<p>Gastrointestinal disorders (especially diarrhea) are observed in a proportion of patients treated with the
currently approved combination treatment for chronic hepatitis C (CHC), pegylated-interferon alpha (PEG-IFNa) plus ribavirin (RIB) [##REF##12324553##1##]. Several reports
suggest that the presence of inflammatory bowel disease (IBD) is not a
contraindication for interferon-alpha- (IFNa-) based treatments [##REF##7795286##2##, ##REF##16091058##3##].
Furthermore, a randomised placebo-controlled trial of PEG-IFNa in patients with active ulcerative colitis
concluded that PEG-IFNa is safe but not effective treatment for these patients
[##REF##14633951##4##]. On the contrary, several reports 
[##REF##7474487##5##, ##REF##11451187##6##, ##REF##16215439##7##, ##UREF##0##8##] revealed that
treatment of chronic viral hepatitis with IFNa or PEG-IFNa with or without RIB
was related with the onset of clinically and histologically confirmed acute
colitis of the IBD type. To our
knowledge the effect of chronic hepatitis C virus (HCV) infection or PEG-IFNa
plus RIB combination treatment on large intestine histopathology has not been
investigated, within a clinical trial. The principal aim of our study was to investigate
the effect of PEG-IFNa plus RIB treatment on the large intestine histology of
treated CHC patients.</p> <p>Twenty-four treatment-naïve CHC patients with
serologically (antiHCV-positive, Abbott Laboratories, Abbott Park, Ill, USA), virologically (serum HCV-RNA detection, Cobas Amplicor HCV test, version 2, Roche Diagnostics, Branchburg, NJ,
USA), and histologically (liver biopsy-Ishak scoring system) confirmed CHC and no contraindication of receiving
combination treatment with PEG-IFNα2b and RIB were enrolled in this pilot study. All patients were treated with weight-based dosing of pegylated
interferon-a2b (Peg-Intron, 1.5<italic>μ</italic>g/kg/week) and genotype-related ribavirin dose
(Rebetol, 800 mg/day for genotype 2/3 and 1000–1200 mg/day for genotype
1/4-infected patients, depending on baseline body weight &lt; or ≥ 85 kg,
resp.) for 24 weeks. Patients were evaluated for the presence of gastrointestinal symptoms,
by receiving a detailed history, before the beginning of treatment, during the
treatment period and at week 24 of treatment. The study population underwent
recto-sigmoidoscopic examination prior to the beginning of the treatment
schedule. Three to five biopsy specimens were taken from the rectosigmoid area.</p> <p>Histological findings characteristic of inflammation as well as the presence of architectural disorders and the quantity of
mucus production, the presence of ulcerations and Paneth cells as well as the
numbers of lymphoid follicles in every biopsy specimen were evaluated. Fifteen
patients underwent the same procedure after the completion of 24-week treatment
course and three of them were also evaluated during treatment because of
diarrhea. Ten age-, sex-, and BMI-matched healthy subjects (control group)
underwent recto-sigmoidoscopic examination and biopsy. All controls had no
history of inflammatory bowel disease or other gastrointestinal diseases, did
not receive any medication and did not report symptoms from the
gastrointestinal tract. Written informed consent was obtained from each
participant for his or her participation in the study. The study conformed to
the ethical guidelines of the 1975 Declaration of Helsinki.</p> <p>No pathological macroscopic (endoscopic)
findings were identified at baseline as well as in endoscopic re-evaluation in
either patients or controls. CHC patients had no statistically significant
difference in the presence of bowel inflammatory infiltration compared to
controls as shown in ##TAB##0##Table 1##. It is important to note that 
a <italic>respectable proportion</italic> of CHC patients
exhibited architectural disorder and <italic>decreased</italic> mucus production (25%) as well as presence
of Paneth cells (16.7%), compared to controls, but this does not reach
statistical significance possibly due to the small sample size of the study
population. This finding needs further investigation because of the documental
lymphotropism of HCV and the well-known HCV-related autoimmune manifestations.</p> <p>No patient reported diarrhea before the initiation of treatment whereas 3 patients
reported diarrhea during the treatment course. In particular, the first patient
reported diarrhea at week 6 of treatment, the second one at week 12, and the
third one at week 14. Baseline histology was normal in all three patients.
