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Steatosis (fatty liver) accelerates the progression of liver damage of

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  • claudine intexas
    NATAP - www.natap.org Steatosis (fatty liver) accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV
    Message 1 of 1 , Jun 23, 2001
      NATAP - www.natap.org

      Steatosis (fatty liver) accelerates the progression of
      liver damage of
      chronic hepatitis C patients and correlates with
      specific HCV genotype
      and
      visceral obesity

      This study from the current issue of Hepatology (pdf
      attached)
      discusses how
      fatty liver is associated with faster progression of
      fibrosis & liver
      disease. Although there appears to be some uncertainty
      about the
      absolute
      cause of seatosis and its association with accelerated
      fibrosis, the
      authors
      find associated with steatosis are elevated lipids,
      insulin, abdominal
      (visceral) fat, and diet an obesity. They also discuss
      a potential
      connection
      with mitochondrial damage and the presence of HCV in
      the liver cell. A
      small
      recent study reported finding that improved diet
      resulting in reduced
      lipids
      and weight improved steatosis & fibrosis in a
      percentage of study
      patients.

      The role of steatosis (fatty liver: fat deposited in
      the liver) in the
      progression of liver damage in chronic hepatitis C
      (CHC) was studied.
      Enrolled were 180 consecutive liver biopsy-proven CHC
      patients and 41
      additional subjects with a known duration of
      infection. We evaluated
      the
      histological activity index (HAI), grade of fibrosis
      and steatosis,
      body mass
      index (BMI; kg/m2), distribution of body fat, HCV
      genotype, and levels
      of HCV
      RNA. Eighty six (48%) patients showed steatosis, and a
      higher
      prevalence was
      observed in genotype 3a infection (P < .01). A
      correlation between the
      grade
      of steatosis and fibrosis was observed (P < .001).
      Fibrosis was also
      associated with age (P < .001). After adjusting for
      age, the
      association
      between steatosis and fibrosis remained significant.
      The grade of
      steatosis
      also correlated with the HAI (P < .007) with a
      significant increase in
      periportal necrosis. No relation was found between
      steatosis and age,
      gender,
      iron storage, or levels of HCV RNA. Patients with a
      high grade of
      steatosis
      (>30%) showed higher serum levels of -GT and ALT (P <
      .001). Overall,
      steatosis was not significantly associated to BMI.
      Analysis by single
      genotype showed a significant association between the
      grade of
      steatosis and
      BMI in type 1 infection r = .689; P < .001) and with
      levels of HCV RNA
      in
      type 3a infection r = .786; P < .001). Visceral fat
      distribution rather
      than
      BMI proved to be associated with steatosis (P < .001).
      Data obtained
      from
      patients with a
      known date of infection confirmed that steatosis
      grades 3-4 were
      associated
      with a higher annual rate of fibrosis progression, and
      showed that
      alcohol
      and steatosis act together in increasing fibrosis (P <
      .05). Our data
      indicate that steatosis is an important cofactor in
      increasing liver
      necroinflammatory activity and in accelerating
      fibrosis in CHC.
      Visceral
      obesity and genotype 3a play a role in the development
      of steatosis.
      (HEPATOLOGY 2001;33:1358-1364.)

      Patients with steatosis grade 3-4 showed a higher HAI
      than those
      without
      steatosis (HAI: 6.24 � 0.56 vs. 4.69 � 0.30;
      respectively, P < .005).
      An
      analysis of the different components of HAI showed
      that the presence of
      steatosis grade 3-4 significantly increases periportal
      necrosis, but
      not
      portal inflammation or lobular degeneration.
      After adjustment for age, the grade of steatosis was
      still associated
      with
      the grade of liver fibrosis (P < .001). A correlation
      between the grade
      of
      steatosis and serum levels of aminotransferases (r =
      .40; P < .001) and
      of
      -glutamyl transferase (r = .385; P < .001) was also
      observed. Overall,
      there
      was no association between serum HCV RNA levels and
      the grade of
      steatosis.

      The correlation between BMI and the grade of steatosis
      did not reach
      statistical significance (r = .183; P = .068) when all
      patients were
      included
      in the evaluation (data not shown). When the analysis
      was done for each
      genotype, the grade of steatosis in genotype 1
      infection correlated
      with the
      BMI (r = .689; P < .001; Fig. 2), and a value close to
      statistical
      significance was found in patients infected with
      genotype 2a/c (P =
      .078),
      whereas no correlation was observed in those with 3a
      infection (data
      not
      shown).

