Iron as a Comorbid Factor in Chronic Viral Hepatitis
Kim
American Journal of Gastroenterology
Editorial
January 2002
Volume 97, Number 1
Pages 1-4
Iron as a Comorbid Factor in Chronic Viral Hepatitis
Herbert L. Bonkovsky, M.D.a
Iron Deficiency and Iron Overload
Gold is for the mistress, silver for the maid; copper for the
craftsman, cunning at his trade. "Good" said the baron, sitting in his
hall;
"But iron-cold-iron-is master of them all."
Rudyard Kipling
Iron is an abundant element of the earth, and it has served an
essential role in the emergence of oxygen-based plant and animal life
on our
planet. Deficiency of iron is the most common cause of anemia and, when
severe, is associated with many symptoms and signs. To help prevent
such
occurrences, virtually all forms of life on earth have developed
schemes and
means to assure their acquisition and retention of iron. In fact, we
humans
have virtually no natural means of excreting excess iron, probably
because,
for most of our natural history as an evolving species, we were more
prone
to problems related to iron deficiency than to iron excess.
The situation for some of us has changed dramatically during the
past
couple of millennia, with the emergence of iron overload or
hemochromatosis
as a common condition. Indeed primary, or hereditary, hemochromatosis
is the
most common inborn error of metabolism among whites from central and
northern Europe. Most causes of hereditary hemochromatosis are due to a
single homozygous mutation (nt: g845a) of the HFE gene, which produces
the
now familiar substitution of tyrosine for cysteine at amino acid 282 of
the
HFE protein [the C282Y mutation (1)]. Most men and at least one third
of
women who are C282Y +/+, if undiscovered and untreated, will develop
pathological iron overload (2). Hereditary or acquired hemochromatosis
may
also occur as a result of other mutations of HFE [especially H63D and
S65C
(1, 3)], as a result of mutations in other genes involved in iron
metabolism
[e.g., ferroprotein (4, 5) or hepcidin (6, 7, 8)], or as a result of
dyserythropoietic anemias, the most important of which are the
thalassemias
(9).
Regardless of cause, excess iron is toxic and potentially fatal,
and
the liver, which in all forms of hemochromatosis is the major organ for
iron
storage, is the principal site of iron-mediated toxicity. Thus, iron
overload per se may cause hepatic fibrosis, cirrhosis, decompensation,
and
hepatocellular carcinoma. Indeed, the latter complication of cirrhosis
is
especially common in hemochromatosis (10).
Iron as a Comorbid Factor in Nonhemochromatotic Liver Disease
Evidence continues to mount indicating that lesser amounts of
iron,
even so-called normal amounts, may increase hepatic injury due to
causes
unrelated to iron. Chief among these are porphyria cutanea tarda,
steatohepatitis, and chronic viral hepatitis. In addition, heavy
hepatic
iron overload sometimes develops in advanced liver disease, regardless
of
underlying cause, and/or in patients with spontaneous or surgically
constructed portosystemic shunts ("shunt siderosis"). The reasons that
such
nonhemochromatotic iron overload develops in some patients are not yet
understood, but based upon our current notions of iron-mediated tissue
injury, when such iron overload does occur, it probably increases
morbidity
and mortality of the primary, underlying liver disease. A discussion of
liver diseases other than viral hepatitis is beyond the scope of this
editorial. Readers are referred to recent reviews (11, 12, 13) for
additional information.
Iron and Viral Hepatitis
A link between iron and viral hepatitis was first stressed a
generation ago by Blumberg and colleagues (14), who noted that the
outcome
of acute hepatitis B was correlated with levels of serum iron and
ferritin.
Specifically, patients with higher levels of serum iron or ferritin
were
found less likely to recover spontaneously from acute hepatitis B
infection.
Shortly after the hepatitis C virus had been cloned and methods for its
unequivocal detection established, it was noted that many patients with
chronic hepatitis C (CHC) had elevations in serum ferritin (15, 16).
These
increases did not seem to be due solely to the fact that serum ferritin
is
an acute phase reactant. Elevations in serum iron saturations were less
frequent but also noted.
In the great majority of patients with elevated serum ferritin
and/or
iron saturation in whom hepatic iron concentrations (HICs) were also
measured, the HICs were within the normal range or, at most, only
mildly
increased (<3-fold above the upper limit of normal) and thus not
usually
thought to be hepatotoxic (17). In several careful histopathological
studies
it was shown that the lobular and cellular distribution of stainable
iron in
the liver was correlated with therapeutic responses to interferon.
Specifically, the presence of cells in portal tracts (stromal and
endothelial lining cells) that stained positive for iron was associated
with
reduced responses to interferon. The iron staining was an independent
and
significant inverse correlate of therapeutic response, on a par with
viral
genotype and load (18).
