An Exploration of Depressive Symptoms in Hepatitis CPatients Taking Interferon-alpha: Increase in SicknessBehaviors but not Negative Cognitions

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An Exploration of Depressive Symptoms in Hepatitis CPatients Taking Interferon-alpha: Increase in SicknessBehaviors but not Negative Cognitions Powered By Docstoc
					Original Article                                                    JOURNAL OF CLINICAL AND EXPERIMENTAL HEPATOLOGY

       Hemochromatosis Gene Mutations: Prevalence and
      Effects on Pegylated-Interferon and Ribavirin Therapy
           Response in Chronic Hepatitis C in Sardinia
                                    Margherita Sini, Orazio Sorbello, Alberto Civolani, Luigi Demelia
             Department of Gastroenterology, Azienda Ospedaliero-Universitaria di Cagliari, SS 554 bivio per Sestu, 09130 Cagliari, Italy

        Background/Aims: Considerable evidence suggests that iron could be a comorbid factor for liver injury in chronic
        hepatitis C (CHC). Elevated iron indices are frequently described in CHC and may impact negatively on the
        course of liver disease and on the response to interferon alfa therapy. The aim of this study was to evaluate
        the frequency of hemochromatosis gene mutations in Sardinian CHC patients, the association with iron overload
        and the impact on response to therapy. Methods: Sixty-nine CHC patients were enrolled. Iron indices, hepatic
        and viral parameters were detected. C282Y, H63D and S65C mutations were identified through a PCR. Liver
        biopsy was performed for hepatic fibrosis evaluation. All patients were treated for 6 months (viral genotype
        2/3) or 12 months (viral genotype 1/4) with pegylated-interferon 180 mcg once weekly and ribavirin 1000–
        1200 mg/daily. Sustained virological response (SVR) was defined as undetectable HCV RNA 24 weeks after the
        end of treatment. Results: HFE gene mutation was detected in 29 patients (42%). The presence of HFE mutations
        was significantly associated with elevated transferrin saturation (P < 0.01). Hepatic fibrosis was more advanced in
        HFE mutation carriers (c2, P = 0.04). Among mutation carriers 27.5% achieved responses at the end of treatment
        compared with 60% of non-carriers (P = 0.005). Patients with HFE wildtype produced significant SVR compared
        with patients with HFE mutations (P = 0.03). Conclusions: The literature shows discordant results about the prev-

                                                                                                                                                     Chronic Hepatitis C
        alence, hepatic distribution and possible therapeutic implications of iron overload in chronic hepatitis C. Our
        findings shows that HFE gene mutations could favor, synergically with CHC and other genetic or acquired fac-
        tors, the development of liver damage and could influence the outcome of interferon treatment with higher rate
        of non-response. ( J CLIN EXP HEPATOL 2012;2:211–217)

