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Iron in liver diseases other than
hemochromatosis
Bonkovsky HL, Banner BF, Lambrecht RW, Rubin RB
Department of Medicine, University of Massachusetts Medical
Center, Worcester 01655, USA.
Semin Liver Dis 1996 Feb;16(1):65-82
There is growing evidence that normal or only mildly
increased amounts of iron in the liver can be damaging,
particularly when they are combined with other hepatotoxic
factors such as alcohol, porphyrogenic drugs, or chronic viral
hepatitis. Iron enhances the pathogenicity of microorganisms,
adversely affects the function of macrophages and lymphocytes,
and enhances fibrogenic pathways, all of which may increase
hepatic injury due to iron itself or to iron and other
factors. Iron may also be a co-carcinogen or promoter of
hepatocellular carcinoma, even in patients without HC or
cirrhosis. Based on this and other evidence, we hope that the
era of indiscriminate iron supplementation will come to an
end. Bloodletting, a therapy much in vogue 2 centuries ago, is
deservedly enjoying a renaissance, based on our current
understanding of the toxic effects of iron and the benefits of
its depletion.
[Markers of chronic hepatitis B in children after
completion of therapy with isoprinosine]
Kowalik-MikoLajewska B; Barszcz T; Ladyzynska E; Wojnarowski
M
Kliniki C Chorob Zakaznych i Paso.ANG.zytniczych Wieku
Dzieciecego Instytutu Chorob Zakaznych i Paso.ANG.zytniczych
AM, Warszawie.
Pol Tyg Lek (Poland) Mar 15-29 1993, 48 (11-13)
p263-4
Fourteen children with chronic active hepatitis B treated
with isoprinosine were followed-up for 3-8 years. In no child
HBs antigen was eliminated. No seroconversion was noted in
children in whom HBe antigen was eliminated. Anti-HBe
antibodies were found in 11 children, including 6 children in
whom they were present all the time following therapy, and 2
children in whom these antibodies reappeared after an initial
elimination. These results suggest that the inhibition of
hepatitis B virus replication produced by isoprinosine may be
transient. Therefore, longer lasting immunomodulating therapy
should be considered.
[Course of chronic virus hepatitis B in children
and attempts at modifying its treatment]
Kowalik-MikoLajewska B
Kliniki Chorob Zakaznych i Paso.ANG.zytniczych Wieku
Dzieciecego
Pol Tyg Lek (Poland) Mar 15-29 1993, 48 (11-13)
p258-60
60 children with chronic virus hepatitis B were followed
from there to nine years. 34 children received isoprinosine, 6
prednisone and 20 children were without any therapy. There
were no cases of death. In 2 cases treated with isoprinosine
cirrhosis was found. Eight children with chronic active
hepatitis (4 treated with isoprinosine, 1 with prednisone, and
3 without any treatment) had histological recovery.
Isoprinosine significantly accelerated seroconversion in HBe
system in children with chronic active hepatitis but not in
children with persistent, hepatitis. Isoprinosine shortened
also the time of normalisation of aminotransferases activity
children. Prednisone had no influence on the course of chronic
active hepatitis B in treated group.
Isoprinosine in the treatment of chronic active
hepatitis type B.
Cianciara J; Laskus T; Gabinska E; Loch T
Scand J Infect Dis (Sweden) 1990, 22 (6) p645-8
21 patients with chronic active hepatitis B (CAH-B) were
treated for 1-2 years with isoprinosine, while another 18
patients served as control group. All patients were initially
DNA polymerase (DNAp) and HBeAg positive. Nine (43%) treated
patients became persistently negative for DNAp, seroconverted
to anti-HBe and showed histological remission on follow-up
biopsy. Among simultaneously followed controls 5 (28%) lost
DNAp and 4 (22%) also lost their HBeAg. However, only 2 (11%)
seroconverted to anti-HBe. Histological improvement was seen
in 5 (28%) controls. Thus, it seems that isoprinosine may
exert a beneficial effect on the course and outcome of
CAH-B.
[Evaluation of the treatment of chronic active
hepatitis (HBsAg+) with isoprinosine. II. Immunological
studies]
Dabrowska-Bernstein B; Stasiak A; Dabrowski M; Pawinska A;
Cianciara J; Loch T; Babiuch L
Pol Tyg Lek (Poland) Apr 16-30 1990, 45 (16-18)
p347-51
A two-month treatment of the chronic active hepatitis
(HBsAg+) with isoprinosine produced quantitative and
functional T-cells populations in patients with cellular
response disorders. Immunological studies have shown that such
an effect of isoprinosine lasted for about 4-5 months.
