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.