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Pilot Study of the Relationship Between Histologic Progression and Hepatic Iron Concentration in Chronic Hepatitis C

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  • claudine intexas
    NATAP - www.natap.org Pilot Study of the Relationship Between Histologic Progression and Hepatic Iron Concentration in Chronic Hepatitis C Journal of Clinical
    Message 1 of 1 , Jan 29, 2004
      NATAP - www.natap.org


      Pilot Study of the Relationship Between Histologic Progression and
      Hepatic Iron Concentration in Chronic Hepatitis C

      Journal of Clinical Gastroenterology 2003; 37(5):406-411

      Anne M. Larson, MD; Shari L. Taylor, MD; Donald Bauermeister, MD;
      Leonard
      Rosoff, Jr., MD; Kris V. Kowdley, MD

      From the Department of Internal Medicine, Division of
      Gastroenterology,
      University of Washington, Seattle WA (Drs. Larson and Kowdley); GI
      Pathology
      Partners, Memphis TN (Dr. Taylor); Department of Pathology, Virginia
      Mason Medical
      Center, Seattle WA (Dr. Bauermeister); and Department of Internal
      Medicine,
      Division of Gastroenterology, Virginia Mason Medical Center, Seattle
      WA
      (Dr.
      Rosoff).

      Comments by Jules Levin: there was no discussion about eating foods
      high in
      iron such as red meat and iron overload in this article. You can have

      iron
      levels checked, but experts I speak with do not feel there is any
      reason to avoid
      red meat in diet unless perhaps if HCV disease is very advanced,
      decompensated
      cirrhosis; in which consultation with your doctor about this is
      advisable.


      Abstract:

      Hepatic iron deposition is common in patients with chronic hepatitis
      C
      (HCV)
      and may play a role in progression of liver disease. This pilot study

      examines
      the relationship between hepatic iron concentration (HIC) and
      histologic
      progression over time in patients with HCV. HIC was retrospectively
      measured in 14
      patients with HCV who had 2 serial liver biopsies prior to the era of

      interferon therapy. The mean interval between biopsies was 56 � 46
      months. Mean
      Knodell score worsened between first and second biopsies (10.0 � 2.8
      versus 12.4 �
      3.3; P = 0.007). There was increased portal inflammation (3.2 � 0.4
      versus 3.6
      � 0.5; P = 0.028) and fibrosis (1.8 � 1.3 versus 2.7 � 1.2; P =
      0.002),
      but
      no significant change in piecemeal necrosis or lobular degeneration.
      There was
      no significant change in HIC between first and second biopsy (P =
      0.66).
      However, HIC was noted to increase significantly among patients with
      cirrhosis on
      initial biopsy or those who progressed to cirrhosis (P = 0.009). In
      this pilot
      study, histologic progression in patients with precirrhotic HCV was
      not
      associated with an increase in HIC, whereas hepatic iron accumulation

      was observed
      in 3 patients once cirrhosis was present. The interaction between
      progression
      of hepatitis C and iron deposition warrants further study.

      The liver is the primary site of iron storage and the only site for
      synthesis
      of transferrin (the plasma iron transport protein) and ferritin. Free

      ferrous
      iron is highly toxic and normally is protein-bound within the liver.
      Unbound,
      iron catalyzes the production of free radicals, which have been
      implicated in
      lipid peroxidation and hepatotoxicity. Lipid peroxidation may be the
      primary
      event causing hepatocellular injury secondary to iron overload.

      Cross-sectional studies have suggested that there is a positive
      correlation
      between body iron stores and disease severity in HCV. Patients with
      chronic
      HCV who have precirrhotic disease generally have normal HIC, whereas
      HCV
      patients with end stage liver disease have increased transferrin
      saturation and HIC,
      particularly when compared with patients with end stage liver disease

      from
      other causes of chronic hepatitis. Thus, it is possible that
      progressive hepatic
      iron deposition may lead to increased disease severity in HCV.
      However,
      no
      previous studies have examined whether histologic progression in HCV
      is
      associated with an increase in HIC.

      The purpose of this pilot study is to determine whether HIC increased

      over
      time in chronic hepatitis C infection and whether change in histology

      correlates
      with change in HIC.

      Patients

      Fourteen adult patients with chronic HCV infection, referred to a
      tertiary
      care center's hepatology clinic, who underwent paired liver biopsies
      were
      retrospectively identified. HCV infection was confirmed by finding
      HCV-RNA in serum.
      All patients had persistently elevated serum aminotransferases (ALT)
      for at
      least 1 year prior to liver biopsy. Liver biopsy revealed chronic
      hepatitis
      with variable levels of activity in all patients. All patients were
      negative for
      hepatitis B surface antigen. None were treated with interferon,
      ribavirin, or
      other antiviral agents (the patients had undergone liver biopsy prior

      to the
      availability of these therapies). Second biopsies were performed as
      part of
      ongoing clinical care by the hepatologist caring for the patient.
      However, in no
      case was the second biopsy done because of a concern about iron
      overload. A
      few had undergone a short course of corticosteroid therapy between
      their first
      and second biopsies. The medical record of each patient was reviewed
      for
      demographic data, route of transmission, laboratory data, and
      treatment
      history.