Repeated administration of isoprinosine for one month
normalized recurrent abnormalities in the monitored
immunological parameters.
In vitro studies on the effect of certain natural
products against hepatitis B virus.
Mehrotra R; Rawat S; Kulshreshtha DK; Patnaik GK; Dhawan
BN
Indian J Med Res (India) Apr 1990, 92 p133-8
Picroliv (active principle from Picrorrhiza kurroa), its
major components picroside I, catalpol, kutkoside I,
kutkoside, andrographolide (active constituent of Andrographis
paniculata), silymarin and Phyllanthus niruri extract were
tested for the presence of anti hepatitis B virus surface
antigen (anti HBs) like activity. HBsAg positive serum samples
obtained from hepatitis B virus (HBV) associated acute and
chronic liver diseases and healthy HBsAg carriers were used to
evaluate the anti-HBs like activity of compounds/extract. The
latter were mixed with serum samples and incubated at 37
degrees C overnight followed by HBsAg screening in the Elisa
system. A promising anti-HBsAg like activity was noted in
picroliv (and its major components) catalpol, P. niruri which
differed from the classical viral neutralization. Picroliv
also inhibited purified HBV antigens (HBsAg and HBsAg)
prepared from healthy HBsAg carriers. The in vitro testing
system appears to be a suitable model to identify an agent
active against HBV, prior to undertaking detailed studies.
Effects of glycyrrhizin on hepatitis B surface
antigen: a biochemical and morphological study.
Takahara T; Watanabe A; Shiraki K
J Hepatol (Denmark) Oct 1994, 21 (4) p601-9
Glycyrrhizin, a major component of a herb (licorice), has
been widely used to treat chronic hepatitis B in Japan. This
substance improves liver function with occasional complete
recovery from hepatitis; its effects on the secretion of
hepatitis B surface antigen (HBsAg) were examined in vitro.
Glycyrrhizin suppressed the secretion of HBsAg and accumulated
it dose-dependently in PLC/PRF/5 cells. Its action was further
analyzed and determined in the HBsAg-expression system using
the varicella-zoster virus. Glycyrrhizin suppressed the
secretion of HBsAg, resulting in its accumulation in the
cytoplasmic vacuoles in the Golgi apparatus area. HBsAg
labeled with 35S-methionine and cysteine accumulated in the
cells and its secretion was suppressed dose-dependently in
glycyrrhizin-treated culture. The secreted HBsAg was modified
by N-linked and O-linked glycans but its sialylation was
inhibited dose-dependently by glycyrrhizin. Thus glycyrrhizin
suppressed the intracellular transport of HBsAg at the
trans-Golgi area after O-linked glycosylation and before its
sialylation. HBsAg particles were mainly observed on the cell
surface in the glycyrrhizin-treated culture but not in the
untreated culture. This suggests that asialylation of HBsAg
particles resulted in the novel surface nature of
glycyrrhizin-treated HBsAg particles. We elucidated the unique
mechanism of action of glycyrrhizin on HBsAg processing,
intracellular transport, and secretion.
Glycyrrhizin withdrawal followed by human
lymphoblastoid interferon in the treatment of chronic
hepatitis B.
Hayashi J; Kajiyama W; Noguchi A; Nakashima K; Hirata M;
Hayashi S; Kashiwagi S
Gastroenterol Jpn (Japan) Dec 1991, 26 (6)
p742-6
Seventeen patients with chronic hepatitis B were treated
with a 4-week administration of glycyrrhizin followed by a
4-week treatment with human lymphoblastoid interferon, then
followed for 6 months after the end of treatment. All were
positive for hepatitis B surface antigen (HBsAg), hepatitis B
e antigen (HBeAg), and hepatitis B virus-associated DNA
polymerase (DNA-p) for at least 6 months before entry. All
patients were Japanese and none of them were homosexuals.
Eleven patients lost DNA-p activity and 10 of them lost HBeAg.
Three of these 10 patients had antibody to HBeAg. In 10
patients who became HBeAg-negative, alanine aminotransferase
levels after glycyrrhizin administration were higher and
initial DNA-p activities relatively lower than the levels
found in seven patients who remained HBeAg-positive. The
immunomodulator provided by a short course of glycyrrhizin
before administration of human lymphoblastoid interferon may
be an effective treatment for patients with chronic hepatitis
B.
