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Findings:       
The authors concluded that long term maintenance of iron depletion by
therapeutic phlebotomy prevents progression of fibrosis in CHC. 

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 

       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.



Subject: hepatitis/bloodletting

   
   Dig Liver Dis 2001 Mar;33(2):157-62
   
Chronic hepatitis C treated with phlebotomy alone: biochemical and histological
outcome.

    Sartori M, Andorno S, Rigamonti C, Boldorini R
    
   Department of Internal Medicine, University of Piemonte Orientale A.
   Avogadro, Ospedale Maggiore della Carita, Novara, Italy.
   sartori@fauser.edu
   
   [Medline record in process]
   
   BACKGROUND: In patients with chronic hepatitis C, the histological
   outcome of long term phlebotomy is unknown. AIM: To investigate
   biochemical and histological findings before and after phlebotomy in
   chronic hepatitis C. PATIENTS: Twenty-four non-haemochromatotic
   patients with chronic hepatitis C were treated with long-term
   phlebotomy alone. RESULTS: Hepatic iron concentration had decreased in
   all patients who underwent a second liver biopsy, two years after iron
   depletion was attained and maintained. Histological grading score
   decreased in four patients, was unchanged in two, and increased in
   five. Histological staging score decreased in two patients, was
   unchanged in five, and increased in four. Pretreatment high serum
   selenium level predicted the reduction of the inflammatory grading
   score in univariate analysis (p=0.008, while low serum aspartate
   aminotransferase (p=0.02) and low propeptide of procollagen III
   (p=0.08) levels predicted the lack of progression of liver fibrosis.
   Furthermore, when iron depletion was reached, significant reductions
   of serum levels of aminotransferase, gamma glutamyl transferase
   (-47%), propeptide of procollagen III, alpha foetoprotein, selenium
   were observed in 24 patients. No changes in serum hepatitis C
   virus-RNA levels were found. CONCLUSIONS: Phlebotomy alone seems to be
   efficacious in suppressing progression of chronic hepatitis C in some
   patients. Phlebotomy not only induces iron depletion, but it even
   modifies serum levels of other trace elements involved in the balance
   between oxidant and antioxidant processes.
   
   PMID: 11346145, UI: 21243511
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Subject: low iron diet/hepatitis

   
   Br J Nutr 2000 Mar;83(3):235-9
   
Beneficial influence of an indigenous low-iron diet on serum indicators of iron
status in patients with chronic liver disease.

    Tandon N, Thakur V, Guptan RK, Sarin SK
    
   Department of Gastroenterology, G.B. Pant Hospital, New Delhi, India.
   
   The main Fe storage organ in the body is the liver. In patients with
   chronic liver disease, secondary Fe overload is common. Phlebotomy,
   often used in the West to reduce Fe overload to improve the efficacy
   of interferon therapy, is not socially acceptable in India. We
   assessed the efficacy of a low-Fe diet in reducing serum Fe levels.
   Nineteen patients with hepatitis B- and C-related chronic liver
   disease, ten with normal (< 25 mumol/l) baseline serum Fe levels
   (group A) and nine with high (> 25 mumol/l) serum Fe levels (group B)
   were included. All the subjects were advised to eat a low-Fe diet. The
   daily Fe intake was reduced approximately 50% by consumption of the
   rice-based diet. Haemoglobin, serum Fe, transferrin saturation index
   (TSI), ferritin and alanine transaminase (EC 2.6.1.2) levels were
   studied at 1 and 4 months. Dietary Fe intake and body weight were
   closely monitored. All patients complied with the dietary regimen and
   at 4 months significant (P < 0.001) reductions from baseline were seen
   in serum Fe (20 (SD 3) v. 12 (SD 4) mumol/l group A; 30 (SD 3) v. 19
   (SD 7) mumol/l group B) and TSI (38 (SD 8) v. 23 (SD 9)% group A; 53
   (SD 15) v. 34 (SD 13)%, group B) in both the groups, albeit earlier in
   group B subjects. Serum ferritin levels, however, reduced only in
   group A (112 (SD 62) v. 43 (SD 25) ng/ml, P < 0.05) and not in group
   B. Non-significant reductions in haemoglobin levels were seen in both
   groups. Alanine transaminase levels reduced significantly (P < 0.05)
   in both the groups (95 (SD 49) v. 44 (SD 25) IU/l, group A; 82 (SD 16)
   v. 51 (SD 14) IU/l group B). Thus, a low-Fe diet results in
   significant reductions in serum Fe and TSI levels, irrespective of
   baseline Fe levels. This diet should be evaluated to improve the
   efficacy of interferon therapy in patients with hepatitis B- and
   C-related chronic liver disease.
   