      Liver Biopsy

      Percutaneous needle biopsies of the liver were obtained on each
      patient
      at 2
      separate time points ranging from 14 to 182 months. The mean interval

      between
      first and second biopsy was 56 � 46 months. Biopsies were performed
      in
      the
      right lobe of the liver using the Menghini aspiration method with a
      16-gauge
      Klatskin needle. 11 The liver tissue specimens were all more than 2
      cm
      in length
      and contained at least 6 portal tracts.

      RESULTS

      The 14 patients ranged in age from 28 to 66 years (mean 42) at the
      time
      of
      first biopsy; the mean age for males was 41 � 10 years and for
      females,
      43 � 13
      years (P = 0.77). Nine patients reported alcohol use of over 20 g a
      day; the
      remaining 5 reported rare or no use of alcohol. Risk factors for
      hepatitis C
      included transfusions (21%), intravenous drug use (22%), multiple
      (29%;
      intravenous drug use; tattoo, transfusion), unknown (21%), and sexual

      transmission
      (7%).

      There was a trend toward lower serum albumin and higher prothrombin
      time
      between the first and the second biopsy, although both values
      remained
      within the
      normal range. There was no significant difference in alkaline
      phosphatase,
      serum bilirubin, or serum aminotransferases (AST, ALT) between the
      first and
      second biopsies. Serum iron studies were not available in enough
      patients to make
      a meaningful determination. No patient was receiving iron-containing
      medications.

      The mean interval between biopsies was 56 � 46 months (range 14 to
      182).
      There was an increase in overall Knodell score between the first
      (10.0
      � 2.8) and
      second (12.4 � 3.3) biopsies (P = 0.007), reflecting increases in
      portal
      inflammation and fibrosis. There was no significant change in mean
      HIC
      (756 � 380
      versus 719 � 299 [mu]g/g dry weight; P = 0.659) or in HII (0.4 � 0.2
      versus 0.3
      � 0.2; P = 0.236) between first and second biopsies. The interval
      between
      biopsies was similar between those whose HIC increased and those
      whose
      HIC
      decreased (60 � 69 versus 53 � 33; P = 0.795). There was also no
      relationship
      between overall Knodell score, or individual components thereof, and
      HIC. However,
      HIC did increase significantly among patients with cirrhosis (P =
      0.0014). An
      increase in HIC of 350 [mu]g/g dry weight between the first and
      second
      biopsy
      was seen in the patient with cirrhosis on both biopsies. Likewise,
      the
      two
      patients who progressed to cirrhosis showed increased HIC (444
      [mu]g/g
      dry weight
      and 397 [mu]g/g dry weight, respectively; P = 0.00001). There was no
      increase
      in HIC among patients with fibrosis grades lower than 3 (bridging
      fibrosis) or
      among patients with bridging fibrosis who did not progress to
      cirrhosis
      (P =
      0.255). Five patients had bridging fibrosis and one had cirrhosis on
      the first
      biopsy. Eight patients had bridging fibrosis, and three had cirrhosis

      on
      second biopsy. Among noncirrhotics, there was no correlation between
      change in HIC
      and change in fibrosis score between biopsies when controlled for
      patient
      age, interval between biopsies, gender, corticosteroid use, and
      alcohol
      use (P =
      0.710; CI -559.4 418.5). Among cirrhotics, however, there was a
      significant
      correlation between changes in HIC between biopsies (P = 0.009; CI
      200.3 966.5).


      Individual Hepatic Iron Concentration

      [Unable to display image]


      Eight of the 11 patients (73%) had stainable iron in at least one of
      the two
      biopsies. Iron deposition was primarily within Kupffer cells in the
      majority
      of patients (5 of 8); the pattern of iron staining was mixed in the
      remainder.
      In most cases, the iron deposition was mild (grade 1-2+); only one
      patient had
      grade 3+ iron deposition and this was in a pattern involving
      hepatocytes and
      reticuloendothelial cells. HIC and HII did not approach ranges
      associated with
      hereditary hemochromatosis in any case. In 6 of 11 patients (55%),
      there was
      no change in stainable iron between the first and second biopsies. In
      4
      of 11
      patients, there was a decrease in stainable iron. The stainable iron
      increased
      in only one patient. Knodell score worsened in 10 of 14, was
      unchanged
      in 2
      of 14, and improved in 2 of 14. There was no relationship between
      change in
      total Knodell score or fibrosis score and change in hepatic iron
      staining. There
      was also no correlation between change in total Knodell score and
      change in
      HIC.