Combination therapy of glycyrrhizin withdrawal and
human fibroblast Interferon for chronic hepatitis B.
Hayashi J; Kashiwagi S; Noguchi A; Ikematsu H; Tsuda H; Tsuji
Y; Motomura
Clin Ther (United States) 1989, 11 (1) p161-9
In ten carriers positive for chronic hepatitis B surface
antigen (HBsAg), hepatitis B e antigen (HBeAg), and DNA
polymerase, the authors investigated the efficacy of the
combination therapy consisting of glycyrrhizin withdrawal and
human fibroblast interferon (locally produced). Glycyrrhizin
was given for four weeks and was stopped without tapering off
the dose. Human fibroblast interferon was given continuously.
Thirty-six weeks after the end of this treatment, three of the
ten patients were HBeAg negative but not anti-HBe positive,
and in one of these three DNA polymerase became undetectable.
Another patient showed a loss of DNA polymerase with HBeAg.
Transaminase levels decreased in nine of the patients.
Glycyrrhizin appeared to act as an antiviral agent in four
patients and had a corticoid-like effect in three. DNA
polymerase decreased remarkably after interferon
administration, and serum transaminase levels increased. No
side effects were reported in patients receiving glycyrrhizin.
In contrast, almost all patients receiving human fibroblast
interferon had influenza-like symptoms, which, although
initially severe, decreased with subsequent injections of
interferon. Thus this combination therapy seems safe and
effective.
Alpha-interferon combined with immunomodulation in
the treatment of chronic hepatitis B.
Peters M
J Gastroenterol Hepatol (Australia) 1991, 6 Suppl 1
p13-4
Interferon has profound anti-viral, anti-proliferative and
immunomodulatory effects. Future studies should be directed at
observing how the immunomodulatory effects predict a response
in certain groups of patients. Interferon is very useful in
chronic hepatitis B but may require the addition of a steroid
pulse. Individuals with low serum ALT appear to benefit most
from a steroid pulse. Therapy should be given with a great
deal of caution in patients with decompensated liver disease,
as one may precipitate the untimely demise of the patient even
though viral replication is decreased. One of the patients in
the IFN study in fact did have decompensation after prednisone
therapy, which subsequently led, a couple of months later, to
a variceal haemorrhage. In summary, in treating hepatitis B
viral infection, no single agent is totally effective and
perhaps the combination of suppressing viral replication and
augmenting the immune system is the optimal way to eradicate
the virus. At present, an adequate response is found in only
about 30-40% of patients even with 'optimal' therapy.
Improvement of liver fibrosis in chronic hepatitis
C patients treated with natural interferon alpha.
Hiramatsu N; Hayashi N; Kasahara A; Hagiwara H; Takehara T;
Haruna Y; Naito M; Fusamoto H; Kamada T
J Hepatol (Denmark) Feb 1995, 22 (2) p135-42
To investigate the histological change (change of liver
fibrosis) produced by the anti-viral effect of interferon on
hepatitis C virus, 40 patients with chronic hepatitis C
treated with natural interferon alpha were divided according
to the existence of viremia at the end of treatment and 6
months after the end of treatment. The condition of liver
fibrosis was scored numerically with a new "hepatic fibrosis
score" which is sensitive to more subtle changes than
Knodell's fibrosis score. Each portal zone was evaluated
separately. End-of-treatment biopsy for the HCV RNA-negative
group (negative for HCV RNA at the end of treatment) showed a
significant improvement of the "hepatic fibrosis score" as
well as the alleviation of necrosis and inflammation. At the
end of treatment and 6 months after that, serum procollagen
type III peptide levels and serum type IV collagen-7s levels
had also decreased significantly in the HCV RNA-negative
group. The present study showed that treatment with interferon
alpha could alleviate fibrosis in addition to necrosis and
inflammation.
Diagnosis and treatment of the major hepatotropic
viruses.