   PMID: 10884711, UI: 20343090
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Are you aware of some recent studies over the past several years where
patients with chronic hepatitis C (but without Hemochromatosis) have
been treated with phlebotomy to lower their serum ferritin levels to 10
ng/ml at which point they ceased to have any clinical evidence of the
disease?  

This means that the hepatogenic virus requires iron to do its damage,
and below a certain stored iron level, the virus can no longer do it's
damage, so the liver enzymes revert to normal.   
The diagnosis of "autoimmune" hepatitis is suspect anyway.   

People use "autoimmune" when they can't find a reason for the liver
sustaining chronic damage.  This is misleading, as it implies that the
body is attacking itself, which may have nothing whatsoever to do with
it.   As an example, lupus is said by many to be an autoimmune disorder,
but there is virtually no evidence that this is true--they just don't
know what it is and what causes it.  

The fact that there are "anti-DNA antibodies" is not evidence that it is
in fact autoimmune.  Anti-DNA antibodies are found in other conditions
that are not considered autoimmune, and they are a weak, weak
correlation by themselves....

Subject: HEPATITIS/IRON



J Hepatol 22 (3): 268-271 (1995)

Serum aminotransferase levels as an indicator of the
effectiveness of venesection for chronic hepatitis C.

Hayashi H, Takikawa T, Nishimura N, Yano M

Research Laboratory for Development of Medicine, Faculty of
Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan.

BACKGROUND/AIMS: Iron cytotoxicity may play an important role in chronic
hepatitis C. The
effects of venesection suggest that a slight iron overload contributes
to hepatic injury in subjects
infected with hepatitis C virus. A better indication of the efficacy of
venesection was studied in
patients with and without overt iron overloading. METHODS: All 40
patients had chronic hepatitis C
but none had hemochromatosis of a known etiology. A serum ferritin level
of 10 ng/ml or less was
chosen as the treatment goal. A mean blood volume of 2400 +/- 1100 ml
was removed during
treatments lasting 5 +/- 3 months. RESULTS: Treatment significantly
reduced the mean serum levels
of alanine aminotransferase activity from 128 +/- 74 to 63 +/- 28 IU/l
(p < 0.01). The baseline
enzyme activity was highly correlated with reduction in activity after
treatment (r = 0.94, p < 0.01),
but the baseline levels of ferritin and histochemistry for iron showed
poor correlations with the
reduction in enzyme activity (r = 0.63 with p < 0.01 and r = 0.38 with p
< 0.05, respectively).
CONCLUSIONS: Thus, serum levels of aminotransferases were a more
important indicator for
venesection than conventional indices of iron overload, probably because
cytotoxic iron includes
some reactive iron species rather than stored iron alone.





Am J Gastroenterol 89 (7): 986-988 (1994)

Improvement of serum aminotransferase levels after
phlebotomy in patients with chronic active hepatitis C and
excess hepatic iron

Hayashi H, Takikawa T, Nishimura N, Yano M, Isomura T, Sakamoto N

Laboratory for Development of Medicine, School of Pharmacy, Hokuriku
University, Kanazawa,
Japan.

OBJECTIVES: Iron metabolism may be altered in patients with chronic
active hepatitis C. In an
attempt to evaluate whether excess iron contributes to liver injury, we
used phlebotomy for removal
of iron from patients with chronic hepatitis C. METHODS: All 10 patients
had histochemically
detectable iron in the liver and underwent an initial period of weekly
or monthly phlebotomy of 200
or 400 ml. A serum ferritin level of 10 ng/ml or less was chosen as the
endpoint, and maintenance
phlebotomy was performed if the level rebounded. RESULTS: The treatment
reduced mean serum
alanine aminotransferase activity from 152 +/- 49 to 55 +/- 32 IU/L;
this level became normal in five
of the 10 patients. Anti-HCV antibodies could be detected in all
patients throughout the study.
Histologic abnormalities of the liver were unchanged except for
disappearance of iron deposits from
seven of the patients studied. CONCLUSIONS: Our findings suggest that
iron removal may be
beneficial for patients with chronic active hepatitis C and
histochemical iron in the liver.