    ron is an essential micronutrient which plays a key role                   proteins and nucleic acids.2 Iron-induced oxidant stress
    in a wide range of biochemical pathways that govern                        is involved in this process as the primary cause of parenchy-
    cellular metabolism, including those that are essential                    mal cell necrosis or as activator of cells that are effectors or
for cellular respiration as well as DNA, RNA and protein                       key mediators of hepatic fibrogenesis. The fibrogenic po-
synthesis. Iron balance is regulated at the absorptive step,                   tential of iron in the liver is even more important when
but the mechanism by which the mucosa accomplishes                             iron acts simultaneously with other hepatotoxic factors.3
this has not been defined. There is no effective physiologi-                        The intestinal iron absorption appears to be disturbed in
cal mechanism for the excretion of excess body iron, hence                     Hereditary Hemochromatosis (HH). The homozygous state
increased absorption of iron would increase body iron                          in which both alleles of chromosome 6 possess the C282Y
stores, mainly in the liver.1 Iron has been shown to increase                  mutation or the compound heterozygous state with
the formation of reactive oxygen intermediates that lead to                    C282Y on one chromosome and H63D on the other, are
lipid peroxidation and subsequent oxidative damage to                          the predominant genetic abnormalities associated with phe-
                                                                               notypic HH.4 A third mutation, S65C, is considered to be
                                                                               a rather new polymorphism.5 “In Europe, the C282Y allele
Keywords: HFE gene, iron overload, viral hepatitis                             has a north to west frequency- decreasing gradient, with
Received: 15.5.2012; Accepted: 9.6.2012; Available online: 27.8.2012           higher frequencies reported in Ireland (28.4%) and lower fre-
Address for correspondence: Orazio Sorbello, Department of Gastroenterology,   quencies in Italy (3.2%). Conversely, the H63D allele has
Azienda Ospedaliero-Universitaria di Cagliari, SS 554 bivio per Sestu, 09130
Cagliari, Italy. Tel./fax: +39 070 51096100
                                                                               a higher frequency in southern Europe (Spain, 32.3%) and
E-mail:                                                       a lower frequency in the Celtic populations (5%).6
Abbreviations: ALT: alanine aminotransferase; AST: aspartate aminotrans-           The Sardinian population is genetically differentiated
ferase; AP: alkaline phosphatase; CHC: Chronic hepatitis C; ETR: End of        from the other Caucasian populations. It represents a ge-
treatment response; GGT: g-glutamyl transpeptidase; HFE: Human he-             netic isolate where the p.C282Y mutation is considered as
mochromatosis protein; HCV: Hepatitis virus C infection determination;
HH: Hereditary Hemochromatosis; SVR: Sustained virologic response;
                                                                               rare or even absent. Candore et al studied the frequency of
TSI: Transferin saturation index; ULN: Upper normal limit; WT: wildtype        the HFE gene mutations in five Italian populations. In Italy,                                   the allele frequency of the C282Y mutation decreases from

© 2012, INASL                                          Journal of Clinical and Experimental Hepatology | September 2012 | Vol. 2 | No. 3 | 211–217
                      HEMOCHROMATOSIS GENE MUTATIONS                                                                                    SINI ET AL

                      northeast Italy (Friuli, 6%) to northwest Italy (Piemont,         Liver Function Tests
                      4.8%) and to central Italy (Emilia-Romagna, 1.7%). However,       Liver function tests including alanine aminotransferase
                      this mutation is lacking in Sardinia. In contrast, no differ-     (ALT), aspartate aminotransferase (AST), alkaline phos-
                      ence was observed in allele frequency of H63D in the five          phatase (AP), g-glutamyl transpeptidase (GGT), pseudo-
                      Italian regions (Friuli 12%—Sardinia 17.5%).7 Several studies     cholinesterase, bilirubin and albumin were detected.
                      assessed that no association exist between the HFE genetic
                      variants and chronic liver disease. Overall, only a few studies   HCV Determination
                      have suggested an increased prevalence of HFE mutations in
                      CHC patients,8,9 with respect to the general population; this     Diagnosis of hepatitis C virus infection was based on a pos-
                      observation was not confirmed in other studies.10 Labora-          itive anti-HCV assay (ELISA III) and quantification of
                      tory abnormalities of iron metabolism have been detected          Hepatitis virus C infection determination (HCV) RNA by
                      in 15–20% of heterozygotes, but heterozygosity for hemo-          PCR (Cobas Amplicor; Roche, Basel, Switzerland), HCV ge-
                      chromatosis is rarely associated with liver damage due            notypes were determined by INNO-LiPA HCV II assay
                      only to iron overload. Complications have been recognized         (Bayer Diagnostics, Leverkusen, Germany) and classified
                      only when other disorders, such as porphyria cutanea tarda,       according to Simmonds et al.19
                      chronic anemia, alcoholism and hepatitis are also present.11
                      Over the last 20 years, considerable evidence suggested that      Iron Parameters
                      a pathogenetic link exists between the iron content of the        Quantitative determination of iron concentrations in se-
                      liver and viral hepatitis. Elevated iron indices are frequently   rum was performed on automated clinical chemistry ana-
                      described in CHC and may impact negatively on the course          lyzers (Hitachi), using a colorimetric assay (Roche). Both
                      of liver disease and on the response to interferon alfa           ferritin and transferrin levels were measured by immunotur-
                      therapy.12À14 HFE gene mutations may play a role in the           bidimetric assays using the Tina-quant reagents (Roche).
                      development of significant iron overload in patients with          Transferrin saturation index (TSI) was calculated as Fe/total
                      CHC and could represent a clinically relevant comorbid            Fe-binding capacity  100 (normal value 16–45%).
Chronic Hepatitis C