      In the selected group of 31 patients with genotype 1b
      and a duration of
      disease of 10 to 14 years, steatosis was found in 14
      (45%), of whom 8
      (26%)
      with grade 3-4, and 6 (19%) with grade 1-2. The
      patients with steatosis
      of
      grade 3-4 showed a higher hepatic fibrosis score (2.63
      � 0.33) than
      those
      with steatosis grade 1-2 (1.58 � 0.47) and
      significantly higher than
      those
      without steatosis (1.43 � 0.15; P < .001). In patients
      with steatosis
      grade
      3-4, the yearly rate of fibrosis progression,
      calculated by dividing
      the
      score of fibrosis by the duration of infection, was
      significantly
      higher
      than that found in patients with steatosis grade 1-2
      (fibrosis rate:
      0.23 �
      0.03 vs. 0.14 � 0.01; respectively; P < .03) or than
      in patients
      without
      steatosis (0.12 � 0.01, respectively; P < .001). The
      levels of viremia
      and
      hepatic iron deposition were similar in the 3 groups
      of patients (high
      grade,
      low grade, and no steatosis). The median duration of
      disease was no
      different
      in the 3 groups (11.5 vs. 12 vs. 12 yrs). The fibrosis
      score in the
      subgroup
      with steatosis and alcohol intake was significantly
      higher than that
      observed
      in patients with steatosis and no alcohol intake (2.82
      � 0.19 vs. 2.05

      0.20, respectively; P < .02).

      Discussion by authors:






      TOP


      The results of our study indicate that steatosis, and
      particularly the
      higher
      grades, is of clinical relevance because it plays an
      important role in
      accelerating the progression of chronic hepatitis C
      infection. Indeed,
      patients with significant steatosis, i.e., greater
      than 30%, showed a
      higher
      hepatic fibrosis score than those with a lower grade
      (< 30%) or without
      steatosis.

      Thus, chronic hepatitis C patients with a high grade
      of steatosis may
      represent a group at risk for a more rapid progression
      to cirrhosis.
      Indeed,
      the fact that steatosis
      and fibrosis do occur together could also promote an
      alternative
      hypothesis
      that both of these histologic features follow
      protracted injury, i.e.,
      without influencing each other, they may both be
      secondary to another
      independent variable. Thus, steatosis, by promoting
      greater hepatic
      necrosis,
      may accelerate fibrosis deposition. Our data also
      showed that males
      have a
      higher prevalence of steatosis grade 3-4 than females.
      This may in part
      explain the greater progression of liver disease
      reported in the male
      sex.
      Indeed, visceral fat, but not total fat mass, has been
      shown to be a
      predictor of steatosis. Our data show that steatosis
      is strictly
      correlated with the abdominal fat mass.

      It has been reported that visceral obesity is a
      predictor not only of
      steatosis, but also of hyperinsulinemia and peripheral
      insulin
      resistance.25
      In addition, visceral lipolysis is resistant to
      insulin suppression and
      is
      the source of liver fatty acids in hyperinsulinemic
      states such as
      liver
      disease.26 Similar mechanisms may also be implicated
      in the
      pathogenesis of
      steatosis in chronic hepatitis C patients. We also
      showed that, in
      addition
      to visceral obesity, viral factors play an important
      role in the
      development
      of steatosis.

      The mechanisms underlying the development of
      parenchymal steatosis in
      HCV
      infection are not known. In transgenic mice, it has
      been shown that the
      HCV
      core protein, which can also be detected in the liver
      of HCV patients,
      induces hepatic steatosis.13 The core protein
      expression within the
      mitochondria alters the double membrane structure and
      causes an
      impairment of
      lipid oxidation, which produces steatosis.14 Influenza
      B virus may also
      induce steatosis by altering mitochondrial enzyme
      activity.32 Steatosis
      may
      be a result of alterations in the lipid metabolism.
      It is well known that steatosis can be associated with
      hepatic
      inflammatory
      changes and fibrosis by causing oxidative stress and
      mitochondrial
      dysfunction.

      We conclude that in chronic HCV infection, steatosis
      is an important
      cofactor
      in accelerating the development of hepatic fibrosis
      and in increasing
      necroinflammatory activity, and that both host and
      viral factors play a
      role
      in the pathogenesis of steatosis in chronic hepatitis
      C patients. A
      correct
      therapeutic approach to steatosis would slow down the
      evolution of
      chronic
      hepatitis, which would be of particular importance for
      patients who are
      nonresponders to current antiviral therapies. Host
      (obesity, diet,
      diabetes,
      hyperinsulinemia, alcohol) and HCV virus factors play
      a
      role in the development of steatosis; in particular
      visceral obesity
      and HCV
      type 3a seem to be the major determinants of steatosis
      in this subset
      of
      patients. It is important to underscore that genotype
      3a has only
      recently
      been introduced to our country and affects young
      people, mainly drug
      users,
      and that the progression of fibrosis is time-related.
      We can therefore
      expect
      in the future an increasing number of cirrhotics among
      these patients.
      The
      different causes of steatosis should be sought in each
      single patient
      because
      treatment may differ according to the factor(s)
      involved in the process. However, we share the belief
      of others that
      the
      restoration of a normal weight in subjects with
      visceral obesity may be
      of
      clinical importance in chronic hepatitis C patients.

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