Kiyasu PK; Caldwell SH
Am J Med Sci (United States) Oct 1993, 306 (4)
p248-61
The hepatotropic viruses currently include hepatitis A, B,
C, D, and E, and are associated with a spectrum of acute and
chronic liver disease syndromes. The epidemiology and natural
history of each are discussed, with emphasis on uncommon or
newly recognized clinical presentations. The serodiagnosis of
hepatitis A, B, and D is well established; the serodiagnosis
of hepatitis C and E continues to evolve as serologic and
virologic assays become refined. Hepatitis A and E only cause
acute liver injury; current medical approaches therefore focus
on vaccination strategies. Hepatitis B, C, and D can cause
both acute and chronic liver injury. Sequelae of chronic liver
disease, including portal hypertension and hepatocellular
carcinoma, are not uncommon. Medical therapy of resulting
chronic liver disease currently consists of interferon, though
other anti-viral strategies are being explored. Advanced
chronic liver disease due to hepatitis B, C, or D can be
treated by orthotopic liver transplantation, but viral
recurrence is near uniform and can be problematic. Further
study of the hepatotropic viruses at the molecular biologic,
epidemiologic, and clinical levels will continue to provide
greater insight into the diagnosis and management of their
associated clinical syndromes. (161 Refs.)
Treatment of chronic viral hepatitis.
Dusheiko GM; Zuckerman AJ
J Antimicrob Chemother (England) Jul 1993, 32 Suppl A
p107-20
A substantial number of anti-viral compounds have been
evaluated for the treatment of patients with chronic viral
hepatitis. A few of these compounds have now achieved clinical
applicability. alpha-Interferon is the most widely studied and
remains the main treatment for chronic hepatitis B and C.
Unfortunately in both these conditions only a minority of
patients respond to interferon therapy, although the response
can be complete in some patients. Some parameters have been
identified which assist in the selection of patients for
treatment. Several other cytokines, including thymosin, have
been evaluated for the treatment of chronic hepatitis B. There
are a number of promising new nucleosides which may inhibit
hepatitis B virus and their action is being studied. Relapse
rates are unknown however with these compounds. Ribavirin, a
guanosine analogue, is also efficacious in treating a
proportion of patients with chronic hepatitis C and the drug
may be useful in treating patients with cirrhosis or patients
who have an auto-immune diathesis. (88 Refs.)
[Mechanisms of the effect of interferon (IFN)
therapy in patients with type B and C chronic hepatitis]
Karino Y
Hokkaido Igaku Zasshi (Japan) May 1993, 68 (3)
p297-309
The relationship between 2', 5'-oligoadenylate synthetase
(2-5AS) and HLA class I antigen in the hepatocyte of patients
with type B or type C chronic hepatitis with and without
interferon (IFN) therapy was investigated. The expression of
HLA class I antigen of hepatocytes of biopsied specimen and
PBL HLA class I antigen expression showed relevancy. Then, the
HLA antigen expression of peripheral blood lymphocyte (PBL)
and the 2-5AS activity of peripheral blood mononuclear cell
(PBMC) were analyzed. In patients with type B or type C
hepatitis, the mean activity of PBMC 2-5AS was significantly
higher than that of healthy controls. Also the HLA class I
antigen expression of PBL was significantly intense in
patients with type B or type C hepatitis compared with healthy
controls. In the acute exacerbated phase of type B chronic
hepatitis, the HLA class I antigen expression of PBL and 2-5AS
activity of PBMC increased along with elevation of serum GPT
and then decreased with the remission of serum GPT. These
results suggest that endogenously produced IFN leads the lysis
of hepatocyte infected with hepatitis B virus (HBV) by
cytotoxic T cells, and the restriction of HBV replication by
activation of the 2-5A system simultaneously, and then leads
the elimination of HBV. The activity of PBMC 2-5AS and the
expression of PBL HLA class I antigen increased significantly
during IFN therapy. In type B chronic hepatitis, the effective
cases showed relatively high activity of serum 2-5AS compared
with the non-effective cases. On the other hand, there were no
significant differences in PBL HLA class I antigen expression
between effective cases and non-effective cases. In type C
chronic hepatitis, most patients with type III and type IV HCV
genotype showed disappearance of HCV-RNA regardless of serum
2-5AS activity. In patients with type II HCV genotype, the
serum 2-5AS activity was related to the anti-viral effect of
IFN therapy.
A pilot study of ribavirin therapy for recurrent
hepatitis C virus infection after liver transplantation.