                      factor in patients with chronic hepatitis C.15–17
                          There are several host characteristics known to affect out-   Histological Evaluation
                      come of interferon treatment, including age, gender, im-          Liver biopsies were obtained employing the Menghini tech-
                      mune surveillance system, nutritional state and iron status.18    nique under ultrasound guidance in 69 patients. For histo-
                          The aim of our study was to evaluate the impact of HFE        logical examination, paraffin-embedded 4 mm sections
                      gene mutations on disease severity and response to inter-         were stained with hematoxylin and eosin, trichrome, and
                      feron therapy in a cohort of Sardinian patients with              Perl's Prussian blue. Liver histology was evaluated in
                      Chronic Hepatitis C.                                              a blinded manner according to the Desmet classification.20

                      MATERIALS AND METHODS                                             Genetic Analysis
                      Patients                                                          Genomic DNA was isolated from either EDTA anticoagu-
                      Sixty-nine patients with chronic hepatitis C (53 male/16 fe-      lated whole blood. Detection of C282Y, S65C and H63D
                      male, mean age 51 Æ 2 years) were enrolled at the Division        mutations in the Human hemochromatosis protein
                      of Internal Medicine and Digestive Pathologies, University        (HFE) gene were performed using PCR amplification.
                      Hospital of Cagliari.
                          The following specific inclusion criteria were fulfilled by     Study Design and Protocol
                      all patients: age 18–65 years, elevated serum ALT levels          All patients were treated for 6 months (viral genotype 2/3)
                      above twice the normal range for at least 6 months before         or 12 months (viral genotype 1/4) with pegylated-inter-
                      enrollment; positive test for anti-HCV antibodies; positive       feron (PEG-IFN) (Pegasys—Roche) 180 mcg once weekly,
                      test for HCV RNA; histological diagnosis of chronic hepa-         self-administered subcutaneously together with ribavirin
                      titis with or without cirrhosis.                                  (Rebetol—Schering-Plough) 1000–1200 mg/daily by body
                          The exclusion criteria included: decompensated liver          weight, orally in two divided doses.
                      disease, systemic diseases, cancer, hemolytic anemia, neu-           All patients were observed every 2 weeks for the first
                      tropenia <1000/mcl, thrombocytopenia <100 Â 103/mcl,              month and every 4 weeks thereafter during treatment. Af-
                      serological HBsAg positivity, HIV infection, drug addic-          ter the 24–48-week therapy period, patients were followed
                      tion, alcohol abuse, hepatotoxic drugs usage, autoimmune          up at 4 week intervals for 6 months. For assessment of ther-
                      hepatitis, pregnancy, psychiatric illness, renal impairment,      apy compliance, adverse effects, response to the treatment
                      Wilson's Disease, Hereditary Hemochromatosis and alpha-           and its relationship with HFE gene mutations, patients un-
                      1-antitrypsin deficiency. None of the patients had received        derwent laboratory measurements of liver function tests,
                      previous interferon-alpha therapy.                                full blood count, serum HCV RNA concentration, thyroid

