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Lipids/Diabetes & HCV Liver disease
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Alimentary Pharmacology & Therapeutics
Volume 22 Issue s2 Page 74 - November 2005
Review article: chronic hepatitis C natural history and cofactors
A. ALBERTI, A. VARIO, A. FERRARI & R. PISTIS
Department of Clinical and Experimental Medicine, University of Padova, Padova, Italy
Summary
Chronic hepatitis C is highly heterogeneous in clinical presentation and outcomes.
This heterogeneity is largely related to host factors that have been clearly proven to affect the severity and rapidity of disease progression. The most relevant factors that have been shown to accelerate progression to cirrhosis include age at infection, alcohol abuse and the metabolic syndrome with insulin resistance, obesity and hepatic steatosis.
Co-infection with HIV and/or HBV also increases the risk of progression to cirrhosis and to hepatocellular carcinoma.
Surprisingly enough, viral related factors appear as less important and neither the virus genotype and load have been found to exert a clear influence on disease severity and progression, although more data in this field, and particularly on the role of different viral proteins in causing cytopathic effects, are awaited and may change this view in the near future.
ARTICLE TEXT
There have been many controversies around the issue of the natural history of hepatitis C. The disease has been described as either inexorably progressive towards cirrhosis and its complications, albeit over a quite long period of time, or as a benign and non-progressive chronic infection in the vast majority of HCV carriers. Recently, it has been recognized that these discrepancies reflect the great heterogeneity of hepatitis C as to its severity and outcome and to the many cofactors that can influence its course and progression.1 A general view of the natural history of hepatitis C is given in Figure 1.
Retrospective studies conducted in patients with hepatitis C observed for 1030 years after infection indicate that 1755% (mean 42%) developed cirrhosis, 123% developed HCC and 415% died of liver-related causes. These figures are quite reduced in most prospective studies where over a follow-up period of 816 years after exposure 716% of the patients developed cirrhosis (mean 11%), 0.71.3% developed HCC and 1.33.7% died of liver-related causes.2
In a series of retrospectiveprospective studies lasting 945 years, cirrhosis developed in 0.315% of the cases, HCC in 01.9% and liver death occurred in 02.8%. These studies have provided clear evidence that a number of host and environmental variables influence the course and outcome of chronic hepatitis C and explain the great heterogeneity of this disease. These differences are very well described by the quite different outcomes and rates of progression to cirrhosis seen when distinct cohort of patients were followed-up for a similar period of time (2025 years) after infection.
In adult patients, mainly males, infected at the age of 4565 years with a large inoculum through blood transfusion or polytransfusion in the preserologic era, 1527% developed cirrhosis35 compared with 4% with community-acquired hepatitis C,6 1% of young drug-addicts,7 0.42% of young women contaminated by anti-D Ig preparations8 and 0.3% of children with hepatitis C.9 These findings indicate that size and source of infection, age and gender are important variables affecting the course and outcome of chronic hepatitis C. Many other factors with an effect on the natural history of chronic hepatitis C have been identified in recent years and are summarized in Table 1.
Table 1. Factors and variables that have been shown to influence the course of chronic hepatitis C
Factors/variables associated with progression
Age at infection
Gender
Race
HIV*/HBV
Alcohol
Smoking
Haemochromatosis
NASH/obesity
Schistomiasis
Genetics
ALT profile
*HIV, Human immunodeficiency virus;
HBV, Hepatitis B virus;
NASH, Non-alcoholic steatohepatitis;
ALT, Alanine aminotransferase.
Interestingly, virus-related variables have very little influence on the course of hepatitis C. Although HCV-1b was in the past suggested to associate with a more severe and progressive course of chronic hepatitis C, it has not been confirmed as an independent variable. At variance with what is typically seen with HIV, serum levels of HCV-RNA do not associate with the severity of hepatitis C. For these reasons, HCV genotyping and quantitative HCV-RNA measurement do not provide relevant information for clinical management of untreated patients with hepatitis C. On the other hand, many host and environment factors that exist affect the course of hepatitis C.
Host-related factors
Age at infection has been shown in almost all published studies to have an important impact on progression of chronic hepatitis C, that is more rapid in the elderly. Poynard et al.10 found that only 2% of patients infected before the age of 20 years developed cirrhosis over a period of 20 years, compared with 6% of those infected between 31 and 40 years, 37% of those infected between 41 and 50 years and 63% of those who contracted HCV over the age of 50 years. In our own study11, evaluating liver fibrosis progression in initially mild chronic hepatitis C, increasing age was associated with an increasing rate of fibrosis progression over a mean follow-up period of around 8 years.
Modelling of the natural history of hepatitis C indicates that fibrosis progression is not linear over time, being slower in the younger ages of life and accelerating significantly after the age of 4550 years, independently of other cofactors and variables.
Male gender and race have also been shown to affect disease progression in hepatitis C.
In at least three distinct studies, the percentage of patients who developed cirrhosis was lower in African-American patients (2.222%) compared with Caucasian cases (7.230%).1214
Some studies have suggested that genetic factors might also play a role based on HLA class II antigen expression but this is quite controversial and has not been confirmed in all reports. In one study, B54, DRB0405 and DQB10401 were associated with disease progression while DRB11302, DRB11101 and DQB10604 were more frequently found in HCV carriers with minimal disease and normal ALT levels.15 Other studies have linked polymorphisms in the genes of transforming growth factors-.16 and angiotensin II17 to a more progressive type of chronic hepatitis C.
