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Steatosis in Hepatitis C: What Does It Mean?
 
 
  Current Hepatitis Reports 2003, 2:137;144
Tarik Asselah, MD, Nathalie Boyer, MD, and Patrick Marcellin, MD*
*Service d’H╚patologie, H┘pital Beaujon, Clichy, France.
 
Hepatitis C and nonalcoholic fatty liver disease (NAFLD) are both common causes of liver disease. Thus, it is not surprising that they can coexist in the same individual. The prevalence of steatosis in patients with chronic hepatitis C differs between studies, probably reflecting population differences in known risk factors for steatosis, namely overweight, diabetes, and dyslipidemia. The pathogenic significance of steatosis likely differs according to its origin, metabolic (NAFLD or nonalcoholic steatohepatitis) or virus related (due to hepatitis C virus genotype 3). Whether or not steatosis determines fibrosis progression is not yet unproven.
 
Introduction
 
The hepatitis C virus (HCV) is a major cause of chronic liverdisease worldwide infecting approximately 170 millionpeople.The severity of the disease varies widely, fromasymptomatic chronic infection to cirrhosis and hepatocellular carcinoma. Liver lesions are thought to be mainlyrelated to immune-mediated mechanisms. Factors influencing the outcome of chronic hepatitis C, including age,gender, and alcohol consumption, are poorly understood.
 
Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of hepatic pathology, with simple steatosis without anyevidence of necrosis or inflammation at one end, and severeinflammation with extensive fibrosis or cirrhosis at the other.Fatty liver alone probably has a good prognosis; in contrast,nonalcoholic steatohepatitis (NASH) can progress to cirrhosisin a significant proportion of cases. It is important to note thatall the data available have been retrospectively collected.
 
Hepatic steatosis is a common histologic feature ofchronic hepatitis C. This finding is also associated withother risk factors, including obesity, high alcoholconsumption,type 2 diabetes, or hyperlipidemia. Thesefactors may contribute to steatosis in patients with chronichepatitis C. In addition, virologic factors may also play animportant role. In this article we focus on the meaning ofsteatosis in patients with chronic hepatitis C.
 
Steatosis
 
Mechanisms of steatosis
Hepatic steatosis develops in the setting of multiple clinical conditions, including obesity, diabetes mellitus,alcohol abuse, protein malnutrition, total parenteralnutrition,acute starvation, drug therapy (eg, corticosteroid,amiodarone, perhexiline, estrogens, methotrexate), andcarbohydrate overload [1–4,5 **].
 
 
 
   
 
  In the fed state, dietary triglycerides are processed by theenterocyte into chylomicrons, which are secreted into thelymph. The chylomicrons are hydrolyzed into fatty acids bylipoprotein lipase. These free fatty acids are transported to theliver, stored in adipose tissue, or used as energy sources bymuscles. Free fatty acids are also supplied to the liver in theform of chylomicron remnants, which are then hydrolyzed byhepatic triglyceride lipase. During fasting, the fatty acids supplied to the liver are derived from hydrolysis (mediated by ahormone-sensitive lipase) of triglycerides stored in the adiposetissue. In the liver, the free fatty acids from all these sources areoxidized by mitochondria, used for triglyceride synthesis, orused to form phospholipids and cholesterol esters.
 
There are several mechanisms that can lead to hepaticsteatosis(Fig. 1). Hepatic triglyceride accumulation occurswhen the amount of fatty acid supplied to the liver from theintestine or adipose tissue exceeds the amount needed formitochondrial oxidation, synthesis of phospholipids, andsynthesis of cholesterol esters. This is the presumed mechanisms for steatosis in the setting of obesity, diabetes mellitus,and excessive dietary intake of fats or carbohydrates. Insulinresistance is found in obesity, type 2 diabetes, and cirrhosis.Patients with NAFLD demonstrate markedly increasedinsulinresistance compared with control subjects. Insulinresistance could contribute to hepatic steatosis by favoringperipheral lipolysis and hepatic uptake of fatty acids. It mayalso be the reason for increased expression of CYP2E1,thereby contributing to the production of pro-oxidantsin afatty liver. Decreased fatty acid oxidation with subsequentfatty infiltration of the liver may also contribute to the genesis of steatosis, particularly in the setting of hyperinsulinemia. Triglycerides can also accumulate in the liver because ofdecreased synthesis of lipoprotein and decreased export oflipids from the liver.
 