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                                                             JOURNAL OF CLINICAL AND EXPERIMENTAL HEPATOLOGY

function tests, autoantibody screening including antinu-                 Table 1 Base-line characteristics of 69 patients with HCV
clear factors and anti-thyroid antibodies and serum iron                 infection.a
parameters.                                                                                                                              Range
    A complete response at the end of treatment was de-                      N                                         69
fined as the normalization of serum ALT levels and nega-
                                                                             Gender (M/F)                              53/16
tive serum HCV RNA. A sustained complete response
was defined as maintenance of remission after cessation                       Age (years)                               51 Æ 2           25–65
of treatment for 24 weeks or more. Patients were divided                     Alanine aminotransferase (UI/dl)          139 Æ 29         85–480
in two groups according to HFE gene mutations: Group                         Viral genotype—n (%)

A, which included subjects with HFE gene wildtype and                            1–4                                   46 (67%)
Group B, subjects with HFE gene mutations. Biochemical
                                                                                 2–3                                   23 (33%)
parameters, iron indices, liver histology, End of Treatment
Response (ETR) and Sustained Virologic Response (SVR)                        HFE genotype—n (%)
were compared between the two groups. Patients who dis-                          Wildtype                              40 (58%)
continued treatment during follow-up were considered as                          HFE mutation                          29 (42%)
virologic non-responders. All patients were informed of                      Serum iron (mg/dl)                        127 Æ 8          15–312
the purpose of the study and of known side-effects associ-
                                                                             Serum ferritin (ng/ml)                    271 Æ 24         18–856
ated with both drugs, and written informed consent for
liver biopsy and therapy was obtained.                                       Transferrin saturation index (%)          46%              26–62

                                                                         Normal range: Transferrin, 110–370 mg/dl.
Statistical Analysis                                                     Plus–minus values are means Æ SEM.
                                                                           Upper normal limit (ULN) of laboratory data: ALT, 41 UI/l; Serum iron,
Results are presented as mean Æ SEM. Statistical analyses                158 mg/dl; Serum ferritin, 250 ng/ml; Transferrin saturation, 45%.
were performed using StatView 5.0 (SAS Institute). De-
scriptive statistics were calculated and test of normality

                                                                                                                                                     Chronic Hepatitis C
were performed. For continuous variables, the values of
which were found to be distributed normally, parametric
statistical procedures were used, including paired t-test
and unpaired t-test. For discontinuous variables, non-                   Table 2 Base-line characteristics of 40 HFE wildtype patients
parametric procedures, including Wilcoxon's signed-rank                  and 29 patients with HFE mutation.a
test and Mann–Whitney U test, were carried out as appro-
                                                                                                        HFE wildtype    HFE mutation    P-value
priate. Comparisons between the frequencies of observa-
tion were performed using the c2 test. Significance                           N                         40              29
criteria of P < 0.05 was used for all inferences.                            Gender (M/F)              32/8            25/4            ns
                                                                             Age (years)               50 Æ 1          52 Æ 2          ns
                                                                             ALT (UI/dl)               186 Æ 59        151 Æ 27        ns
                                                                             AP (U/l)                  183 Æ 13        209 Æ 22        ns
HFE Genotypes
                                                                             GGT (U/l)                 71 Æ 8          108 Æ 20        <0.05
The clinical characteristics of the 69 HCV-infected pa-
                                                                             Bilirubin total (mg/dl)   0.6 Æ 0.06      0.8 Æ 0.1       ns
tients are reported in Table 1. The base-line characteristics
of the 69 patients grouped by HFE genotype are shown in                      Serum iron (mg/dl)        118 Æ 9         149 Æ 13        ns
Table 2. At least one of the three HFE gene mutations was                    Serum ferritin (ng/ml)    280 Æ 34        327 Æ 32        ns
present in 42% of the patients. One patient was heterozy-                    Transferrin saturation(%) 43.4%           50%             <0.01
gous for the C282Y mutation (1.4%), 22 were heterozy-                        Histological fibrosis
gous for the H63D mutation (31.8%), three (4.3%) were
                                                                                 Stage I               10/40 (25%)     4/29 (13.8%)    P = 0.04b
heterozygous for the S65C mutation, two patients
(2.8%) were homozygous for the H63D mutation and                                 Stage II              15/40 (37.5%) 5/29 (17.2%)
one patient (1.4%) was a compound heterozygote for                               Stage III             11/40 (27.5%) 10/29 (34.5%)
the H63D and S65C mutation.                                                      Stage IV              4/40 (10%)      10/29 (34.5%)
   No significant differences were observed for age, gender                   Genotype—n (%)  
distribution, ALT, serum iron and ferritin levels and viral
                                                                                 1–4                   27 (67.5%)      19 (65.5%)      ns
genotype between HFE mutant patients and wildtype ho-
mozygotes.                                                                       2–3                   13 (32.5%)      10 (34.5%)
   Transferrin saturation index (TSI) showed a significant                a
                                                                             Plus–minus values are means Æ SEM.
statistical difference between HFE mutant patients (50%)                 b 2
                                                                             c test.