Cattral MS; Krajden M; Wanless IR; Rezig M; Cameron R; Greig
PD; Chung SW; Levy GA
Transplantation (United States) May 27 1996, 61 (10)
p1483-8
Ribavirin is a guanosine analogue that normalizes serum
liver enzymes in most nontransplant patients with chronic
hepatitis C virus (HCV) infection. We conducted an
uncontrolled pilot study of ribavirin in 9 liver
transplantation recipients that had persistently elevated
liver enzymes, active hepatitis by liver biopsy, and HCV RNA
in serum by polymerase chain reaction. Ribavirin was given
orally at dosages of 800-1200 mg per day for 3 mo. All 9
patients promptly responded to ribavirin: mean (+/- SD) ALT
decreased from 392 +/- 377 IU/L immediately before treatment
to 199 +/- 185 and 68 +/- 37 IU/L after 1 and 12 weeks of
treatment, respectively, complete normalization of enzymes
occurred in 4 patients. None of the patients cleared the virus
from their serum during therapy, and biochemical relapse
occurred in all patients 4 +/- 4.2 weeks after cessation of
therapy. The hepatitis activity index of liver biopsy
specimens obtained before and at the cessation of therapy was
similar. Ribavirin treatment was resumed in 4 patients because
of increasing fatigue (2 patients), rising bilirubin (3), or
increasing necroinflammation on liver biopsy (2); the
biochemical response to the second course of therapy was
similar to the first course in all 4 patients. Ribavirin
caused reversible hemolysis in all patients, including
symptomatic anemia in 3 patients that resolved after reduction
of drug dosage. These results suggest that ribavirin may be of
benefit in the treatment of HCV infection after liver
transplantation. Further studies are needed to determine the
optimal dosage and duration of therapy.
Ribavirin as therapy for chronic hepatitis C. A
randomized, double-blind, placebo-controlled trial.
Di Bisceglie AM; Conjeevaram HS; Fried MW; Sallie R; Park Y;
Yurdaydin C;
Ann Intern Med (United States) Dec 15 1995, 123 (12)
p897-903
OBJECTIVE: To evaluate ribavirin, an oral antiviral agent,
as therapy for chronic hepatitis C.
DESIGN: Randomized, double-blind, placebo-controlled
study.
SETTING: Clinical Center of the National Institutes of
Health, a tertiary referral research hospital.
PATIENTS: 29 patients with chronic hepatitis C who received
oral ribavirin (600 mg twice daily) for 12 months and 29
controls with chronic hepatitis C who received placebo for 12
months.
MEASUREMENTS: Effects of therapy were evaluated by
measuring serum aminotransferase and hepatitis C virus (HCV)
RNA levels before, during, and for 6 months after therapy and
by histologic examination of liver specimens before and at the
end of treatment.
RESULTS: Patients treated with ribavirin had a prompt
decrease in serum aminotransferase levels (54% overall)
compared with levels before treatment and levels in controls
(5% decrease). Serum aminotransferase levels became normal or
nearly normal in 10 patients treated with ribavirin (35% [95%
CI, 18% to 54%]) but in no controls (0% [CI, 0% to 12%]).
Aminotransferase levels remained normal in only 2 patients
after ribavirin therapy was discontinued (7% [CI, 1% to 23%]).
Serum HCV RNA levels did not change during or after therapy.
Liver biopsy specimens showed a decrease in hepatic
inflammation and necrosis among ribavirin-treated patients
whose aminotransferase levels became normal.
CONCLUSIONS: Ribavirin has beneficial effects on serum
aminotransferase levels and histologic findings in the liver
in patients with chronic hepatitis C, but these effects are
not accompanied by changes in HCV RNA levels and are not
sustained when ribavirin therapy is discontinued. Thus,
ribavirin alone for periods as long as 12 months is unlikely
to be of value as therapy for chronic hepatitis C.
Treatment with ribavirin+alpha interferon in HCV
chronic active hepatitis non-responders to interferon alone:
preliminary results.
Scotto G; Ferrara S; Mangano A; Conte PE
J Chemother (Italy) Feb 1995, 7 (1) p58-61
Alpha interferon (IFN-alpha) represents the best therapy
for HCV active chronic hepatitis, but only 25% of treated
patients achieve a complete recovery. Several attempts have
been made to increase this percentage. The objective of our
study is to verify whether the combination ribavirin (R)+
IFN-alpha can lead to positive results in non-responders to
treatment with IFN-alpha alone. The preliminary results for 5
subjects, all non-responders to IFN, treated with R+ IFN for
60 days and then IFN alone for 4 months more show that during
the R+IFN treatment, 2 subjects presented a reduction in
transaminase; a month after the suspension of R, ALT returned
to pre-treatment values. The results are preliminary but we
can say that this combination in the proposed doses and times
in these subjects, cannot be considered adequate to modify the
natural course of this disease.
Combined treatment with interferon alpha-2b and
ribavirin for chronic hepatitis C in patients with a previous
non-response or non-sustained response to interferon
alone.