NAFLD and NASH
 
Nonalcoholic fatty liver disease represents a spectrum ofconditions characterized histologically by macrovesicularsteatosis occurring in patients who do not consume alcohol in amounts generally considered harmful to the liver[1,2]. There are two histologic patterns of NAFLD: fattyliver alone and steatohepatitis. The term NASH was introduced by Ludwig et al. in 1980 to describe the biopsy findings in patients with steatohepatitis in the absence ofsignificant alcohol consumption.
 
Estimates based on imaging and autopsy studies suggestthat approximately 20% to 30% of adults in the UnitedStates and other western countries have excess fat accumulation in the liver [2]. About 10% of these individuals, orfully 2% to 3% of adults, are estimated to have NASH.
 
Risk factors for NAFLD include obesity, diabetes,hypertriglyceridemia, and specific syndromes associatedwith insulin resistance [1,2]. The body mass index (BMI) iscalculated by the following formula: weight in kilograms/height in meters2 (kg/m2). Overweight is defined by a BMIgreater than 25 kg/m2 and obesity by a BMI greater than 30kg/m2. The prevalence of NAFLD increases with increasingbody weight. Wanless and Lentz [6] found steatosis in 70%of obese and 35% of lean patients in a consecutive autopsystudy. The prevalence of steatosis is variable amongstudies,likely as a result of population differences inobesity, type 2 diabetes, and dyslipidemias.
 
The presence of NAFLD should be considered inindividualswith persistent elevation of serum alanineaminotransaminase for which another cause cannot befound. Liver biopsies have been performed in very fewstudies. In one of these studies, the prevalence of steatosisin patients with abnormal liver tests (in whom knowncauses of liver disease were ruled out) was 64%, 32% withpure fatty liver and 32% with steatohepatitis [7].
 
Diagnosis and grading of steatosisIn an individual with abnormal liver tests, particularlyelevationof aminotransferase and -glutamyl transferaseactivities, the presence of NAFLD and NASH may besuspectedon clinical grounds (with associated factors suchas obesity, diabetes, and hyperlipidemia); however, theseare nonspecific findings. In addition, although ultrasonography, computed tomographic scan, and magnetic resonance imaging can demonstrate hepatic fat accumulation,they cannot diagnose or grade necroinflammation or fibrosis [1–4]. Thus, a liver biopsy is the only accurate methodfor the diagnosis and grading of necroinflammation andfibrosis [1–4]. Arguments against liver biopsy for the diagnosis of NAFLD include the generally good prognosis ofmost patients, the lack of an established effective therapy,and the risk and costs associated with the biopsy.
 
Limitations of studies
Histologic criteria used for fatty liver disease are different among studies. For instance, the grading and scores ofsteatosisare different from one study to another. Even theamount of steatosis considered to be the cut-off betweennormal and pathologic is not consistently defined. In addition,variations in the methods used to assess andquantify steatosis likely contribute to the heterogeneity inclinical studies. Thus, for future studies on the naturalhistoryof steatosis or steatohepatitis, it is extremely important to standardize the methodology of assessment of themicroscopic lesions (fatty liver). For instance, standardhistologiccoloration is not appropriate for an accurateassessment of steatosis and oil red coloration is needed.The data on the natural history of NAFLD and NASH areextremely limited and commonly based on retrospectivestudies. It is generally believed that there are several distincthistologic states in the natural history of these disordersthatindicate progression of the lesions: fatty liver alone, steatohepatitis, steatohepatitis with fibrosis, and eventually cirrhosis [1–4]. It is also currently believed that although fattyliver alone has a good prognosis, NASH can progress to cirrhosis in a significant proportion of cases.