Journal of Clinical and Experimental Hepatology | September 2012 | Vol. 2 | No. 3 | 211–217                                                    213
                      HEMOCHROMATOSIS GENE MUTATIONS                                                                                                                      SINI ET AL

                      and wildtype homozygotes (43%) (P < 0.01). The degree of                                           120

                      hepatic fibrosis was evaluated by HFE genotype in 69 pa-

                                                                                                Percentage of subjects
                      tients (Figure 1). Thirty-five of 69 (51%) patients had ad-                                                           ETR                       SVR
                      vanced fibrosis (Stage score III–IV); twenty of 29 (69%)
                      patients had a HFE gene mutation and a histological stage                                           60
                                                                                                                                          P=0.005                    P=0.03
                      III–IV, while only 15 of 40 (39%) HFE wildtype patients pre-                                        40
                      sented histological stage III–IV. There was a close associa-
                      tion between advanced histological score and the
                      presence of HFE gene mutation (c2, P = 0.04).                                                        0
                                                                                                                                NR                  R      NR                  R
                                                                                                                                          HFE mutation          WT
                      End of Treatment Response and Sustained
                      Virological Response Evaluation of Antiviral                            Figure 2 End of the Treatment Response (ETR) and Sustained Viral
                                                                                              Response (SVR) were lower among patients with HFE gene mutations
                      Therapy                                                                 compared to those with HFE gene WT (wildtype) (c2, P = 0.005 and
                      At the end of treatment, both serum ALT levels normalized               P = 0.03 respectively).
                      and HCV RNA became negative in 32 of 69 patients (46%).
                         Seven of 69 patients (10%) did not complete the treat-
                      ment; these patients stopped prematurely for side-effects
                      associated with the use of PEG-IFN and ribavirin combina-               Interest in the role of iron in CHC began when Di Bisceglie
                      tion therapy (1 for neutropenia and thrombocytopenia, 3                 et al found that up to 36% of patients with chronic hepati-
                      for hypothyroidism and 3 for depression). The relationship              tis C had elevated serum iron parameters.7
                      between HFE gene mutations and response to antiviral                        A substantial number of these patients also have in-
                      therapy was investigated.                                               creased iron deposition in the liver.21 Furthermore, HCV-
                         At the end of treatment the viral and biochemical re-                infected patients with stainable iron in liver biopsies showed
                      sponse rates were lower among the patients with HFE                     enhanced liver fibrosis compared with controls without de-
Chronic Hepatitis C