Schvarcz R; Yun ZB; Sonnerborg A; Weiland O
J Med Virol (United States) May 1995, 46 (1)
p43-7
Ten patients with chronic hepatitis C, six of whom had not
responded and four of whom had responded in a non-sustained
fashion to interferon-alpha treatment alone, were given
interferon alpha-2b and ribavirin in combination during 24
weeks. Interferon alpha-2b was given subcutaneously, at a dose
of 3 MU thrice weekly, together with ribavirin orally, at a
dose of 1,000-1,200 mg/day. All four patients with a prior
non-sustained response to interferon alone had normal alanine
aminotransferase (ALT) levels at the end of treatment as well
as during follow-up (> or = 24 weeks post treatment).
Furthermore, all four lost serum HCV-RNA at the end of
treatment and three continued to be negative during follow-up.
Among patients with a prior non-response to interferon alone
three of six had normal ALT levels at the end of treatment and
one at follow-up. Two of six became HCV-RNA negative at
cessation of treatment, one of whom was negative also at
follow-up. All former non-sustained responders and one of six
non-responder patients thus showed a sustained biochemical
response with eradication of HCV-RNA from serum in all cases
but one. It is concluded that combination therapy with
interferon alpha-2b and ribavirin offers a chance of sustained
biochemical response with eradication of the viremia in
patients who have not shown a persistent response to
interferon-alpha alone.
Increase in hepatic iron stores following prolonged
therapy with ribavirin in patients with chronic hepatitis
C.
Di Bisceglie AM; Bacon BR; Kleiner DE; Hoofnagle JH
Liver Diseases Section, National Institute of Diabetes and
Digestive and Kidney Diseases, National Institutes of Health,
Bethesda, Md 20892.
J Hepatol (Denmark) Dec 1994, 21 (6) p1109-12
Ribavirin, an oral nucleoside analogue being evaluated as
therapy for chronic hepatitis C, is associated with hemolysis.
Other hemolytic conditions are known to be associated with
accumulation of iron within the liver. We therefore examined
hepatic iron stores before and after 6 to 12 months of therapy
with ribavirin in 15 patients with chronic hepatitis C.
Although there were no significant changes in serum iron or
ferritin levels, hepatic iron staining increased in almost all
patients. Using a ranking system to quantitate the amount of
hepatic iron staining, we found that the mean rank increased
from 3.9 to 8.5 after therapy (p < 0.01). In six patients
in whom hepatic tissue was available for determination of
hepatic iron, concentrations also increased in all cases from
a mean of 826 to 1857 micrograms/g dry weight (p < 0.01).
The average rate of iron accumulation in these six patients
was approximately 1500 micrograms/g per year. Thus hepatic
iron concentrations might enter the range clearly associated
with hepatic fibrosis after approximately 15 years of
continuous therapy.
Therapy for chronic hepatitis C.
Davis GL; Lau JY; Lim HL
Gastroenterol Clin North Am (United States) Sep 1994, 23 (3)
p603-13
Hepatitis C is the silent epidemic of the 1970s and 1980s.
Interferon alfa is currently the only effective treatment.
Enthusiasm for interferon therapy must be tempered because
advanced disease usually requires years or even decades to
develop and does not occur in all patients. Few patients with
chronic hepatitis C derive long-term improvement from a single
6-month course of interferon therapy. Most initial responders
relapse and require long-term interferon treatment to suppress
the virus. Obviously, the initial goals and expectations for
interferon therapy require rethinking. Therapy should not be
undertaken by physician or patient with the idea that therapy
will be limited to 6 months. The most appropriate goal of
therapy now appears to be the long-term control of the
biochemical, virologic, and histologic activity of the
disease. Unfortunately, the most effective therapeutic regimen
for achieving this goal is not yet known and will require
continued clinical research. (52 Refs.)
Treatment of chronic viral hepatitis.
Marcellin P; Benhamou JP
Baillieres Clin Gastroenterol (England) Jun 1994, 8 (2)
p233-53
Recent advances have been made in the treatment of chronic
viral hepatitis, mainly with recombinant interferon (IFN)
alpha. However, the present treatment of chronic viral
hepatitis is not entirely satisfactory because the efficacy is
inconstant and/or incomplete. In chronic hepatitis B IFN-alpha
induces a sustained interruption of hepatitis B virus (HBV)
replication, with a HBeAg to anti-HBe seroconversion in about
30% of patients. Patients most likely to respond are those
with no immunosuppression, HBV infection acquired during
adulthood or active liver disease with low HBV replication.
