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FW: NATAP: Steatosis May Cause Fibrosis & Cancer

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  • alleypat
    Hepatitis C and steatosis: a reappraisal Journal of Viral Hepatitis Volume 13 Page 73 - February 2006 Lonardo1,2, P. Loria2, L. E. Adinolfi3, N. Carulli2 and
    Message 1 of 1 , Jan 31, 2006
      Hepatitis C and steatosis: a reappraisal

      Journal of Viral Hepatitis
      Volume 13 Page 73 - February 2006
      Lonardo1,2, P. Loria2, L. E. Adinolfi3, N. Carulli2 and G. Ruggiero3
      1UnitC Operativa di Medicina Interna e Gastroenterologia, Nuovo Ospedale
      Civile-Estense di Baggiovara, Modena; 2Dipartimento di Medicina Interna,
      UniversitC degli Studi di Modena e Reggio Emilia, Modena and 3Cattedra di
      Medicina Interna, UniversitC degli Studi di Napoli, Napoli, Italy

      The overall prevalence of steatosis in patients with Hepatitis C virus (HCV)
      chronic infection is 55.5% (range 34.8-81.2%). This is a two to threefold
      increase compared with the prevalence of steatosis in chronic hepatitides
      because of other aetiologies and of the figures expected on the grounds of a
      steatosis-HCV chance association. HCV genotype 3 (HCV-3) has specific
      epidemiological features; furthermore, as compared with HCV-non-3 genotypes,
      it is associated with a higher prevalence (74.1%vs 47.9%, P < 0.01) and with
      more severe grades of steatosis (prevalence of grade 3 steatosis 29.6 vs 5.5
      P < 0.01). Host and viral factors play a role, although to a variable
      extent, in the pathogenesis of HCV-3 and non-3 steatosis. HCV load and body
      mass index are associated with steatosis in HCV-3 and in HCV-non-3 patients
      respectively. Serum cholesterol levels and liver steatosis at baseline
      follow an inverse relationship in HCV infection. As hypocholesterolaemia
      corrects only in those sustained responders to antiviral treatment both in
      genotype 3 and in non-3 genotypes, the occurrence of a virally induced,
      acquired and reversible hypobetalipoproteinaemia seems plausible. Steatosis
      affects the natural course of HCV infection: it is associated with fibrosis,
      a possible mediator of increased risk to develop type 2 diabetes, it impairs
      the response to antiviral treatment in HCV-3 patients and might constitute a
      risk factor for the development of hepatocellular carcinoma. These
      observations indicate the need to evaluate the efficacy of combined
      antiviral and 'metabolic' approaches vs standard antiviral regimes in
      patients with steatosis and HCV chronic infection.

      Which are the risk factors for steatosis in HCV infection?

      Various papers have addressed the issue of which risk factors are associated
      with steatosis in HCV infection. The results allow us to classify such
      factors to 'host-related'- including BMI/central adiposity -
      [2,5,15-17,22,23,25,27,30,31,34,36,40,42] and 'viral'- including genotype 3
      [2,5,23,25,29-31,34-36,39,42]. It is of interest that a number of authors
      report exactly the same two risk factors [2,5,23,25,27,30,31,34,36,42] while
      few report only one of the two [15-17,22,29,35,39,40]. This impressive body
      of literature strongly suggests that steatosis should be studied separately
      in HCV genotype 3 ('viral steatosis') from non-3 infections ('metabolic
      steatosis'). By following such an approach, it has been convincingly shown
      that hepatic/blood viral load is the factor associated with steatosis in
      genotype 3-infected patients and BMI is associated to steatosis in 'non-3'
      patients (Table 3). Clinical experience suggests that serum cholesterol
      levels are low in some HCV-infected patients and that such an abnormality is
      corrected by effective antiviral treatment. Therefore, the following
      question should be addressed.

      What are the consequences of steatosis in patients with HCV?
      Steatosis observed in HCV-positive chronic hepatitis has the potential to
      affect the natural course of the infection through different routes (Fig.