 
 
 
   
 
  Evidence that HCV Can Induce Steatosis
In vitro and animal models
Both in vitro studies and the transgenic mouse model havesuggested that the HCV core protein is possibly responsiblefor lipid accumulation. In cell culture at least two HCVproteins, core and NS5A, have been credited with theabilityto alter lipid metabolism [8,9]. These proteins bindto the apolipoproteins A1 and A2, which are likelyinvolved in triglyceride accumulation and storage in livercells. Both the core and NS5A proteins are localized on thesurface of lipid droplets. Overexpression of core proteinfurther stimulates the formation of lipid droplets.
 
In transgenic mice, it has recently been reported that HCV core protein can inhibit microsomal triglyceridetransfer protein (MTP) activity and very low density lipoprotein secretion, leading to steatosis [10]. Although adirect interaction with the MTP is unlikely because itwould require the secretion of the core protein into theendoplasmic reticulum lumen, which has not beenreported to date, the MTP inhibition may still be mediatedby unknown factors. However, mice made transgenic withthe HCV core protein have normal apolipoprotein B levels.In another work, the expression of both structural andnonstructural (core and NS5A) proteins in transgenic micewas confirmed to lead to steatosis [11]. Finally, it has alsobeen shown that the core protein causes mitochondrialinjury leading to oxidative stress which, in turn, disturbslipid metabolism, thus contributing to steatosis [12].Thus, there is evidence that HCV proteins can causehepatic steatosis in the absence of immune response, atleast under certain experimental conditions. It should bekept in mind though, that all models have used constructsderived from genotype 1 isolates. Because HCV genotype 3has been more frequently associated with steatosis thanHCV genotype 1 in humans, further studies using genotype3 isolates are needed.
 
Frequency of steatosis in patients with chronic hepatitis C
The overall prevalence of steatosis in patients with chronichepatitis C is 54%. Because steatosis directly increases withincreasing BMI, its prevalence in patients with chronichepatitisC largely depends on the population evaluated, withpercentages that range from 40% to 86% (Table 1) [13–18,19 **,20,21 **,22,23 **,24 **]. The majority of patients withchronic hepatitis C and steatosis (80%) have a mild degree ofsteatosis affecting less than 30% of hepatocytes (Table 1).Therefore, steatosis is more frequent in patients with chronichepatitis C than in the general population, where steatosis isestimated (based on imaging and autopsy studies) to affect20% to 30% of adults [2]. In contrast, steatosisis lessfrequentin patients with chronic hepatitis C than in patientswith abnormal alanine aminotransaminase levels, in whommajor causes of chronic liver disease and hepatitis C havebeen ruled out. In these patients, steatosis is the morefrequentfinding. For instance, in a study from Italy the prevalence of steatosis in patients with abnormal liver tests was64% [7]. In addition, steatosis is highly frequent in obesepatients, occurring in 70% of cases in an autopsy study [6].
 
 
 
   
 
  Factors associated with steatosis in patients with chronic hepatitis C
Host factors
Hepatitis C and NAFLD are both common causes of liverdisease; therefore, it is not surprising that they can coexistin the same individual. The same factors (eg, obesity, alcohol, diabetes, and hyperlipidemia) associated with NAFLDhave been found to be associated with steatosis in patientswith chronic hepatitis C.
 
In almost all studies a link between steatosis and highBMI has been reported (Table 2) [13–18,19 **,20,21 **,22,23 **,24 **]. Adinolfi et al. [17] reported that although steatosis was not significantly associated with BMI in the overallcohort of HCV-infected patients, the association became significant in those infected with HCV genotype 1 patients (andnot in HCV genotype 3). In fact, visceral fat distribution ratherthan BMI was associated with steatosis. This led to the ideathat in patients with HCV infection there is a “metabolic fat”(especially in patients with HCV genotype 1 infection) and a“viral fat” (especially in those infected with HCV genotype 3).
 
Alcohol intake is a known factor inducing steatosis.However, several studies have not found a significant association between the presence of steatosis and alcoholconsumption.One potential explanation for this lack ofassociation may be the exclusion of those with heavy alcohol intake in most studies.
 