Responders usually show a significant decrease in serum HBV
DNA levels during the first 2 months of therapy, followed by a
significant increase in the level of aminotransferases. New
nucleoside analogues might be useful in combination with
IFN-alpha in the treatment of those who do not respond to IFN
therapy. In chronic hepatitis B-D, the rate of sustained
response to IFN-alpha therapy is low. To be effective,
IFN-alpha must be used at a high dosage (9-10 mega units) with
a long duration (1 year). In chronic hepatitis C, IFN-alpha at
a dosage of 3 mega units over 6 months, induces a sustained
response in about 20% of patients. A higher dosage of IFN
(5-10 mega units) and a longer duration of treatment increases
the rate of sustained response but is associated with poor
tolerance. Non-responders to a first course of IFN do not
respond to a second course of treatment. In patients who
respond but relapse after treatment, the rate of sustained
response after a second course of IFN needs to be assessed.
Ribavirin, which has a significant antiviral effect on
hepatitis C virus, might be useful in combination with
IFN-alpha. At the dosage (3-6 mega units) usually used,
IFN-alpha is relatively well tolerated. In about 10% of the
patients therapy is interrupted, mainly because of severe
fatigue, thyroid dysfunction or depression. (84 Refs.)
Elevated serum iron predicts poorresponse to
interferon treatment in patients with chronic HCV
infection.
Arber N; Moshkowitz M; Konikoff F; Halpern Z; Hallak A; Santo
M; Tiomny E ; Baratz M; Gilat T
Dig Dis Sci (United States) Nov 1995, 40 (11)
p2431-3
To date, there are no firm clinical, demographic,
biochemical, serologic, or histologic features predicting
which patients with chronic hepatitis C are more likely to
respond to therapy with interferon-alpha. Serum iron, total
iron-binding capacity, transferrin saturation, and ferritin
were measured in the fasting state. The amount of stainable
iron in liver biopsy specimens was evaluated histochemically
as well. All patients received subcutaneous recombinant human
IFN-alpha 2a three million units thrice weekly by
self-administration. Eleven of 13 (84%) responders had low to
normal serum iron levels as compared to one of 26 (4%)
nonresponders (P < 0.001). The serum transferrin was
similar in both groups, but iron saturation was significantly
lower in responders (30 +/- 10%) than in nonresponders (53 +/-
12%) (P< 0.001). Serum ferritin and hepatic iron content
were higher in nonresponders (NS). It is suggested that
increased serum iron and transferrin saturation blunt the
action of interferon, as they have opposite effects on the
immune system. Iron overload can thus lead to a poor response
to interferon. It remains to be seen whether reducing iron
overload will improve the response to interferon therapy.
Distribution of iron in the liver predicts the
response of chronic hepatitis C infection to interferon
therapy
Barton AL; Banner BF; Cable EE; Bonkovsky HL
Am J Clin Pathol (United States) Apr 1995, 103 (4)
p419-24
[published erratum appears in Am J Clin Pathol 1995
Aug;104(2):232]
Recent evidence suggests that patients with chronic
hepatitis C virus (CHCV) who respond to interferon-alpha (IFN)
therapy have a lower hepatic iron concentration than those who
do not. The object of this study was to assess the
concentration and distribution of iron in liver biopsies from
15 patients with CHCV seen at the authors' medical center
between June 1992 and March 1993. Patients with complete
response to IFN were compared to those with non-complete
response with respect to quantitative hepatic iron
concentration, serum iron indices, and a detailed analysis of
histologic features of hematoxylin-and-eosin and iron-stained
pre-IFN biopsies. Patients with non-complete response had
significantly higher scores for stainable iron in sinusoidal
cells (P = .02) and portal tracts (P = .05) than did patients
with complete response. Total hepatic iron scores, mean
quantitative hepatic iron, and mean serum ferritin were higher
in patients with noncomplete response, but the differences
were not significant. In conclusion, iron deposition in
sinusoidal cells and portal tracts is significantly less
frequent in patients with complete response to IFN than in
those with poor or no response, and may be a useful, objective
predictor of response to IFN therapy.
Increased serum iron and iron saturation without
liver iron accumulation distinguish chronic hepatitis C from
other chronic liver diseases.