      Fibrosis - Several Authors have found that steatosis is associated with
      fibrosis in cross-sectional studies [2,5,22,23,25,34,36,40,45-47]. Two
      studies have reported that alcohol interacts with steatosis in the
      development of fibrosis [23,47]. Additional risk factors for fibrosis have
      been reported to be: age of the patients/disease duration [5,40],
      necroinflammation [25,45,47] and noninsulin dependent diabetes mellitus
      (NIDDM) [40]. Perhaps the best evidence for a link between steatosis and
      fibrosis comes from paired biopsies and interventional studies. Westin et
      al. [42] retrospectively analysed 98 patients who underwent dual liver
      biopsies before antiviral treatment. The median follow-up time was 5.8
      years. The authors found that progressive fibrosis was more prevalent in
      patients whose initial biopsy showed steatosis, an effect seen mainly in
      genotype 3 infection. CastC(ra et al. [48] studied paired biopsies from 96
      patients with chronic hepatitis C and found worsening of steatosis to be the
      only factor independently associated with the progression of fibrosis in a
      multivariate analysis (OR 4.7, 95% CI 1.3-10.8; P = 0.0001). Hickman et al.
      [49] studied the effect of an effective 3-month weight reduction programme
      in 10 subjects with steatosis and chronic hepatitis C examining paired liver
      biopsies prior to and 3-6 months following intervention. Nine of 10 patients
      had a reduction in steatosis irrespective of viral genotype. In these
      subjects, the median modified Knodell fibrosis score decreased from 3 to 1
      (P = 0.04) and activated stellate cells significantly decreased (P < 0.004)
      despite the persistence of the virus. Although a single study failed to
      disclose steatosis in the initial biopsy as a factor associated to
      progression of fibrosis [50], the steatosis-fibrosis association appears to
      be biologically plausible as fat is a recognized precursor of fibrosis in
      NAFLD (reviewed in Ref. 38). The mechanisms of fibrosis associated with
      steatosis in HCV have been reviewed elsewhere [4]. In short, with analogy to
      the pathogenesis of NAFLD, we speculate insulin resistance, oxidative stress
      leading to lipid peroxidation and cytokines to play a major role [4]. The
      fact that fibrosis appears to be more common and severe in HCV-related
      steatosis than in NAFLD suggests that HCV or viral products, the host's
      metabolic alterations and the antiviral inflammatory response represent an
      'extra' source of biological mediators leading to increased-collagen
      deposition [4]. A HCV genotype-specific effect has been suggested, but which
      genotype is more fibrogenic is still controversial [8]. While three
      published studies suggest HCV-3 to be more fibrogenic [34,42,48] a single
      study blames genotype 1 [36]. The mechanism through which steatosis causes
      fibrosis might be via the induction of apoptosis [51] or, similar to what
      was observed in NASH [52], via increased oxidative stress and hepatic
      stellate cell activation [21]. While it remains to be ascertained if
      abstinence from alcohol is an effective means of preventing fibrosis in
      these patients, it appears wise to advise HCV-positive patients to quit

      Response to antiviral treatment

      An impaired therapeutic effect of antiviral treatment has been consistently
      observed in patients with HCV and steatosis [2,53,54]. It has been
      speculated that this phenomenon is linked to steatosis and might be
      differentiated from those which are linked to obesity [7]. However, there is
      such a close association between steatosis and obesity, even in genotype 3
      infection [36], that studies addressing steatosis in HCV-positive subjects
      with a normal BMI are needed. Indeed, a logistic regression model provided
      an odds ratio (OR) of the weight effect of 0.90 per each 10 Kg weight
      increase (95% CI 0.79-1.04) [55]. In the largest multi-centre study
      published so far, the impact of steatosis on the response rate to antiviral
      treatment was substantial in that the OR for SVR was 0.48 (CI 0.35-0.66)
      [22]. These data have also been confirmed by other authors [53]. By studying
      28 patients with genotype 1 and 34 with genotype 3 HCV, these authors found
      that in patients with HCV genotype 1, there was no change in hepatic
      steatosis after treatment, irrespective of the treatment response. Among
      those infected with genotype 3, SVR significantly reduced steatosis (P <
      0.001), but there was no change in steatosis among those without a SVR. By
      logistic regression analysis, SVR was the only variable predictive of
      improvement in hepatic steatosis (OR = 36, 95% CI = 2.7-481, P = 0.007).
      CastC(ra et al. [56] found that the percentage of SVR in those patients with
      steatosis is 16.5%. This figure is 30% less than the expected response rate
      following the current gold standard combination of peginterferon (PEG-IFN)
      and Ribavirin this being 54-61% (ranges 42-51% for patients with genotype 1
      infection through 78-82% of cases with genotypes 2 or 3) (reviewed in Ref.
      57). In Poynard's experience [2], steatosis is more prevalent in
      nonresponders (65%) than among sustained responders (47%, P < 0.001).
      However, steatosis-associated resistance to antiviral treatment is specific
      for metabolic steatosis because the viral steatosis observed in genotype 3
      is not associated with lower sustained response [2].

