RESEARCH - Hepcidin mediates anemia of chronic disease - reason iron supplements won't help

[Guest guest]

Hepcidin mediates " anemia of chronic disease " and is reason iron

supplements won't help

Rheumawire

Dec 2, 2004

Janis

New Orleans, LA - The small peptide hepcidin is the link between chronic

inflammation, increased macrophage iron, and decreased serum iron, the

familiar constellation known as anemia of chronic disease. Drs Hugh

McGrath Jr and PG Rigby (Louisiana State Health Sciences Center, New

Orleans) write in an editorial in the November 2004 issue of

Rheumatology that hepcidin appears to be the reason that iron depletion

to the verge of anemia reduces attacks of gouty arthritis and that

intramuscular iron injections can induce acute flares of joint

inflammation in rheumatoid arthritis (RA) [1].

" The importance of recognizing that iron is phlogistic, ie,

proinflammatory, is that such recognition helps us to understand that in

giving iron to patients with inflammatory joint disease, we supply the

means for increasing the inflammation, " McGrath tells rheumawire. " When

we give iron, we supply the macrophage, the cell making up much of the

diseased proliferating synovium, with the means to do damage to bone and

cartilage. That's because giving iron increases hepcidin, which

increases the sequestration of iron in the macrophage, where iron

facilitates the Fenton reaction, resulting in the production of toxic

oxygen radicals. These toxic oxygen radicals increase the capacity of

the macrophage to damage cartilage and bone. Unless patients are truly

iron deficient, we probably should not be giving iron to them at all. "

The inflammation-hepcidin-iron relationship appears to be a part of the

body's attempt to fend off microbial infection. Drs Elizabeta Nemeth,

Tomas Ganz, and colleagues recently reported that reduced blood iron

levels during infection or inflammation are due to induction of hepcidin

production in response to the proinflammatory cytokine interleukin-6

(IL-6) [2]. Hepcidin increases iron by locking it up in macrophages that

degrade old erythrocytes and would normally return recycled iron to the

circulation. Hepcidin also impairs intestinal iron absorption. The

resulting decrease in circulating iron appears to be an attempt to

defend against infection, denying invading organisms the iron they need

for growth.

" The discovery of hepcidin answered an age-old vexing problem for

rheumatologists. Patients with rheumatoid arthritis or other chronic

inflammatory diseases develop an anemia that looks like iron-deficiency

anemia but does not respond to iron. It is an anemia that has been known

for a century. It was originally designated the anemia of infection.

After chronic infection was eliminated with antibiotics and

rheumatologic diseases percolated to the top of those with unexplained

anemia, it became the anemia of chronic disease. Now that we know it is

inflammation and not chronic disease that begets this anemia, it is

called the anemia of inflammation, " McGrath says.

Infections and inflammatory diseases such as RA are the second leading

cause of anemia worldwide, and anemia is a particular concern in

juvenile RA. McGrath notes that hepcidin is not only the iron-regulatory

hormone responsible for the anemia of chronic disease but is also an

acute-phase reactant that responds to infection and inflammation.

" Although there may be plenty of iron in the body, it is unavailable for

the production of red blood cells, so patients develop iron-deficiency

anemia, " McGrath says. " When physicians check for iron loss or for poor

iron intake, there is none. They may then check the bone marrow and find

plenty of iron. Despite this, many physicians will go ahead and give

iron, believing that it can do no harm. I believe it can. "

Two previous lines of research also suggested that iron contributes to

inflammatory joint diseases. Facchini found that using serial

phlebotomies to reduce body iron to the lowest level compatible with

normal erythropoiesis (and thereby avoiding anemia) decreased flares of

gout [3]. " This is consistent with an inflammatory role of iron, "

McGrath says.

Conversely, Blake et al found that giving intramuscular iron injections

increased joint inflammation in patients with rheumatoid arthritis [4].

" Some will object that hemochromatosis, a disease in which the body is

oversaturated with iron, does not lead to inflammatory arthritis. This

is because, surprisingly, there is a macrophage block in

hemochromatosismacrophages are depleted of iron. In fact,

hemochromatosis has been postulated to protect from tuberculosis. The

tuberculosis organism lives in the macrophage and without iron cannot

survive, " McGrath says.

McGrath says that a hepcidin inhibitor might be useful in rheumatoid

arthritis by eliminating anemia and energy deficits related to iron

deficiency but emphasizes that this is a highly speculative idea.

Sources

McGrath H, Rigby PG. Hepcidin: inflammation's iron

curtain (editorial). Rheumatology 2003; 43:1323-1325.

Nemeth E, S, Gabayan V, et al. IL-6 mediates

hypoferremia of inflammation by inducing the synthesis of the iron

regulatory hormone hepcidin. J Clin Invest 2004; 113:1271-1276.

Facchini FS. Near-iron deficiency-induced remission of

gouty arthritis. Rheumatology 2003; 42:1550-1555.

Blake DR, Gallagher PJ, Potter AR, et al. The effect

of synovial iron on the progression of rheumatoid disease. Arthritis

Rheum 1984; 27:495-501.

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org