Histopathological evaluation of the large intestine at the onset of symptoms
revealed mild chronic nonspecific colitis in the first patient (##FIG##0##Figure 1##) and
normal large intestine histology in the other two patients, respectively. The
same findings were repeated in these patients in the histological re-evaluation
at week 24 of treatment. Diarrhea spontaneously resolved in all of them within
5–7 days and none of them followed treatment discontinuation.</p> <p>There was no statistically
significant difference between the percentage of patients with large intestine
inflammation before the initiation and at week 24 of treatment (66.7% versus
53.3% resp., <italic>P</italic> = .71). Particularly, 6/15 patients exhibited mild
inflammatory infiltration before the initiation as well as at week 24 and 3/15
exhibited absence of inflammation both before and at week 24 of treatment.
Moreover, 4/15 positive patients for the presence of inflammation before
treatment had normal large intestine histology at week 24 and finally, 2/15
patients had no findings of inflammation before treatment but exhibited mild
nonspecific inflammatory lesions at week 24. No statistically significant
differences were observed before the beginning and at week 24 of combination
treatment regarding architectural disorder and decrease of mucus production (<italic>P</italic> = .70),
presence of Paneth cells (<italic>P</italic> = .10), and the number of lymphoid follicles
in every biopsy specimen (<italic>P</italic> = .97) as shown in ##TAB##1##Table 2##. Interestingly none
of 4 patients with detectable Paneth cell at baseline evaluation exhibits
presence of them at week 24. This finding needs further investigation in
large-scale studies because of the proposed importance of these multifaceted
cells in the pathophysiology of IBD [##REF##11846026##9##].</p> <p>In conclusion, according to the preliminary results of our
pilot study, it seems that the immunomodulatory-antiviral treatment of CHC with
PEG-IFNa2b plus ribavirin for 24 weeks possibly does not significantly affect
the large intestine histology of treated patients, despite the appearance of
symptoms from the gastrointestinal tract in a subgroup of them. The effect of
chronic HCV infection in the intestine histopathology needs further
investigation.</p>
<fig id="fig1" position="float"><label>Figure 1</label><caption><p>Histopathological evaluation of the large
intestine at baseline (a) and at the onset of symptoms (b) revealed normal
large intestine histology and mild chronic nonspecific colitis in the first
patient with diarrhea, respectively.</p></caption></fig>
<table-wrap id="tab1" position="float"><label>Table 1</label><caption><p>Comparison of epidemiological and large intestine histopathology data between untreated CHC
patients and controls.</p></caption><table frame="hsides" rules="groups"><thead><tr><th rowspan="1" colspan="1"/><th align="center" rowspan="1" colspan="1">CHC patients <italic>n</italic> = 24</th><th align="center" rowspan="1" colspan="1">Controls <italic>n</italic> = 10</th><th align="center" rowspan="1" colspan="1">