   
     _________________________________________________________________
   

Subject: hepatitis/bloodletting

   
   Nagoya J Med Sci 57 (3-4): 153-157 (Dec 1994)
   
Biochemical improvement of chronic hepatitis C after gastrointestinal bleeding.

   
   
    Kato S, Arao M, Kuriki J, Tagaya T, Takiya S, Kato K, Takikawa T, Hayashi H
    
   
   
   Department of Medicine, Inazawa City Hospital, Japan.
   
   Although chronic hepatitis C is frequently complicated by iron
   overload, it remains unclear whether iron cytotoxicity is involved in
   the disease process. Five patients with chronic hepatitis C showed
   rapid reduction of serum aminotransferase activity after
   gastrointestinal bleeding. Posthemorrhagic reduction of liver enzyme
   levels lasted for more than one week. Anemia was associated with a
   reduction of serum ferritin concentration. Considering the short
   half-lives of circulating liver enzymes, reduced release of enzymes,
   that is inactivation of cell lysis, is the likely cause of the
   improved biochemical indices. Reactive iron, which is cytotoxic for
   patients infected by HCV, may be rapidly incorporated into hemoglobin
   when erythropoiesis is stimulated. Our observation also suggests that
   intensive iron removal by phlebotomy is a safe, economic treatment for
   patients with chronic hepatitis C.
   
Subject: hepatitis/iron

Factors associated with persistence of hepatitis C viremia identified

WESTPORT, Apr 01 (Reuters Health) - Route and timing of exposure to the
hepatitis C virus appear to affect patients' chances for spontaneous resolution
of viremia.

In the March issue of the American Journal of Gastroenterology, Dr. Patrick G.
Quinn and colleagues at the University of New Mexico School of Medicine in
Albuquerque, New Mexico, report on a study of 44 patients with positive
hepatitis C antibody tests in whom virus was undetectable with polymerase chain
reaction. The researchers compared these patients to 214 controls with
persistent hepatitis C viremia.

On multivariate analysis, "...a history of parenteral exposure and a long time
interval since the most recent exposure were both associated with an increased
likelihood of persistent viremia," the authors said. Monogamy and low serum
ferritin levels appeared to protect against persistent viremia.

Patients with and without persistent viremia were not
different in terms of demographics, concomitant diseases, medical histories,
blood group or risky health or sexual habits, according to the authors.

"[O]ur data support the concept that the route of exposure
and the time when the exposure occurred may be important factors in the
development of persistent [hepatitis C virus] infection," Dr. Quinn's team
concludes.

"They also suggest that host factors, such as iron stores, may
modulate...outcome. A better understanding of the environmental and host
factors in the development of chronic...infection will help us to intervene in
the spread of this epidemic."

                 Am J Gastroenterol 1999;94:668-673.



Subject: iron/hepatitis c/treatment/virus

  (HOME)   Subject: INFO: Iron Reducton Therapy
   [REPRINT 970 EDITORIALS AJG-
   Vol. 89, No. 7,1994]
   
   IRON REDUCTION THERAPY: SIMPLY CAMOUFLAGE, OR A REAL WEAPON?
   
   All organisms require iron for growth and normal metabolic
   functioning.Iron participates in a wide range of biochemical pathways
   that govern cellular metabolism. It is an integral component of
   heme-containing enzymes, such as the cytochromes and the oxygenases,
   and many non-heme-containing enzyme systems such as the iron-sulfur
   clusters of the mitochondrial respiratory chain and ribonucleotide
   reductase (1). Thus,iron plays a key role in oxidation-reduction
   reactions, including those which are essential for cellular
   respiration as well as DNA, RNA, and protein synthesis ( I ).
   
   In addition, there exists a considerable body of data that indicate
   that iron is critical for both immune and non-immune host defense
   mechanisms (2).Specifically, iron and iron-binding proteins play an
   important role in Iymphocyte and natural killer cell (NK)
   proliferation and function, as well as mononuclear cell phagocytic
   activity (2).
   
