Key Point

Hepcidin is a peptide that affects iron transport and absorption during acute inflammation. Its role in the pathogenesis of anemia of inflammation is currently being investigated.

MONTREAL—Anemia of inflammation is almost impossible to avoid in the ICU, and it develops very quickly in most critically ill patients. "Iron disturbances take place within hours of onset of critical illness," said Seth Rivera, MD, Clinical Instructor of Medicine at the David Geffen School of Medicine at the University of California at Los Angeles. Hypoferremia—low serum iron—is the defining feature of anemia of inflammation. Anemia of inflammation is also characterized by high ferritin levels and maintenance of iron stores in organs. At the annual meeting of the American College of Chest Physicians, Dr. Rivera presented his latest findings on this type of anemia.¹

"I think that anemia of inflammation and hypoferremia evolved as a genetic response to infection," said Dr. Rivera. "We’re in a constant fight with bacteria over iron—iron is very hard for bacteria to obtain in the bloodstream. By sequestering it in the organs, it becomes even harder."

HEPCIDIN—MORE THAN ANTIMICROBIAL

One key player in anemia of inflammation is hepcidin, an antimicrobial peptide. It was discovered, in part, when French researchers accidentally knocked out the hepcidin gene in a group of mice. These mice then developed severe iron overload and did not develop anemia of inflammation. Additionally, when hepcidin was overexpressed, mouse fetuses died in utero because they had no iron in their blood.²

Dr. Rivera and his coworkers studied patients with a diagnosis of acute sepsis who had developed anemia of inflammation. In these patients, hepcidin levels increased more than 1,000-fold from their baseline levels. However, in patients with chronic infection—as opposed to acute infection—hepcidin levels actually decrease slightly.

"In mice, a single dose of hepcidin causes a very rapid fall in serum iron (to about 20% of its starting value), which persists for quite some time," Dr. Rivera noted. This effect is specific to hepcidin.

Thus, hepcidin may not be the cause of anemia of inflammation, but it is one cause, maintained Dr. Rivera. Using radiolabeled hepcidin, he and his colleagues were able to track it to three organs—the liver, spleen, and duodenum. These organs are important for iron import and storage because the only iron exporter—ferroportin—is enriched only in the liver, spleen, and duodenum.

How does hepcidin promote anemia of inflammation? "When you have some sort of stimulation of hepatocytes, they make more hepcidin, which causes internalization and destruction of ferroportin, stopping any further absorption of iron," Dr. Rivera explained. "You get iron accumulation in the duodenal cells, which are then shed; you aren’t allowed to recycle iron from blood, and as blood ages, the iron gets trapped there. Anemia of inflammation can be defined as inappropriate retention of iron in the setting of anemia."

IL-6 UP-REGULATES HEPCIDIN

In an attempt to link hepcidin to inflammation, Dr. Rivera used the proinflammatory cytokine interleukin-6 (IL-6) to see if it resulted in increased hepcidin levels. After infusion of IL-6 in human volunteers, hepcidin levels increased while iron saturation decreased. This showed that IL-6 was sufficient to up-regulate hepcidin.

Mice with the IL-6 knockout showed no hepcidin up-regulation. In fact, in a turpentine model of inflammation, IL-6 increased dramatically in wild-type mice, but it decreased in the knockout mice. Likewise, in wild-type mice, hypoferremia developed, but in the knockout mice, it did not.

Surprisingly though, in another experiment using a chronic peritonitis model, both wild-type and IL-6–knockout mice developed anemia of inflammation. The researchers were not expecting to see anemia develop in the IL-6–knockout mice. "Apparently, for acute infection, IL-6 is necessary for up-regulation of hepcidin, but chronically, it is not," concluded Dr. Rivera.

Anemia of inflammation is a complicated syndrome, said Dr. Rivera. "We still need a hepcidin-knockout mouse. Once we have that, we’ll be able to prove whether hepcidin is necessary for anemia of inflammation."

—Gale Jurasek

Reference
1. Rivera S. Hepcidin is the principle mediator of anemia of inflammation. Presented at: annual meeting of the American College of Chest Physicians; October 31, 2005; Montreal, Quebec.
2. Nicolas G, Bennoun M, Devaux I, et al. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc Natl Acad Sci U S A. 2001;98:8780-8785.

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