      Noninsulin dependent diabetes mellitus

      Several lines of evidence support a close relationship between HCV chronic
      infection and NIDDM [3,58]. Up to one-third of patients with HCV chronic
      infection develops NIDDM. This prevalence is much higher than that observed
      in the general population and in patients with other chronic liver diseases
      such as hepatitis B virus, alcoholic liver disease and primary biliary
      cirrhosis. Further, HCV seropositivity in patients with NIDDM appears to be
      higher than in the general population. Postliver transplantation NIDDM also
      appears to be higher among patients with HCV. Finally, HCV infection
      substantially increases the risk of developing NIDDM. As both NIDDM and HCV
      chronic infection are closely linked to steatosis, steatosis has been
      postulated to be a mediator of insulin resistance in HCV-positive subjects
      [4]. Although some studies failed to demonstrate that this is the case
      [59,60], our data indicate that homeostasis model assessment-insulin
      resistance (HOMA-IR) in HCV-positive subjects is higher than that observed
      in healthy and FHBL control subjects and is in the same order of magnitude
      to that observed in NAFLD (A. Lonardo, unpublished observation), a condition
      widely accepted to be a prototype insulin-resistant state [61]. Clearly,
      additional studies are needed in this area before any firm conclusions can
      be drawn.

      Hepatocellular carcinoma

      A single study has reported steatosis to be a risk factor for the
      development of HCC in HCV-positive patients. Ohata et al. [32] followed-up
      for up to 15 years 161 patients with chronic HCV infection and found that
      the presence of steatosis was significantly associated with the incidence of
      HCC (risk ratio 2.81, 95% CI 1.24-6.37 P = 0.0135) in a multivariate
      analysis. The mechanisms through which hepatic steatosis might contribute to
      hepatocarcinogenesis remain unknown. HCV might exacerbate oxidative stress
      produced by steatosis: e.g. HCV core protein may alter the
      oxidant/antioxidant state in the liver in the absence of inflammation and
      may interact with retinoid C receptor alpha, a transcriptional regulator
      that controls many aspects of cell proliferation, differentiation and lipid
      metabolism [62]. Although Ohata's data are clinically relevant and
      biologically plausible, they need to be confirmed also in other geographic
      areas where HCC has a lesser incidence.

      In conclusion, steatosis has been convincingly demonstrated to significantly
      impact on the natural history of HCV infection. Therefore, it is of great
      clinical relevance to determine whether life-style alterations might affect
      the natural history of steatosis.

      Do life-style changes impact on steatosis in HCV-positive patients?

      If we assume that genotype 3 directly causes steatosis and that, in
      contrast, steatosis associated with 'non-3' genotypes (particularly genotype
      1) occurs mostly as a consequence of the host's risk factors for steatosis
      [2,8], we would expect no benefit from body weight reduction in patients
      infected with HCV genotype 3. Contrary to this prediction, Hickman et al.
      [63] found a significant reduction in the grade of steatosis in their
      overweight or obese patients who were ineligible for, or nonresponders to,
      antiviral treatment. Interestingly, this was found not only in four HCV
      genotype 1 but also in those seven genotype 3 patients with steatosis after
      a weight reduction programme based on a 15-month diet and exercise
      intervention. These findings need to be confirmed by larger studies.
      However, it is of interest that in patients with genotype 3 infection on
      antiviral treatment, after disappearance of HCV RNA from serum, the same
      associations were observed with metabolic parameters than were seen in
      patients infected with non-3 genotypes [2]. Taken collectively these data
      probably indicate that a clear-cut distinction between 'viral' and
      'metabolic' steatosis should be viewed with caution. It appears likely that
      both host and viral factors are present, though to a variable extent, both
      in HCV genotype 3 and in 'non-3' steatosis. Before drawing any conclusions,
      an effort should be made to understand the reasons why discrepancies exist
      among the various studies about HCV-related steatosis.