The association between HCV infection and type 2 diabetes has been shown by cross-sectional studies that included prevalent cases of diabetes. Although most of the evidencesupports that HCV infection antedates type 2 diabetes, it isalso possible that persons with diabetes are at increased riskfor acquiring HCV infection because of frequent hospitalinterventions and daily use of syringes [25]. Because theprevalence of other metabolic disorders, includinghyperlipidemia and diabetes, is low in most populationswith HCV chronic infection, their impact on steatosis cannotbe correctly evaluated in cross-sectional studies.
 
Steatosis and HCV genotype 3
Several studies have found a significant associationbetween HCV genotype 3 infection and the presence ofsteatosis(Table 2). Recently, we conducted a study to determine the characteristics (epidemiologic, biological, andhistologic) associated with steatosis in patients withchronic hepatitis C [23 **]. From November 2000 to July2001, all consecutive adults with chronic hepatitis Cadmitted for liver biopsy were included in this study. Theday of the liver biopsy a questionnaire for risk factors wascompleted prospectively, and a blood sample was taken forlaboratory analysis. Our study included 290 patients (143men, 147 women). The mean BMI was 24.1 ± 3.8. Proportions of genotype 1 and 3 were 54% and 20%, respectively.Steatosis was present in 135 patients (46.6%), in 63% ofpatients with genotype 3, and 39% of those with genotype1 (P = 0.03). In multivariate analysis, liver steatosis wasassociated with HCV genotype 3 infection, high BMI, andhigh grade of necroinflammation. Thus, in patients without associated factors for steatosis, steatosisis morefrequentin those with HCV genotype 3 than in those withHCV genotype 1. And based on the data available frompublished studies (Table 1), steatosis is present in 73% ofpatients infected with HCV genotype 3 and in 51% ofpatients infected with HCV genotype other than 3 (Table1). The mechanisms underlying this steatosis genotypespecific association are unknown. We have recently foundthat HCV genotype 3 is associated with higher quasispeciesheterogeneity than HCV genotype 1 [26].
 
Steatosis and HCV replication
Rubbia-Brandt et al. [16] found a significant correlationbetween steatosis score and titer of intrahepatic HCV RNA inpatients infected with genotype 3, indicating that steatosiscould result from a virus-related cytopathic effect in thesepatients. In this study, when only the 18 liver biopsies frompatients with HCV genotype 3 and steatosis were considered,a significant correlation was found between high steatosisscore and high intrahepatic HCV RNA titer (for both strandsof HCV RNA genomic and minus). Two other studies, alsobased on patients infected with HCV genotype 3, found anassociation between degree of steatosis and serum HCV RNAlevels [17,21 **].
 
Additional studies, however, have not confirmed thesefindings. This may be due, in part, to the fact that HCVRNA viral load was not included in the initial evaluation.Interestingly, intrahepatic HCV RNA levels were not correlated with the degree of liver injury, including steatosis,necroinflammation, and fibrosis in 47 patients withchronic hepatitis C (25 with genotype 1, 20 with genotype3, and two with genotype 2) [27]. Therefore, in genotype 3infection, the relationship between high level of HCVreplicationand high grade of steatosis is controversial andneeds confirmation. If confirmed, it would stronglysuggestthe existence of a direct viral cytopathic effecthypothesis, which sharply differs from the generallyaccepted idea of immune-mediated liver cell damage [28].Furthermore, HCV is a noncytolytic virus in various expression systems (cell line and transgenic mice).
 
HCV-related steatosis and antiviral therapy
Rubbia-Brandt et al. [29,30] reported the case of a patientwith chronic HCV genotype 3 infection and steatosis, inwhom steatosis disappeared when HCV replication wasinhibited by treatment, and recurred when the viral replication (and hepatitis) relapsed after treatment withdrawal.This observation supports the direct relationship betweenHCV genotype 3 infection and steatosis.
 
In a recent study, Kumar et al. [31] tested the hypothesisof whether antiviral treatment altered hepatic steatosis inchronic hepatitis C. In 28 patients with HCV genotype 1 and34 patients with HCV genotype 3, they determined the severity of steatosis in pre- and post-treatment liver biopsies usingcomputer-assisted morphometric image analysis as well asconventional semiquantitative scoring. Before treatment,hepatic steatosis was present in 16 (57%) patients infectedwith HCV genotype 1 and 21 (62%) of those with HCV genotype 3. Whereas in the former group there was no change insteatosis after treatment, regardless of the treatment response,a sustained virologic response was significantly associatedwith reduction of steatosis (P < 0.001) in the latter. Interestingly, in this group of genotype 3 infected patients, there wasno change in steatosis among those without sustainedvirologicresponse. By logistic regression analysis, sustainedvirologic response was the only variable predictive ofimprovement in hepatic steatosis (P = 0.007).
 