In the 1990s higher levels of serum ferritin or HICs were
variably
associated with decreased likelihood of responding to standard,
short-acting
interferons, at the time the only effective antiviral therapy for CHC
(17).
Unfortunately, the effectiveness of such therapy is limited, and the
costs
and side effects are high. Therefore, it was a natural next step to
suggest
that iron reduction therapy might be of benefit to increase the
response
rates to interferon therapy. Indeed, this hypothesis has been confirmed
in
at least three prospective, randomized, controlled trials (19, 20, 21).
In another United States multicenter trial, patients with CHC who
previously had failed to respond to interferon were randomized to
receive
iron reduction alone versus iron reduction plus additional interferon.
Neither group achieved significant improvements in terms of cure of
CHC, but
both showed evidence of histological improvements, with less severe
hepatic
inflammation (22). These favorable effects of iron reduction alone
confirmed
and extended earlier reports showing significant improvements in serum
ALT
levels in patients with CHC who previously had not responded to
interferon
when they underwent iron reduction by therapeutic venesection (23, 24).
There were even suggestions that iron chelation therapy of only modest
intensity improved CHC (25).
Iron Reduction for Long Term Management of Chronic Viral
Hepatitis
During the past decade, we have made clinically important
advances in
our management of chronic viral hepatitis, with the development of
interferon and/or lamivudine for chronic hepatitis B and of interferon
plus
ribavirin for CHC. The recent introduction of pegylated interferons
plus
ribavirin has improved the therapeutic response rates further, so that
we
can now expect to cure more than 50% of patients who are able to afford
and
to tolerate such combination therapy for 1 yr (26, 27). However, the
glass
still is only half full. What therapy should be offered to those who
can not
afford or tolerate such medicines or who have not responded?
Specifically,
might long term iron reduction be of benefit to such patients? In this
issue, Yano et al. (28) provide evidence that the answer to this
question is
"Yes." They report the results of 29 patients with CHC whom they
enrolled
into a study of iron reduction between July, 1991 and December, 1993.
They
excluded people who admitted to drinking more than 40 g of ethanol per
day,
those who had been transfused more than 5 U of blood, and those with
anemia
or "decompensated liver cirrhosis." Therapeutic venesections of 200-400
ml
of blood were performed every 2-4 wk, until an iron-depleted state was
reached (serum ferritin < 11 ng/ml). Twenty-six of the 29 were then
treated
with standard interferon (details of regimen not stated). The
percentage of
patients who achieved a fall in serum ALT into the "normal" range was
significantly higher in the iron reduction group than in controls. Four
of
26 (15%) experienced sustained virological responses and were excluded
from
the study. (This rate of sustained virological response was "not
significantly different" than that of historical controls, but numbers
of
patients studied and other details were not provided.)
Thirteen of 25 patients agreed to undergo baseline and 5-yr
follow-up
liver biopsies. Twelve of these were nonsustained virological
responders,
and the 13th did not receive any interferon, but was treated by iron
reduction alone. Thirteen controls were selected from among patients at
the
authors' hospitals who had been nonresponders to interferon without
iron
reduction and who had undergone two liver biopsies at least 3 yr apart.
The
iron reduction and control groups were reasonably well matched,
although
there is concern because the study was not a prospective, randomized,
controlled trial analyzed on an intention-to-treat basis.
The mean serum levels of ALT, in the phlebotomy group, fell from
117
to 75 IU/L and remained less than 72 IU/L for the ensuing 5 yr, during
which
time additional phlebotomies were needed every 8 months or so to
maintain an
iron-depleted state. There were no adverse effects of chronic iron
reduction.
Of greatest importance, the severity of fibrosis (by the Desmet
scoring system) in the iron reduction group decreased from 2.3 to 1.7
(p <
0.05), whereas in controls the mean values were 1.7 at baseline and 2.0
at
follow-up (p > 0.05, ns). Furthermore, the severity of inflammation
increased in only one of 13 of the chronic iron reduction group
(unchanged
in 12/13; mean values = 1.8 and 2.0, p > 0.05), whereas it increased in
12/13 controls (unchanged in the 13th) (mean values = 2.0 and 2.9, p <
0.005).
The authors concluded that long term maintenance of iron
depletion by
therapeutic phlebotomy prevents progression of fibrosis in CHC. They
suggest
that chronic iron reduction is a good alternative to interferon in
treatment
of CHC. To these positive results may be added recent reports of
decreases
in serum -fetoprotein (29) and less frequent development of
hepatocellular
carcinoma (HCC) (30) in small groups of patients with CHC chronically
treated with iron reduction. The notion that iron in the liver is a
risk
factor for HCC is supported by the known cocarcinogenicity of iron (10)
and
by a recent report showing a 5.2-fold increased risk of HCC development
in
patients with cirrhotic CHC and hepatic iron deposition relative to
those
without (31).