      Can discrepancies be reconciled and any conclusions be drawn?
      The discrepancies in the results reported by various authors who have
      studied steatosis in HCV-patients can be traced back to differences in some
      of the features of the case series, including BMI, alcohol consumption,
      prevalence and extent of steatosis in relation to genotypes, treatment
      schedules, and criteria of exclusion (i.e. patients with NIDDM). Some of
      these items, such as prevalence, body distribution and severity of
      adiposity - probably the most powerful determinant of hepatic steatosis -
      reflect the varying prevalence rates of obesity in the general population,
      with studies from USA and Australia reporting higher rates than European
      studies [8]. In addition, the role of alcohol is also inherently difficult
      to be ascertained as patients might alter their drinking habits when
      notified that they have chronic HCV hepatitis [8]. Furthermore, different
      drinking patterns i.e. in the fasting as opposed to the postprandial phase
      might differently affect the risk of hepatotoxicity [64]. Failure to study
      epidemiological, pathogenic and clinical patterns separately in 3 vs'non-3'
      genotypes might be another reason why earlier studies appear to have
      provided less dependable results than modern studies.

      If we are to make an effort to reconcile these discrepancies, the following
      conclusions can be drawn: on the grounds of its high prevalence rate and of
      its heavy impact on the history of treated and untreated HCV chronic
      infection, steatosis represents a distinct disease entity. Its pathogenesis
      is diverse and involves both host (prevalently observed in those patients
      infected with non-3 genotypes) and viral factors (more important in
      untreated HCV genotype 3 infection) though to a variable extent as a
      function of the genotype involved. Alcohol consumption should prudently be
      discouraged and specific follow-up schedules need to be instigated for
      patients displaying steatosis in the context of HCV infection, because of
      their inherent risk for fibrosis progression and perhaps of their increased
      oncogenic risk. Finally, numerous patients do not benefit from current
      antiviral combination regimes. They should be offered the chance of a
      'metabolic' treatment aimed at steatosis, similar to those are currently
      being tested in nonalcoholic fatty liver disease. The impact of combined
      antiviral and 'metabolic' approaches should also be evaluated vs current
      standard antiviral treatment.

      What is the background of the epidemiological burden imposed by hepatitis C?

      Hepatitis C virus is a small enveloped virus belonging to the Flaviviridae.
      Based on molecular biology techniques six different (1-6) genotypes are
      recognized. Over the past decades, there have been two major HCV epidemics.
      The first one took place in the 1960s; it was mainly because of transmission
      of HCV genotype 1 through medical procedures. The second occurred in the
      1980s, was transmitted by needle-sharing among drug addicts and was because
      of HCV genotype 3 [9]. The natural course of HCV infection is variable and
      modulated by the interaction of host [age, gender, HLA, genetic
      polymorphisms in TGF-N21 and angiotensinogen, TNF-N1, Body mass index (BMI)]
      and viral factors (viral load) [10-12]. However, following acute infection
      that occurs through the parenteral route, chronicity ensues in approximately
      85% of those who are exposed. Given that it affects approximately 3% of the
      world's population, HCV infection represents a leading cause of chronic
      hepatitis, cirrhosis, end-stage liver failure necessitating transplantation
      and hepatocellular carcinoma (HCC). Our weapons against HCV infection have a
      limited efficacy, are costly and are not devoid of side-effects. A recent
      study performed in 327 patients referred to a liver clinic after a positive
      result for antibody against HCV found that 72% were not treated on account
      of failure to adhere to evaluation procedures, patient preference or normal
      liver enzymes [13]. Only 23% were treated and 13% had a sustained viral

      The varying patterns of transmission of 3 vs non-3 HCV genotypes justifies a
      study of the extent and prevalence of steatosis as a function of the

      Are the prevalence and the extent of steatosis related to HCV genotype?