In another study, Poynard et al. [21 **] assessed theeffect of treatment with peginterferon or interferon alfa-2band ribavirin on steatosis. They analyzed 1428 naivepatients included in a randomized trial. Among virologicresponders, steatosis was markedly improved in patientswith HCV genotype 3. An improvement of at least onegrade occurred in 77% of these patients, compared with46% of those infected with other genotypes. Likewise, adisappearance of steatosis was observed in 46% and 29%,respectively (P < 0.001 for both comparisons). In genotype3 responders, the baseline low serum cholesterol was alsocorrected by treatment (P < 0.001). In conclusion, thesedata provide strong support for a direct causal associationbetween HCV genotype 3 infection and hepatic steatosis.
 
Steatosis in Hepatitis C: What Does It Mean?
Limitations of studies
Published data on the influence of steatosis on the naturalhistory of chronic hepatitis C have several limitations thatmay explain discrepancies between studies.Variations in the methodologyOnly limited studies are available that in addition aregenerallycross-sectional or retrospective. Furthermore,differenthistologic criteria have been used in the variousstudies of fatty liver disease. Moreover, all factors affectingsteatosis are not always collected (eg, alcohol consumption, BMI, and so forth) and multivariate analysis is infrequently done.
 
Variations in the populations and the HCV genotype distribution
Populations studied have different risk factors for steatosis(eg, obesity is more frequent in the United States). In a studyfrom the United States, the mean BMI was 28.5 kg/m2 withthe following distribution: 31% less than 25 kg/m2, 37%from 25 kg/m2 to 30 kg/m2, and 32% greater than 30 kg/m2[19 **], meaning that 69% of the patients were overweightand 32% were obese. In our study including 290 patientswith chronic hepatitis C, the mean BMI was 24 kg/m2 withthe following distribution: 62% less than 25 kg/m2, 30%from 25 kg/m2 to 30 kg/m2, and 8% greater than 30 kg/m2[23 **]. The setting of the study gives an idea of the population studied (recruitment shift): internal medicine (moremetabolic disorders) and transplantation center (morepatients with advanced liver disease).
 
In addition, HCV genotype distribution differs fromone region to another in the world. Genotype 3 is morefrequentin Europe than in the United States. In a studyfrom the United States with 297 patients with chronichepatitisC, HCV genotype 3 was present in only 39patients (14% of cases), making subanalysis in thissubgroupdifficult [19 **]. In contrast, in a recent studyfrom Europe, 178 of 755 patients (24%) had an HCVgenotype3 infection [24 **].
 
 
 
   
 
  Steatosis and fibrosis
Factors influencing the outcome of chronic hepatitis C arepoorly understood [32]. There is some controversy withregard to the influence of steatosis on the progression offibrosis. Among 11 studies listed (Table 3), eight found anassociation between the presence of steatosis and highstage of fibrosis. However, in four of these studies, thisassociation reached a low statistical degree of significance.The discrepancies observed between studies may be due toseveral reasons, such as the differences in the histologicscores used, the lack of multivariate analysis, and thedifferencesin metabolic risk factors for steatosis.
 
The fact that obesity has been related to the severity ofhepatic fibrosis and risk of cirrhosis is an argument for a roleof steatosis in the progression of fibrosis. In several studieson alcoholics and patients with HCV chronic infection, obesity has been shown to favor hepatic fibrosis [33–37]. Liverfibrosis can develop in overweight patients who are free ofany other cause of liver disease [38]. However, in overweightpatients, the grade of steatosis is not associated with septalfibrosis, underlying the fact that a high BMI may be associated with fibrosis through other mechanisms different fromsteatosis. In the leptin-deficient ob/ob mouse, which hasprofound insulin resistance and glucose intolerance, markedhepatic steatosis is present without steatohepatitis or fibrosis.
 