<italic>P</italic> value</th></tr></thead><tbody><tr><td rowspan="1" colspan="1">Gender (male/female)</td><td align="center" rowspan="1" colspan="1">14/10</td><td align="center" rowspan="1" colspan="1">6/4</td><td align="center" rowspan="1" colspan="1">1</td></tr><tr><td rowspan="1" colspan="1">Age (years)</td><td align="center" rowspan="1" colspan="1">37.04 ± 14.02</td><td align="center" rowspan="1" colspan="1">46.00 ± 13.38</td><td align="center" rowspan="1" colspan="1">.098</td></tr><tr><td rowspan="1" colspan="1">BMI (kg/m<sup>2</sup>)</td><td align="center" rowspan="1" colspan="1">23.09 ± 3.31</td><td align="center" rowspan="1" colspan="1">23.26 ± 3.78</td><td align="center" rowspan="1" colspan="1">.903</td></tr><tr><td rowspan="1" colspan="1">Inflammation (%)</td><td align="center" rowspan="1" colspan="1">14/24 (58.3%)</td><td align="center" rowspan="1" colspan="1">6/10 (60%)</td><td align="center" rowspan="1" colspan="1">1</td></tr><tr><td rowspan="1" colspan="1">Architectural disorder and
decrease
of mucus production (%)</td><td align="center" rowspan="1" colspan="1">6/24 (25%)</td><td align="center" rowspan="1" colspan="1">0/10 (0%)</td><td align="center" rowspan="1" colspan="1">.148</td></tr><tr><td rowspan="1" colspan="1">Paneth cells (%)</td><td align="center" rowspan="1" colspan="1">4/24 (16.7%)</td><td align="center" rowspan="1" colspan="1">0/10 (0%)</td><td align="center" rowspan="1" colspan="1">.296</td></tr><tr><td rowspan="1" colspan="1">Lymphoid follicles</td><td align="center" rowspan="1" colspan="1">1.33 ± 1.50</td><td align="center" rowspan="1" colspan="1">1.60 ± 1.43</td><td align="center" rowspan="1" colspan="1">.440</td></tr></tbody></table></table-wrap> <table-wrap id="tab2" position="float"><label>Table 2</label><caption><p>Comparison of large intestine histopathology and diarrhea data of CHC patients before and 
after 24 <italic>weeks</italic> of treatment.</p></caption><table frame="hsides" rules="groups"><thead><tr><th rowspan="1" colspan="1"/><th align="center" rowspan="1" colspan="1">CHC patients before treatment <italic>n</italic> = 15</th><th align="center" rowspan="1" colspan="1">CHC patients after 24 weeks of treatment <italic>n</italic> = 15</th><th align="center" rowspan="1" colspan="1">
<italic>P</italic> value</th></tr></thead><tbody><tr><td rowspan="1" colspan="1">Inflammation (%)</td><td align="center" rowspan="1" colspan="1">10/15 (66.7%)</td><td align="center" rowspan="1" colspan="1">8/15 (53.3%)</td><td align="center" rowspan="1" colspan="1">.71</td></tr><tr><td rowspan="1" colspan="1">Architectural disorder and decrease of mucus production (%)</td><td align="center" rowspan="1" colspan="1">6/15 (40%)</td><td align="center" rowspan="1" colspan="1">4/15 (26.7%)</td><td align="center" rowspan="1" colspan="1">.70</td></tr><tr><td rowspan="1" colspan="1">Paneth cells</td><td align="center" rowspan="1" colspan="1">4/15 (26.7%)</td><td align="center" rowspan="1" colspan="1">0/15</td><td align="center" rowspan="1" colspan="1">.10</td></tr><tr><td rowspan="1" colspan="1">Lymphoid
follicles</td><td align="center" rowspan="1" colspan="1">1.33 ± 1.54</td><td align="center" rowspan="1" colspan="1">1.73 ± 1.62</td><td align="center" rowspan="1" colspan="1">.97</td></tr><tr><td rowspan="1" colspan="1">Diarrhea (%)</td><td align="center" rowspan="1" colspan="1">0/15</td><td align="center" rowspan="1" colspan="1">3/15 (20%)</td><td align="center" rowspan="1" colspan="1">.22</td></tr></tbody></table></table-wrap>
<graphic xlink:href="GRP2008-637517.001"/>
[{"label": ["8"], "surname": ["Sprenger", "Sagmeister", "Offner"], "given-names": ["R", "M", "F"], "article-title": ["Acute ulcerative colitis during successful interferon/ribavirin treatment for chronic hepatitis"], "italic": ["Gut"], "year": ["2005"], "volume": ["54"], "issue": ["3"], "fpage": ["438"], "lpage": ["439"]}]
Gastroenterol Res Pract. 2008 Mar 19; 2008:637517