                      gene mutations 8/29 (27.5%) compared to those with                      tectable iron.22 The hypothesis that iron is a risk factor for
                      HFE gene wildtype 30/40 (75%) (c2, P = 0.005) (Figure 2).               liver injury in CHC patients was supported by a recent exper-
                      Of the patients with genotype 1–4 infection, the end of                 imental report that excess dietary iron exacerbated liver in-
                      treatment response rate was higher in group A (14/27;                   jury in HCV-infected chimpanzees.23 The mechanism by
                      51.8%) compared to group B (2/19; 10.5%) (c2,                           which iron accumulates in liver infected with chronic
                      P = 0.003), while no significant difference was observed be-             HCV has not yet been established. Di Bisceglie et al reported
                      tween patients with HFE gene mutation (5/10; 50%) and                   that serum iron and ferritin levels were increased in patients
                      HFE gene wildtype with genotype 2–3 infection (11/13;                   with CHC because of their release from hepatocellular stores
                      77%) (Figure 3). At the end of 24 weeks of post-treatment               in association with cell necrosis.6
                      follow-up period, 32/69 (46.3%) patients produced SVR.                      Alternatively, individuals with serum iron levels in the
                      The difference of SVR rate between 25/40 patients                       upper range of normal as a result of genetic polymor-
                      (62.5%) with HFE wildtype and 7/29 of HFE mutant                        phisms or a high iron diet may be predisposed to develop
                      (24.1%) was statistically significant (c2, P = 0.03) (Figure 3).         more severe chronic HCV infections.6 It has been suggested
                                                                                              that iron overload in the liver of patients with CHC is asso-
                                                                                              ciated with higher ALT levels and decreased response to
                             30                                                                                          120

                             25                                                                                          100
                                                                                                Percentage of subjects

                             20                                                                                          80             P=0.003                      ns

                             15                                                                                          60

                             10                                                                                          40
                                            HFE WT               HFE mutation                                                  1-4 NR             1-4 R   2-3 NR              2-3 R
                                  Stage I      Stage II       Stage III       Stage IV                                                    HFE mutation       WT

                      Figure 1 Relationship between stage of fibrosis and HFE gene status. A   Figure 3 Relationship between HFE gene mutation and Sustained Viral
                      significant association exists between advanced histological score and   Response (SVR) in 46 patients with viral genotype 1–4 and 23 patients
                      the presence of HFE gene mutation (c2, P = 0.04). WT, Wildtype.         with viral genotype 2–3. NR, NonResponders; R, Responders.

                      214                                                                                                                                                 © 2012, INASL
                                                             JOURNAL OF CLINICAL AND EXPERIMENTAL HEPATOLOGY

interferon.10 These observations indicate the important                  transferrin saturation index (TSI) showed a significant sta-
role of iron in the pathogenesis of CHC. In fact patients                tistical difference between HFE mutant patients (50%) and
with combined hereditary hemochromatosis and chronic                     wildtype homozygotes (43.4%) (P < 0.01). Instead, no signif-
hepatitis C infection presented advanced fibrosis/cirrhosis               icant difference was observed for other indirect markers of
at a younger age and at a lower hepatic iron concentration               iron stores such as serum iron and serum ferritin. These pa-
compared to HH patients. This supports the concept that                  rameters lack specificity, particularly in the face of chronic
the combination of iron overload and HCV has a potentiat-                inflammatory conditions or alcohol-induced liver disease.27
ing effect on hepatic fibrogenesis.24                                     Previous reports suggested that TSI measurement appears
    Iron can be a profibrogenic factor, acting as activator of            to be the most sensitive method of detecting iron overload
both hepatic stellate cells and Kupffer cells and inducing               states and showed that TSI values exceeding 45% correctly
liver inflammation or hepatocyte necrosis. In fact the pres-              identified 97.9% of homozygotes for Hereditary Hemochro-
ence of stainable iron on liver biopsy of patients with viral            matosis, with no false positives among the normal popula-
hepatitis correlates with a higher degree of necroinflamma-               tion, and 22.2% of the heterozygote population. Detecting
tory activity and a higher score for fibrosis compared to                 the threshold for TSI to 45% could also identify other
those with no stainable iron.25 The coexistence of hemo-                 groups with relatively minor degrees of secondary iron over-
chromatosis gene mutations represents a genetic risk fac-                load, such as chronic hepatitis C.33,34 Recent evidence
tor affecting the severity of chronic hepatitis C and the                suggests that HFE gene mutations and a consequent mild
response rate to interferon therapy.26À28                                iron overload may worsen the course of chronic hepatitis
    The results of our study indicate that the prevalence                C and increase the progression of fibrosis.22–35
of the three known HFE gene mutations in Sardinia is in                      The results of our study showed that a significant asso-
accordance with previous observations in other countries:                ciation exists between advanced histological score and the
(5–10% for the C282Y mutation and 6–30% for the H63D                     presence of HFE gene mutation (c2, P = 0.04). The fact that
mutation),29,30 specifically 42% of our HCV-infected                      patients heterozygote for hereditary hemochromatosis and
patients carried at least one of these mutations.                        infected with hepatitis C virus report greater fibrosis than