In a retrospective study with two paired liver biopsies,aggravation of steatosis was found to be associated with fibrosisprogression [22]. In this study, which analyzed steatosison twoliver biopsies, the number of patients was relatively small (n =91), and the association between increased steatosis andincreased fibrosis does not demonstrate the causal relationship.
 
In a recent study by Rubbia-Brandt et al. [24 **], amultivariateanalysis was carried out in 755 chronic hepatitisC patients consecutively admitted at three referralhospitals.Steatosis was independently associated with fibrosis. When multivariate analysis was repeated on patientsdivided according to viral genotype (ie, 3 vs non-3) to look fortype-specific risk factors, steatosis was associatedwith fibrosisonly in type 3 infected patients. The findings from this studysuggest that “nonviral steatosis” may be as benign as NAFLD,whereas viral steatosis (genotype 3–induced steatosis) mayaccelerate fibrosis progression.
 
Thus, although some studies have found a positive association between steatosis and fibrosis [19 **], not all studieshave been able to confirm these findings. In our recent studyincluding 290 patients with chronic hepatitis C, we found byunivariate, but not multivariate, analysis an associationbetween steatosis and high stage of fibrosis. Discrepanciesbetween these results and those of recent studies showing anassociation between steatosis and high stage of fibrosis maybe explained by the fact that risk factors for nonviral steatosiswere more common in the latter studies. In fact, somepatients may have NASH due to obesity and metabolic disorders, in addition to having chronic hepatitis C.
 
In summary, it seems that there is an associationbetween steatosis and fibrosis. Whether this associationreflects causality is at present unknown. In addition, themechanisms underlying this relationship remainunknown. In fact, steatosis could be a marker but not acause of disease progression. The frequent associationbetween the presence of steatosis and the grade of necroinflammation may suggest that steatosis is a marker ofnecroinflammation that, in turn, is a marker of fibrosisprogression. The question then becomes the following:“Because genotype 3 is associated with steatosis and steatosis is associated with fibrosis progression, how can weexplain the lack of association between genotype 3 infection and stage of fibrosis in several previous studies?”
 
Steatosis and necroinflammation
Several studies have found an association between necroinflammation and steatosis (Table 3). Necroinflammatoryactivity is a dynamic process in chronic hepatitis C andmay fluctuate over time. The activity score reflects theseverity of necrosis and inflammation at a given point. Inmost cross-sectional studies, the degree of necroinflammatory activity has been associated with the presence ofsteatosis. The mechanisms responsible for this associationare unknown. In vitro studies have shown that the HCVcore protein could lead to oxidative stress [12]. In addition, steatosis of any cause can be associated with thedevelopment of inflammatory changes in the setting ofoxidative stress. Moreover, HCV infection is associated withincreased production of cytokines [40] that enhancesinflammation and leads to increased lipid peroxidation.Finally, one may hypothesize that steatosis is the consequence of more severe cell injury and necroinflammationin chronic hepatitis C rather than the direct cause ofworseningof fibrosis.
 
How do we reconciliate all these data?
Hepatitis C and NAFLD are both common causes of liverdisease. Therefore, it is not surprising that they can coexistin the same individual. The wide range of steatosis inpatients with chronic hepatitis C probably reflects theexistence of population differences in overweight, diabetes,and dyslipidemia. Steatosis may not have the same pathogenic significance, whether its origin is metabolic (NAFLDor NASH) or virus related (due to HCV genotype 3).
 
Conclusions
Approximately half of patients with chronic hepatitis Chave steatosis, which is mild in the majority of cases.Steatosiscan be a reflection of necroinflammation ratherthan a cause of progression of fibrosis. Whether or notsteatosisdetermines fibrosis progression is yet to beproven. In clinical practice, risk factors for steatosis alwayshave to be assessed in patients with chronic hepatitis C. Ifpossible, and given their association with pathologicconditionssuch as obesity, diabetes, and hyperlipidemia,these conditions should be treated.
 
References and Recommended ReadingPapers of particular interest, published recently, have been highlighted as: * Of importance ** Of major importance
 
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