Metabolic abnormalities and disease progression
Recently, there have been a number of reports indicating that several metabolic abnormalities and comorbidities may cause significant worsening of the clinical course of chronic hepatitis C contributing to higher rates of cirrhosis development. These conditions include increased hepatic iron stores, liver steatosis, increased body mass index (BMI) and type II diabetes. Liver steatosis seems to play a central role in the pathogenesis of liver disease in hepatitis C and may be caused by many different pathways, including viral and metabolic factors (Figure 2).
The observation that patients with chronic hepatitis C often have increased deposits of iron in the liver and that this condition is associated with more advanced liver damage and poor response to anti-viral therapy promoted a number of studies aimed at assessing the role of mutations in the haemochromatosis gene in hepatitis C. The results so far obtained have been controversial and not conclusive. Although in one study18 patients with hepatitis C and C282Y heterozygotic mutation of the HFE gene had more advanced liver fibrosis and higher frequency of cirrhosis, other reports have not been able to confirm a significant association between mutations of the haemochromatosis gene and severity of hepatitis C.19, 20 Nevertheless, from a practical point of view it seems reasonable to evaluate iron metabolism and overload in patients with chronic hepatitis C, particularly in the presence of more advanced fibrosis, and to remove the excess by phlebotomy, whatever the cause of iron overload might be, as this approach has been shown to reduce ALT levels and disease progression and to improve the response to anti-viral therapy.
During the past 2 years, great interest has been generated by a number of clinical studies indicating that liver steatosis might play a most relevant role in hepatitis C. Liver steatosis is a frequent finding in the biopsy of patients with HCV infection and in some of them it might be extensive and severe. In our own study,21 based on the analysis of more than 400 patients with chronic hepatitis C, steatosis was detected in 65% and was of grade 3 (severe) in 23%. Patients infected with HCV-3 had higher rates and grades of steatosis compared with cases with HCV-1 or HCV-2, in agreement with published data.22, 23
The mechanisms leading to lipid accumulation in the hepatocytes of HCV-infected patients appear multifactorial. In a subgroup of patients, liver steatosis is associated with risk factors of non-alcoholic fatty liver (NAFL) or steatohepatitis (NASH) such as obesity, or type II diabetes, while in other cases such factors are absent and liver steatosis might be directly related to the virus itself (viral steatosis). A 'metabolic' type of steatosis is more frequently seen in patients with HCV-1 or -2 while the 'viral' type is typically seen with HCV-3 and might be related to the direct effect of viral proteins (core protein and NS5A) which interfere with the intracellular uptake and transport of tryglicerides and with the assembling and secretion of lipoproteins.
Whatever the cause, liver steatosis may contribute to progression of fibrosis in patients with HCV. Indeed, obesity with a BMI >30 kg/m2, liver steatosis of moderate/severe grade and type II diabetes have all been associated with more advanced liver disease.2426
These data clearly indicate the need for assessing liver steatosis in patients with hepatitis C and considering dietetic and/or therapeutical strategies able to prevent or reduce it, to be used side by side with more specific anti-viral therapies.
Environmental and external factors
Coinfection with HBV or HIV has been shown to accelerate the course of chronic hepatitis C and facilitate progression to cirrhosis and hepatocellular carcinoma. Therefore, patients with HCV should be tested for HBV and HIV markers in the presence of risk factors, as such coinfections may modify the clinical management and therapeutic strategies. Little is known about how to treat patients with HBV/HCV coinfection. As the two viruses may often interfere in their replicative activity,27 testing for HBV-DNA and for HCV-RNA in serum should be performed in all cases to identify the dominating virus and treat the patients accordingly using an 'HCV' protocol in HCV-RNA-positive/HBV-DNA-negative cases and an 'HBV' protocol in HCV-RNA-negative/HBV-DNA-positive patients. In patients with evidence of active replication of both viruses, our strategy has been to first give interferon plus ribavirin to eradicate HCV, followed by HBV treatment in the case of a persistent HBV-DNA-positive test. Clinical trials of adequate size are clearly needed to better define how and whom to treat with HBV/HCV coinfection.
Coinfection with HCV/HIV is common.28 Approximately 25% of subjects infected with HIV are also infected with HCV. After the introduction of highly active anti-retroviral therapies (HAART) the overall mortality for AIDS and related opportunistic coinfection has declined sharply and liver disease due to HCV has emerged as an important cause of death in HCV/HIV-coinfected patients. HIV coinfection has been shown to increase the risk of HCV chronicity and accelerate progression of liver disease.
On the other hand, HCV and the related liver disease often complicate the clinical management of HIV patients by increasing the grade of immune impairment and the liver and extrahepatic toxicity of anti-retroviral drugs. Therefore, management of HCV infection in HIV-positive patients has become of great importance. A liver biopsy is usually needed to evaluate stage of chronic hepatitis C. Ideally, HCV anti-viral therapy should be started before HAART, when the HIV infection stage allows to do so. HIV-coinfected patients do appear to respond to interferon monotherapy as non-coinfected patients when the pre-treatment CD4 cell count is above 500/mm3. Ongoing studies with IFN plus Ribavirin and PEG-IFNs will provide in the new future more evidence-based guidelines for the management and treatment of HIV/HCV-coinfected individuals.
Alcohol and HCV
Although alcohol abuse has been clearly shown to increase the severity of hepatitis C, with more rapid progression to cirrhosis and hepatocellular carcinoma, these effects relate mainly to patients with quite high daily alcohol intake. Much less is known on whether a light or moderate amount of alcohol might also exert a negative influence on HCV. These issues have been extensively discussed recently by Peters and Terrault.29 These authors have clearly underlined the need of future studies addressing the issue of the effect of minimal to moderate alcohol intake (1 or 2 drinks per day or <20 g daily) on the course of hepatitis C and response to anti-viral therapy.
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