                                                                                                                                         Chronic Hepatitis C
Heterozygous C282Y status and homo- or heterozygosity                    those with homozygous wildtype provides additional evi-
for the H63D and S65C mutations do not usually induce                    dence that iron modulates fibrosis in chronic hepatitis C.
hemochromatosis phenotype and are rarely associated                      Despite these observations, the association between serum
with liver damage in healthy subjects.31 Nevertheless, labo-             iron values, hepatic iron stores and hepatic necroinflam-
ratory abnormalities of iron metabolism (higher serum                    matory activity or fibrosis remains controversial. HFE
iron concentration, transferrin—saturation values and se-                gene mutations may have a potentiating effect on histolog-
rum ferritin concentrations) have been detected in 15–20%                ical severity, acting synergically with CHC in the develop-
of heterozygotes.6–26 Complications have been recognized                 ment of liver damage.
only when other disorders, such as alcoholism and viral                      Iron overload seems to impair antigen-specific immune
hepatitis are present.6–26 HFE gene mutations may                        responses by decreasing the generation of T cells and by
contribute to iron storage and could represent a clinically              impairment of natural killer and T helper cell function. Pi-
relevant comorbid factor in patients with chronic hepatitis              perno et al 3 suggested that iron overload in patients with
C. Sebastiani et al summarize the current status of the                  hemochromatosis may contribute to the persistence of
literature regarding the prevalence, hepatic distribution of             HCV infection: iron overload may in theory promote viral
iron overload in liver disease.32 In this review the role of             replication. Moreover, iron overload has been incriminated
HFE mutations as a risk factor for iron overload in CHC                  as one of the essential factors that hamper response to
has been studied in different populations, with discordant               interferon-alpha in CHC.3–36 The amount of hepatic iron
results. Our results evidenced a correlation between HFE                 has been identified as one of these factors that adversely
gene mutation and iron overload. TSI is the only serum                   affect the likelihood of response to interferon-alpha; those
iron parameter that showed a statistically significant differ-            patients with higher hepatic iron content are less likely to
ence between HFE gene wildtype and mutation, while serum                 respond to interferon therapy.37 Retrospective evidence
iron and serum ferritin were higher in HFE mutation but                  that the amount of hepatic iron may modulate the re-
did not obtain a statistically difference. We can assess that            sponse of the hepatitis C virus to interferon therapy was
several aspecific factors seem to favor marked variations of              provided by Van Thiel et al13 who reported that hepatic
serum iron and serum ferritin and we considered TSI as                   iron content of interferon nonresponders was found to
the most specific and sensitive parameter in identifying                  be almost twice that of responders. The influence of host
iron overload. The present study provides evidence support-              and viral factors on the natural course of CHC and efficacy
ing the view that the HFE gene mutations are associated                  of PEG-IFN and Ribavirin therapy has been intensively
with significant abnormalities of iron metabolism and sug-                studied. The presence of HFE gene mutations may be an
gests that patients with CHC accumulate iron as the result               additional factor to be considered among those implicated
of interplay between genetic and acquired factors. In fact               in the determination of a lower rate of sustained virological