Arber N; Konikoff FM; Moshkowitz M; Baratz M; Hallak A; Santo
M; Halpern
Dig Dis Sci (United States) Dec 1994, 39 (12)
p2656-9
One hundred twenty-three patients with chronic liver
diseases of various etiologies were evaluated for their iron
status. The patients were divided into four distinct groups:
chronic hepatitis C (63), chronic hepatitis B (14), B + C (3)
and nonviral chronic liver diseases (43). In 107 patients
(87%) the chronic liver disease was confirmed by biopsy. Mean
serum iron (+/- SD) levels in the above four groups were: 166
+/- 62, 103 +/- 52, 142 +/- 48, and 115 micrograms/dl;
iron-binding capacity was 346 +/- 80, 325 +/- 72, 297 +/- 27,
and 374 +/- 75 micrograms/dl, and iron saturation 50 +/- 18,
32 +/- 16, 48 +/- 16, and 28 +/- 10%, respectively. Serum
ferritin, increased in all four groups, was highest in HCV;
however, no evidence of hepatic iron accumulation could be
found in any of the patients. There were no significant
differences in liver function parameters measured in the four
groups. We conclude that serum iron, iron saturation, and
ferritin are increased in patients with hepatitis C in
comparison to hepatitis B or other nonviral,
nonhemochromatotic liver diseases. The increased iron status
in hepatitis C patients is not manifested by increased liver
iron. Awareness of these distinct features of chronic
hepatitis C is essential in the diagnosis and treatment of
chronic liver diseases.
Response related factors in recombinant interferon
alfa-2b treatment of chronic hepatitis C.
Perez R; Pravia R; Linares A; Rodriguez M; Lombrana JL;
Suarez A; Riestra
Gut (England) 1993, 34 (2 Suppl) pS139-40
In an analysis of the clinical and laboratory variables
that can influence the response to interferon alfa-2b
treatment, 48 patients with chronic hepatitis C virus
infection received interferon 5 million units (MU)
subcutaneously three times weekly for eight weeks followed by
3 MU three times weekly for seven months. Response related
factors on univariate analysis were found to be age > 40
years, non-parenteral source of infection, pretreatment
positive antinuclear antibodies (ANA), cirrhosis, and high
serum iron, ferritin, gamma glutamyl transferase, and IgM. An
independent predictive value (multivariate analysis) was also
found for cirrhosis, ANA, serum iron, and ferritin. A baseline
aspartate aminotransferase/alanine aminotransferase ratio of
0.5 and a striking increase during interferon treatment were
associated with a complete response.
Measurements of iron status in patients with
chronic hepatitis
Di Bisceglie AM; Axiotis CA; Hoofnagle JH; Bacon BR
Gastroenterology (United States) Jun 1992, 102 (6)
p2108-13
Eighty patients with chronic viral hepatitis were screened
for evidence of iron overload. Elevated serum iron values were
noted in 36% of cases; serum ferritin values were above normal
in 30% of men and 8% of women. Twenty-eight additional
patients with chronic hepatitis for whom liver tissue was
available for determination of iron content were evaluated to
study the significance of iron overload in association with
chronic hepatitis. Although 46% had elevated serum iron,
ferritin, or transferrin-saturation levels, the hepatic iron
concentration was elevated in only four cases, and the hepatic
iron index was in the range for hereditary hemochromatosis
(greater than 2.0) in only two of these. Serum aspartate
aminotransferase activities correlated with serum ferritin
levels in these patients, suggesting that ferritin and iron
levels were increased in serum because of their release from
hepatocellular stores associated with necrosis. Thus, in
patients with chronic hepatitis in whom hereditary
hemochromatosis is suspected, a liver biopsy should be
performed with quantitation of hepatic iron and calculation of
the hepatic iron index to confirm the diagnosis.
[Effect of green tea on iron absorption in elderly
patients with iron deficiency anemia]
Kubota K; Sakurai T; Nakazato K; Morita T; Shirakura T
Department of Medicine, Kusatsu Branch Hospital, Gunma
University School of Medicine.
Nippon Ronen Igakkai Zasshi (Japan) Sep 1990, 27 (5)
p555-8
The effect of green tea on iron absorption from tablets
containing sodium ferrous citrate was investigated in four
elderly patients with iron deficiency anemia and in eleven
normal elderly subjects. In both groups, the serum iron level
reached a maximum value from 2 to 4 hours after taking iron
tablets and returned to the baseline value after 24 hours. No
inhibitory effect of green tea on iron absorption was
recognized.
[Current knowledge in the treatment of chronic
hepatitis C]
Pirotte J
Service d'Hepato-Gastroenterologie, Universite de
Liege.
Rev Med Liege (Belgium) Dec 1995, 50 (12) p501-4, (29
Refs.)
No abstract.
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