Although these important results from our Japanese colleagues
(28)
need confirmation in prospective, randomized trials involving larger
numbers
of patients, they are nevertheless supportive of earlier results from
Japan
and several other countries and consistent with emerging notions of
iron as
a comorbid factor adversely influencing nonhemochromatotic liver
disease.
Currently, we should certainly continue first to try to eradicate all
detectable hepatitis C virus from patients with CHC, absent
contraindications to the use of pegylated interferon plus ribavirin.
Those
who fail to respond to such therapy or who can not tolerate it should
be
considered for enrollment into prospective randomized trials of iron
reduction. It would be a bit complicated to use iron reduction therapy
in
combination with pegylated interferon plus ribavirin because of the
propensity of ribavirin to accumulate as the triphosphate in
erythrocytes
and to cause hemolysis. Indeed, the hemolytic anemia, increased GI iron
absorption, and increased hepatic iron produced by ribavirin may
diminish
its efficacy in CHC (32).
A trial comparing therapeutic venesection to the use of iron
chelation
therapy, especially with oral iron chelators such as deferiprone, seems
indicated and worthy of support. Such studies will need to be of long
duration (>4 yr) and to involve clinical and histopathological
endpoints.
They should especially involve patients with bridging fibrosis or
cirrhosis,
because they will be at greatest risk for complications and death due
to
CHC.
If the current National Institutes of Health-sponsored Hepatitis
C
Antiviral Long Term Treatment to Prevent Cirrhosis Trial (HALT-C) (33)
and/or similar trials show that long term low-dose pegylated interferon
is
of benefit in therapy of patients with difficult to treat, advanced
CHC, and
if chronic iron reduction is also shown to be of benefit, we will have
two
new modalities of chronic therapy to consider and perhaps even to
combine
and/or compare.
Emerging evidence suggests that we would all be better off if we
were
a bit low in iron (stopping short of iron deficiency anemia). Those of
us
without chronic viral hepatitis (or other contraindications) should be
volunteer blood donors. We should consider long term iron reduction for
patients with chronic viral hepatitis who have failed to tolerate or
respond
to antiviral therapies. By so doing, we may be able to loosen the icy
grip
of "cold iron" on us and especially on our patients with chronic
fibrotic
liver disease, including chronic viral hepatitis.
aUniversity of Massachusetts Medical School, Worcester,
Massachusetts
References <snip>
Reprint requests and correspondence: Herbert L. Bonkovsky, M.D.,
Gastroenterology, Hepatology, and Nutrition, University of
Massachusetts
Medical School, 55 Lake Avenue North, Room S-6-737, Worcester, MA
01655-0002.
Received Sep. 10, 2001; accepted Oct. 5, 2001.
watchman
> Sorry if this is a repost! FWD From CharlesDemastus@topica
> American Journal of Gastroenterology
> that chronic iron reduction is a good alternative to interferon in
> treatment
I was wondering what everyone thinks about this?
Is the fact a person has a 'health plan'.. preventing ones' access to the
'cheapest' and many times more 'effective' treatment?
If this were a 'drug' it would be RUSHED through the drug approval process
and would be 'sold' in a lottery to the highest bidder .. such as in the
last Multiple Sclerosis drug?
Simple bloodletting / iron deprivation .. as effective and NO side
effects?
Can you remember what interferon .. the wonder drug .. USED to 'command'
per dose?
Wouldn't 'chelators' such as phytic acid / Ip6 which 'bind up' .. iron ..
and allows the body to excrete this TOXIC load of iron NOW become a
'recommended' inclusion in Hepatitis treatment?
And since vegetarian diet has been shown to induce what seems to be 'low'
levels of iron.. it too should become a 'recommended' diet?
I believe there should be a 'ground swell' for the approval and inclusion
in ALL treatment of hepatitis.
If WE don't do it .. do you think those who will make 'no money' on this
simple iron deprivation protocol .. will FORCE it through approval and
widespread implementation?
They will have to do further studies .. or simply accept the ones already
done which clearly show .. the heme iron found in meat builds to TOXIC
levels in the body and FEEDS and causes disease.
Man IS .. a herbivore.
Be prepared for people to keep you sick through their 'propoganda' as to
what 'levels' of iron are TOXIC.
As the studies clearly show in a vegetarian the levels of iron found lead
to a forty percent reduction of insulin resistance.
Those levels found in the meat eaters were WELL WITHIN the markers
considered by doctors to be safe.
CLEARLY if the iron levels of a meat eater lead to insulin resistance then
the iron levels considered safe by doctors is ACTUALLY .. killing you?
Who loves ya.
Tom
--
Jesus was a Vegetarian! http://www.nucleus.com/watchman
Moses was a Mystic! http://www.nucleus.com/watchman/light.html