Journal of Clinical and Experimental Hepatology | September 2012 | Vol. 2 | No. 3 | 211–217                                       215
                      HEMOCHROMATOSIS GENE MUTATIONS                                                                                                    SINI ET AL

                      response to PEG-IFN plus ribavirin in chronic hepatitis C              3. Piperno A, Fargion S, D'Alba, et al. Liver damage in Italian patients
                      patients.                                                                 with hereditary hemochromatosis is highly influenced by hepatitis B
                                                                                                and C virus infection. J Hepatol. 1992;16(3):364–368.
                         In the present study, ETR rates were lower among pa-                4. Riedel HD, Stremmel W. The haemochromatosis gene. J Hepatol.
                      tients with HFE gene mutations compared to those with                     1997;26:941–944.
                      HFE gene wildtype (P = 0.005). In patients with 1–4 HCV                5. Holmstrom P, Marmur J, Eggertsen G, et al. Mild iron overload in pa-
                      genotype infection, the ETR rate was higher in group A                    tients carrying the HFE S65C gene mutation: a retrospective study
                      (51.9%) as compared with group B (P = 0.003).                             in patients with suspected iron overload and healthy controls. Gut.
                         No significant response difference was observed between              6. Merryweather-Clarke AT, Pointon JJ, Jouanolle AM, et al. Geography of
                      patients with HFE gene mutation and HFE gene wildtype in                  HFE C282Y and H63D mutations. Genet Test. 2000;4(2):183–198.
                      genotype 2–3. The small number of non-1–4 genotype pa-                 7. Candore G, Mantovani V, Balistreri CR, et al. Frequency of the HFE
                      tients could have accounted for the lack of statistical signif-           gene mutations in five Italian populations. Blood Cells Mol Dis.
                      icance between the two groups. A sustained virological                    2002 Nov–Dec;29(3):267–273.
                                                                                             8. Smith BC, Gorve J, Guzail MA, et al. Heterozygosity for hereditary
                      response was seen in 18.8%. The patients with HFE wildtype                hemochromatosis is associated with more fibrosis in chronic hepa-
                      produced significant SVR compared with patients with HFE                   titis C. Hepatology. 1998;27:1695–1699.
                      mutations (P = 0.03). Despite the number of patients in our            9. Kazemi-Shirazi L, Datz C, Maier-Dobersberger T, et al. The relation
                      study being too limited for meaningful statistical analysis,              of iron status and hemochromatosis gene mutations in patients
                      several comments can be made concerning the end of treat-                 with chronic hepatitis C. Gastroenterology. 1999;116:127–134.
                                                                                            10. Martinelli AL, Franco RF, Villanova MG, et al. Are haemochromato-
                      ment and sustained responders. We have observed that                      sis mutations related to the severity of liver disease in hepatitis C
                      PEG-IFN/ribavirin therapy is less effective in patients with              virus infection? Acta Haematol. 2000;102:152–156.
                      1–4 HCV genotype and HFE gene mutation. Moreover, in                  11. Bulaj Zaneta J, Griffen Linda M, Jorde Lynn B, Edwards Corwin Q,
                      our patients with genotype 1–4 infection, TSI was signifi-                 Kushner James. Clinical and biochemical abnormalities in people
                      cantly higher than those with genotype 2–3 infection and                  heterozygous for hemochromatosis. N Engl J Med. 1996;335:
                      viral genotype distribution did not differ significantly               12. Di Bisceglie AM, Axiotis CA, Hoofnagle JH, Bacon BR. Measure-
                      between HFE mutant patients and wildtype homozygotes.                     ments of iron status in patients with chronic hepatitis. Gastroenter-
Chronic Hepatitis C

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                      There are no commercial associations (e.g. consultancies,                 zygosity for hemochromatosis gene in liver diseases: prevalence
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                                                                                                tion as a predictor of response to interferon alpha therapy in
                      Civolani and Luigi Demelia that pose a conflict of interest                chronic hepatitis C. Gastroenterology. 1995;108:1104–1109.
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                      We acknowledge Dr. Barry Mark Wheaton for his expertise                   1998;30:396–401.
                      and help in the execution of this paper with gratitude.               22. Casaril M, Stanzial AM, Tognella P, et al. Role of iron load on fibro-
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Journal of Clinical and Experimental Hepatology | September 2012 | Vol. 2 | No. 3 | 211–217                                                         217

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