   Paradoxically, under certain circumstances, iron is also toxic.
   Hepatic iron overload is responsible, at least in part, for the
   hepatic fibrosis and metabolic dysfunction seen in patients with
   hemochromatosis, hemosiderosis, and porphyria cutanea tarda (3). In
   addition, iron is a potent catalyst of oxidative stress: it reacts
   with oxygen to generate hydroxyl free radicals and ferryl radicals
   which are critically involved in the pathogenesis of the tissue injury
   associated with alcohol toxicity, inflammatory reactions in general,
   and ischemia/reperfusion. For all of these reasons, organisms highly
   regulate iron absorption, transport, and storage in such a way as to
   enable critical metabolic needs to be met while maintaining the risk
   of iron toxicity at minimal levels (4, 5).
   
   Over the last two decades, considerable data have accumulated that
   suggest that a pathogenetic link exists between iron content of the
   liver and hepatitis B virus (HBV) and, more recently, hepatitis C
   virus (HCV) infection of the liver. It has been known for many years
   that individuals with an elevated serum iron or ferritin level are
   more likely than those with normal or low levels of these two markers
   of iron metabolism to become chronic carriers of the hepatitis B virus
   (6-8). The same situation appears to apply for hepatitis C. Thus, a
   greater prevalence of HBV and HCV infections has been found in
   pathological conditions associated with hepatic iron overload, such as
   genetic hemochromatosis, porphyria cutanea tarda, and hemosiderosis
   due to thalassemia (9-11). However, it remains controversial as to
   whether or not chronic viral hepatitis is associated with an elevated
   iron content in the liver (12, 13).
   
   In the last 2 yr, several preliminary reports indicate that the
   therapy of chronic hepatitis C can be influenced by the amount of iron
   present within the liver ( 14-16). In addition, in a study that has
   been published in the Journal of Hepatology, the response to
   cY-lnterferon (IFN) therapy appears to deteriorate from a full
   response through a partial response to a nonresponse as the hepatic
   iron content increases (17). The pathogenetic relationship between the
   iron content of the liver and hepatitis C is further substantiated by
   several additional reports showing that the rate of response to IFN
   increases with the use of iron depletion therapy. Two preliminary
   studies suggest that the combination of IFN and phlebotomy treatment
   to induce iron deficiency produces remissions in patients who
   previously have failed IFN treatment alone (18, 19). Equally
   intriguing is the observation (20) that
   treatment of patients with chronic hepatitis C combined with a low
   iron diet increases the rate at which clinical and biochemical
   remissions of chronic hepatitis associated with hepatitis C occurs in
   Indian patients. Moreover, the study by Hayashi et a/. (21), reported
   in the present issue of the American Journal of Gastroenterology,
   shows that treatment with phlebotomy per se, without IFN, induces a
   significant improvement in serum aminotransferase levels in patients
   with chronic active hepatitis associated with hepatitis C (21).
   
   All of these clinical findings strongly suggest the presence of a
   pathogenetic link between the hepatic iron content and the ability of
   hepatotropic viruses to both persist in liver tissue and enhance the
   mechanisms responsible for liver cell injury. However, it is unclear
   whether the hepatotropic viruses are responsible for the increase in
   hepatic iron deposition or whether the increase in hepatic iron
   content facilitates viral replication and, as a result, chronic
   infection. The latter possibility appears more likely to us.
   Specifically, iron overload may enhance viral replication and, in
   addition,impair the host's cellular immune responses required for
   viral clearance. The rate of viral replication within infected cells
   may be related, at least in part, to the availability of iron within
   the cell. Hepatotropic
   viruses,having once infected the liver cell, capture the metabolic
   machinery of the cell and use it for their own purpose, viral
   replication. Specifically, they utilize both the protein and
   nucleotide synthetic mechanisms of the cell to enable viral
   replication to occur.
   
   Because iron is an essential co-factor for DNA, RNA, and protein
   synthesis, the hepatic pool of metabolically active cytosolic iron
   that is essential for these processes must be captured by the virus in
   its drive to replicate. The ability to obtain iron from the host to
   enable enhanced replication is well-established for bacteria, and
   probably exists also for viruses (22-24).
   