      The reported prevalence of steatosis in patients with HCV infection
      [2,5,14-36] ranges from 34.8 [32] to 81.2% [28] dependent on the
      characteristics of the patients studied (i.e. alcohol consumption,
      percentage with obesity, diabetic, hyperlipidemic cases, etc.) that probably
      mirror local differences in lifestyles and prevalence of disease. By summing
      up 25 studies, collectively including 6400 patients, the overall prevalence
      of steatosis in patients with HCV infection is 55.54% (Table 1). This figure
      represents a two to threefold increase compared with the prevalence of
      steatosis in autoimmune (17%), hepatitis B and cryptogenic (27%) chronic
      hepatitides and to the prevalence expected by chance in of nonalcoholic
      fatty liver disease and HCV infection [1,4]. Table 2 highlights the
      different histological features of steatosis in various steatogenic liver
      diseases [37,38].

      Adinolfi et al. [18,23] were first in reporting that the genotype was a
      major factor associated with steatosis in HCV infection. This finding has
      been confirmed by several authors and by pooling published data
      [2,5,27,34-36,39] it can be calculated that steatosis has a prevalence of
      415/560 (74.10%) in genotype 3 vs 1179/2460 (47.92%) in non-3 genotype (P <
      0.01). Recognition that genotype 3 might be specifically associated with
      steatosis has prompted further correlative studies of the extent and
      prevalence of steatosis according to the genotype. Combining all the studies
      that specify the extent of steatosis divided into three grades, one mild to
      three severe [34-36], an interesting observation can be made. While the
      prevalence of grade 2 steatosis is in the same order of magnitude in non-3
      genotypes and genotype 3 (20%vs 23%P = ns), there is a significant
      prevalence of non-3 genotypes in steatosis grade 1 (73.88%vs 46.92%P < 0.01)
      and of genotype 3 in steatosis grade 3 (29.6 vs 5.52 P < 0.01). Therefore,
      it appears to have been convincingly shown that in the setting of genotype,
      steatosis is both more prevalent and more severe than in infection with
      non-3 genotypes. This conclusion reasonably leads us to next address the
      risk factors for steatosis as a function of HCV genotype.

      Is hypolipidaemia relevant to the pathogenesis of steatosis observed in the
      setting of HCV chronic infection?

      Data correlating serum cholesterol levels and liver steatosis in HCV
      infection follow an inverse relationship at baseline [2,27,29].
      hypocholesterolaemia is corrected only in those patients with sustained
      virological response (SVR) following IFN-Ribarin treatment both in genotype
      3 and in non-3 genotypes [2]. Such a phenomenon is strongly suggestive of an
      acquired (i.e. virus-induced) hypobetalipoproteinaemia (HBL). Familial
      (genetic) HBL (FHBL) is an autosomal co-dominant disease whose prevalence in
      the general population is unknown. FHBL is often because of apo B gene
      mutations that result in the synthesis of truncated apo Bs. Given that
      truncated apo Bs are dysfunctional, FHBL is characterized phenotypically by
      serum cholesterol and serum triglyceride levels <95th percentile. Steatosis
      in this disease results from impaired export of triglycerides from
      hepatocytes into the bloodstream because of truncated apo Bs. Not
      surprisingly, in FHBL, subjects with steatosis have significantly lower
      cholesterol serum levels than subjects without ultrasonographic evidence of
      steatosis (A. Lonardo, P. Loria, L.E. Adinolfi, N. Carulli, G. Ruggiero,
      unpublished data). FHBL represents an extraordinary model of human disease
      to address the relationship between serum cholesterol levels and
      intrahepatic fat accumulation. An Austrian study performed in 137 IFN-naC/ve
      patients with chronic hepatitis C suggests that in addition to inducing
      steatosis HCV-3a lowers serum cholesterol, an effect which is fully
      reversible only in those with a SVR [41]. These findings are not accounted
      for by the effect of antiviral drugs because interferon induces - via
      inhibition of LDL - an increase mostly in those HCV genotypes 1 patients
      with lower triglyceride pretreatment levels [43]. The exact mechanism(s)
      through which HCV induces acquired HBL are unknown. Interactions with apo B
      and microsomal triglyceride transfer protein have been proposed (reviewed in
      Ref. 3). One study reported that higher serum LDL cholesterol at baseline
      predicts a response to IFN therapy [44]. These data have not been confirmed
      by a second study [24] perhaps because low LDL cholesterol levels are
      associated with other predictors for poor response to IFN therapy such as
      advanced fibrosis and high HCV load. In any case, a critical issue to be
      evaluated is whether steatosis represents an innocent bystander in the
      course of HCV infection.


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