronic Hepatitis C Virus
. On the second biopsy, the number of patients with mild steatosis increased, whilst, the number of patients with moderate to severe steatosis decreased. , This is not unexpected because it has been observed previously that steatosis diminishes as fibrosis worsens in CHC[33] and in NAFLD.[41] ,
In contrast, steatosis in patients with genotype 3 appears to occur as a direct action of the virus infection.[19,22] Furthermore, successful eradication of the virus using combination therapy with peginterferon and ribavirin, leads to a diminution of the extent of steatosis among patients infected with genotype 3 but not in those infected with other genotypes.[24,27]
Fatty Liver And Progression Of LIver Fibrosis : The Controversy
The association between hepatic steatosis and progression of liver fibrosis is a source of controversy, as some studies have implicated steatosis as a factor in fibrosis progression,[16,19,27] whereas others have found no correlation.[28,29] Many studies have been criticized for using cross-sectional analysis to examine the relationship with steatosis and fibrosis, when neither the duration of steatosis nor duration of infection was well documented l Therefore, we performed a longitudinal study on 112 patients who had undergone two liver biopsies separated by an average of 4.17 years. Worsening of fibrosis occurred in 21% of patients and on univariate analysis several factors were found to correlate with an increase in fibrosis. . However, using multivariate linear regression analysis only the presence of steatosis on the first biopsy was independently associated with fibrosis progression both to significant fibrosis (Ishak F ≥ 3) and cirrhosis (Ishak F5–6). This finding confirms reports by other groups[16,19,27] and a recent meta-analysis[21] that steatosis is associated with fibrosis progression. The confidence intervals for steatosis and fibrosis progression were extremely broad. . This problem may have been compounded by the small numbers of patients in each steatosis and Ishak Fibrosis group. Steatosis groups were collapsed to a binary variable to allow a simple analysis to be performed to determine if it was associated with fibrosis progression. A further explanation accounting for differences in fibrosis stage between liver biopsies may be sampling error, indeed, the problems of sampling error from liver biopsy in CHC are well documented.[32] .
Progression of Fibrosis In Genotype 1 and 3 .
Although we found that HCV genotype 3 was associated with steatosis, we did not demonstrate an association between this and any other specific genotype and fibrosis progression. / However, this was not unexpected as other studies have presented conflicting evidence, some suggesting an association with genotype 3 and fibrosis progression,[20,31,33] whereas others support a role only for genotype 1.[21,27]
.
The mechanism by which steatosis may lead to worsening fibrosis is not understood. The factors implicated include the impact of oxidative stress, insulin resistance, and an increased susceptibility to apoptosis leading to worsening fibrosis[34] because of its associated with activation of hepatic stellate cells.[35] Evidence in favour of the latter mechanism comes from the observation that caspase activity, which regulates apoptosis,[36] correlates with steatosis activity and is increased in CHC.
.
Our study could be criticized because of the absence of data on quantitative HCV RNA levels and the patient's body mass index. However, these parameters have been extensively studied before and many authorities accept a correlation between genotype 3 HCV RNA level and steatosis,[19,22] and the greater impact of metabolic factors on the development of steatosis in patients with HCV genotype 1.[37–40] In the absence of body mass index data and information regarding insulin resistance, it was not possible to gain further insights into their contribution to steatosis in this study.
. Steatosis Diminishes as Fibrosis Worsens in Chronic Hepatitis C Virus
. On the second biopsy, the number of patients with mild steatosis increased, whilst, the number of patients with moderate to severe steatosis decreased. , This is not unexpected because it has been observed previously that steatosis diminishes as fibrosis worsens in CHC[33] and in NAFLD.[41] ,
Alcohol Consumption and Fibrosis Progression In Hepatic Steatosis
Finally, the authors wanted to evaluate whether concurrent alcohol consumption would exacerbate hepatic steatosis and fibrosis progression. The relationship between chronic hepatitis C infection and alcohol leading to more severe disease is well described.[3] . However, in this study alcohol consumption was shown not to be associated with steatosis or fibrosis progression. This is likely to be because the numbers of patients documented as having high alcohol consumption were small, and also because of the relationship between CHC and steatosis makes it difficult to determine if the observed steatosis is related to alcohol consumption, viral or metabolic factors. . A further problem relates to the method used to assess alcohol consumption. Patients often under-estimate their alcohol consumption and more robust ways to accurately quantify alcohol consumption are needed.[42] Given the retrospective nature of data collection, this aspect of the study is prone to error.
Finally, the authors wanted to evaluate whether concurrent alcohol consumption would exacerbate hepatic steatosis and fibrosis progression. The relationship between chronic hepatitis C infection and alcohol leading to more severe disease is well described.[3] . However, in this study alcohol consumption was shown not to be associated with steatosis or fibrosis progression. This is likely to be because the numbers of patients documented as having high alcohol consumption were small, and also because of the relationship between CHC and steatosis makes it difficult to determine if the observed steatosis is related to alcohol consumption, viral or metabolic factors. . A further problem relates to the method used to assess alcohol consumption. Patients often under-estimate their alcohol consumption and more robust ways to accurately quantify alcohol consumption are needed.[42] Given the retrospective nature of data collection, this aspect of the study is prone to error.
In addition, patients actively drinking were excluded from the final analysis, further complicating interpretation.
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