      Alcohol use was reported by 9 of the 14 patients (64%). Patient
      characteristics were similar between those who used alcohol and those

      who did not, except
      the serum total bilirubin was higher in those who were using alcohol
      (P
      =
      0.040). A greater proportion of males reported alcohol use (P =
      0.091).
      We did not
      find a difference in Knodell score at first or second biopsy between
      patients
      reporting alcohol use and those without. Those with alcohol use
      tended
      to have
      more stainable hepatic iron that those without alcohol use (median
      iron
      staining score 1 + v 0; P = 0.126). Those with alcohol use also
      tended
      to have a
      greater HIC, although this was not significant and the absolute level

      remained
      within the normal range. Neither alcohol users nor non-users showed a

      significant difference in the change in HIC between biopsies (P =
      0.583).

      DISCUSSION

      Hepatic iron overload may be a cofactor in the expression of many
      liver
      diseases. Hepatic iron deposition in patients with alcoholic liver
      disease
      promotes hepatocellular damage. Increased body iron stores were shown

      to be
      associated with increased risk of chronicity among persons exposed to

      hepatitis B.
      Chronic hepatitis C virus infection has been associated with mild to
      moderate
      liver iron loading. Serum ferritin, serum iron, and transferrin
      saturation also
      seem to be increased in some patients (especially men) with chronic
      HCV, and
      there is a positive association between serum ferritin concentrations

      and serum
      ALT level in this disease.

      It has been postulated that iron overload may exacerbate inflammation

      and
      fibrosis in chronic HCV. However, there is controversy regarding the
      prevalence
      and severity of hepatic iron overload in hepatitis C. Several
      investigators
      have reported that hepatic iron stores are usually normal or only
      mildly
      increased, and generally remain within the "normal" range throughout
      the course of
      disease. Others have found a significantly higher HIC in chronic HCV

      when
      compared with controls. Patients who respond to interferon-alpha have

      lower HIC than
      those who do not have a response. Phlebotomy has also been shown to
      reduce
      serum aminotransferase levels in patients with chronic HCV.
      Furthermore, HIC may
      be significantly increased in end-stage liver disease associated with

      HCV,
      with levels occasionally in the range approaching hereditary
      hemochromatosis.
      Thus, the evidence seems to support a relationship between disease
      severity and
      HIC in hepatitis C.

      The gene associated with hereditary hemochromatosis (HHC), entitled
      HFE, was
      identified in 1996. With the exception of one study, these have not
      found an
      association between the presence of HFE mutations, severity of liver
      disease,
      and hepatic iron level. A limitation of the current study is the lack

      of HFE
      mutation data in this cohort since this study was begun prior to
      availability of
      HFE mutation analysis. Furthermore, it is now recognized that
      multiple
      other
      genes may regulate iron metabolism, such as divalent metal
      transporter
      1
      (DMT1), ferroportin, and duodenal cytochrome b ferric reductase
      (dcytb). However,
      we feel that the lack of HFE mutation data does not weaken our
      findings
      for the
      following reasons. Previous studies have shown that body iron levels
      do
      not
      increase linearly over time in C282Y heterozygotes. It is likely that

      only one
      or two of our subjects would have been heterozygous for C282Y based
      on
      population studies. Furthermore, the fact that HIC increased only in
      the presence of
      cirrhosis, suggests that the presence of cirrhosis rather than the
      C282Y
      mutation is associated with increased HIC.

      Histologic progression was noted most of the patients (71%) as has
      been
      described in previous reports. Although mean HIC was higher among
      men,
      there was no
      difference between men and women with regard to those who progressed
      to
      bridging fibrosis or cirrhosis. Patients who drank alcohol showed a
      trend toward
      higher mean HIC than those who did not use alcohol. However, alcohol
      use was not
      associated with presence of bridging fibrosis or cirrhosis. This is
      in
      contrast to previous reports. We suspect this difference is due to
      the
      small sample
      size.

      We acknowledge that our study has several limitations, including the
      retrospective design, possible selection bias, lack of an iron stain
      on
      liver tissue
      for all patients, and small sample size. Nevertheless, we feel these
      findings
      are of interest since we are unaware of any previous study of the
      relationship
      between histologic progression and liver iron content in HCV. Our
      findings
      demonstrate that hepatic iron accumulation is observed only in
      advanced
      stages of
      disease (stage 4). Histologic progression in the precirrhotic phase
      associated with increased hepatic iron deposition. However, it
      remains
      unknown whether
      iron deposition leads to cirrhosis or vice versa. Prospective
      controlled
      studies are warranted to further explore this issue.


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