   Should enhanced viral replication alone not be sufficient to sustain
   hepatic viral infection in patients with hepatic iron overload
   conditions, the increases in cellular iron that impair host cellular
   defense mechanisms against virus-infected cells would serve to
   accomplish the same goal. Indeed, the ability of T-lymphocytes to
   undergo maturational changes and proliferation varies, at least in
   part, as a function of the local iron concentration (2). Moreover an
   increase in the cytosolic free iron down-regulates the cell surface
   expression of the transferrin receptor in virus-infected cells, a
   finding that correlates with their susceptibility to NK cell Iysis
   (22). These two phenomena, either acting alone or in combination,
   probably explain the increased rate of HBV and HCV carriage in
   patients with hemochromatosis, thalassemia, and porphyna cutanea tarda
   (9-11). Were this not enough, iron is also involved in the
   pathogenesis of the tissue injury
   associated with the inflammatory processes caused by the presence of
   the infecting pathogen. Iron catalyzes a number of biochemical
   reactions leading to the generation of highly toxic free radicals that
   produce cellular damage and further amplify the inflammatory process
   (5).
   
   Recently, the serum levels and the hepatic content of thiobarbitunc
   acid-reacting substances, a marker of oxidative injury in tissue, have
   been found to be increased significantly in the liver and serum of
   hepatitis C patients (24,25).  Moreover, patients with hepatitis C who
   respond to Interferon therapy experience a normalization of their
   serum thiobarbitunc acid-reacting of  cell culture systems latently
   infected with the HIV-I virus to oxygen-free radicals enhances viral
   replication, whereas anti-oxidants such as vitamin
   C and glutathione suppress viral replication (26-29).
   
   Taken together, these observations suggest that the untoward
   consequences  of excess hepatic iron in patients with viral liver
   disease appear to I)  enhance viral replication, 2) reduce
   host-cellular defense mechanisms directed at viral clearance, and 3)
   enhance the oxidative injury associated with hepatitis C inflammatory
   response. These data also suggest that a reduction in hepatic iron
   stores by phlebotomy may be an effective way to enhance the response
   rate achieved with currently available agents used to treat viral
   hepatitis.
   Specifically,the addition of iron-reduction therapy to cz-interferon,
   either alone or with other agents such as cytokines (GCSF, GM-CSF),
   antivirals (acyclovir, ganciclovir, ribavinn), or an NSAID
   (indomethacin), should only enhance the common desired effect of such
   therapies, namely, viral clearance.
   Paolo Caraceni, M.D.
   Stefano Fagiuoli, M.D.
   David H. Van Thiel, M.D.
   Oklahoma Transplant Institute
   Baptist Medical Center of Oklahoma Oklahoma City, OK
 

Subject: hepatocellular carcinoma

   
   J Gastroenterol Hepatol 2001 May;16(5):491-4
   
Iron and hepatocellular carcinoma.

    Deugnier Y, Turlin B
    
   *Clinique des Maladies du Foie,Laboratoire d'Anatomie Pathologie B
   and*,Institut National de la Sante et de la Recherche Medicale, Unite
   522, Hopital Pontchaillou, Rennes, France.
   
   [Medline record in process]
   
   The high prevalence of hepatocellular carcinoma (HCC) in genetic
   hemochromatosis (GH) and the association between increased body iron
   stores and occurrence of HCC in subjects with iron overload unrelated
   to GH, and the experimental evidence of a co-carcinogenic role of iron
   strongly support that iron is involved in the development of HCC.
   
   PMID: 11350542, UI: 21248950
     ____________________________________________________________

Subject: Iron and bacteria


    ______________

  

   J Clin Invest 61: 1428-40 (1978)[78194498]

The critical role of iron in host-bacterial interactions.



    S. M. Payne & R. A. Finkelstein



   The ability of potential pathogens to acquire iron in a host is an
   important determinant of both their virulence and the nature of the
   infection produced. Virulent gram-negative bacteria are capable of
   acquiring sufficient iron from the host because their virulence (for
   chick embryos) is unaffected by exogenous iron. Avirulent mutants
   which are apparently limited in their ability to acquire iron could be
   isolated from the virulent strains. The lethality of these mutants was
   significantly enhanced by exogenous iron. Reduction of the relatively
   high serum iron saturation of chick embryos (to levels more closely
   approximating those in man) by pretreatment with iron-binding proteins
   or endotoxin inhibits the lethality of some virulent bacteria. Those
   bacteria whose virulence was reduced include the Shigella, Vibrio
   cholerae and strains of Neisseria gonorrhoeae, all of which are
   nondisseminating pathogens in the normal human host. Pathogens which
   produce septicemic and disseminating infections such as Neisseria
   meningitidis, Haemophilus influenzae type B, Escherichia coli
   possessing K-1 antigen, Pseudomonas aeruginosa and Salmonella
   typhimurium and disseminating strains of N. gonorrhoeae were, in
   general, unaffected by reduced serum iron saturation. These
   disseminating bacteria appeared to produce greater quantities of
   compounds (siderophores) which stimulated microbial growth in low-iron
   media than did the nondisseminating pathogens. Thus, the gram-negative
   bacteria tested can be divided into four major classes according to
   their responses to modifications in iron levels in the chick embryo
   model and these results correlate with the nature of the infections
   which they typically produce in man.

   MeSH Terms:
     * Animal
     * Bacteria/drug effects
     * Bacteria/metabolism
     * Bacteria/pathogenicity
     * Bacterial Infections/immunology
     * Bacterial Infections/metabolism
     * Chick Embryo
     * Conalbumin/pharmacology
     * Iron/metabolism
     * Iron/pharmacology
     * Iron Chelates/metabolism
     * Support, U.S. Gov't, P.H.S.


     _________________________________________________________________

Subject: iron and immune

   
   Ann Clin Lab Sci 2000 Oct;30(4):354-65
   
Effects of iron overload on the immune system.

    Walker EM Jr, Walker SM
    
   Department of Pathology, Marshall University and Huntington DVA
   Medical Center, West Virginia, 25704, USA. walkere@marshall.edu
   
   [Medline record in process]
   
   Iron and its binding proteins have immunoregulatory properties, and
   shifting of immunoregulatory balances by iron excess or deficiency may
   produce severe, deleterious physiological effects. Effects of iron
   overload include decreased antibody-mediated and mitogen-stimulated
   phagocytosis by monocytes and macrophages, alterations in T-lymphocyte
   subsets, and modification of lymphocyte distribution in different
   compartments of the immune system. The importance of iron in
   regulating the expression of T-lymphocyte cell surface markers,
   influencing the expansion of different T-cell subsets, and affecting
   immune cell functions can be demonstrated in vitro and in vivo. The
   poor ability of lymphocytes to sequester excess iron in ferritin may
   help to explain the immune system abnormalities in iron-overloaded
   patients. Iron overload as seen in hereditary hemochromatosis patients
   enhances suppressor T-cell (CD8) numbers and activity, decreases the
   proliferative capacity, numbers, and activity of helper T cells (CD4)
   with increases in CD8/CD4 ratios, impairs the generation of cytotoxic
   T cells, and alters immunoglobulin secretion when compared to treated
   hereditary hemochromatosis patients or controls. A correlation has
   recently been found between low CD8+ lymphocyte numbers, liver damage
   associated with HCV positivity, and severity of iron overload in
   beta-thalassemia major patients. Iron overload, with its associated
   increases of serum iron levels and transferrin saturation, may cause a
   poor response to interferon therapy. Iron overload with hyperferremia
   is associated with suppressed functions of the complement system
   (classic or alternative types). High plasma ferritin content in
   patients with chronic, diffuse diseases of the liver (cirrhosis,
   chronic hepatitis), beta-thalassemia major, dyserythropoiesis, and
   hereditary hemochromatosis may induce the development of anti-ferritin
   antibodies with the production of circulating immune complexes.
   Increased body stores of iron in various clinical situations may tip
   the immunoregulatory balance unfavorably to allow increased growth
   rates of cancer cells and infectious organisms, and complicate the
   clinical management of preexisting acute and chronic diseases.
   
   PMID: 11045759, UI: 20498458
     _________________________________________________________________
   
     _________________________________________________________________


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