ANEMIA OF CHRONIC DISEASE
LEARN HOW IT AFFECTS YOU
ABOUT TOO LITTLE IRON
Iron deficiency with and without anemia are a key focus areas for Iron Disorders Institute.
Anemia of Chronic Disease
Anemia of chronic disease (ACD) is also referred to as anemia of inflammatory response. Although ACD can accompany life-threatening illness, anemia of inflammatory response is in fact a protective and natural mechanism that the human body uses to limit the amount of iron available when potentially harmful things get into our body. All living things, including bacteria and cancer cells, which are living things, depend upon iron to sustain life just like humans and plants do. This system was described by Eugene Weinberg, Ph.D., Indiana University in the early 1980’s.
When the body senses a potential threat, iron gets shuttled to ferritin to be contained so that the harmful invader cannot get to the iron. Just enough iron is made available to make red blood cells but no surplus is left to nourish harmful pathogens. Depending on the underlying cause of disease, a person with ACD will experience a modest decline in hemoglobin. This will take place over time following the onset of inflammation due to the presence of the infection or disease. Hemoglobin values will generally reach a low normal range of 9.5–10.5 g/dL and remain there within this moderately low range until the underlying condition is cured. If disease that results in blood loss is present, the person will develop iron deficiency anemia (IDA). ACD and IDA can be distinguished with a serum ferritin test.
Taking iron pills for anemia of chronic disease could be harmful, even fatal.
The exact mechanism of ACD is not fully understood. Dr. Eugene Weinberg, Professor of Microbiology Indiana University and Iron Disorders Institute Medical & Scientific Advisory Board Member, is an expert in anemia of chronic disease. Since the mid 1950s Weinberg has been aware of the body’s alteration of iron metabolism during disease. He first defined the Iron Withholding Defense System in the early 1980’s where he described how the human body recognizes iron as a potential hazard to health. Iron is one metal that cannot be excreted by the body efficiently; so, extra precautions are taken by humans to avoid absorbing too much iron. When a harmful germ invades the body, the immune system team of white blood cells charge to the site to destroy the pathogen before it has time to multiply. Inflammation results as a part of this natural immune response. Inflammation triggers the release of chemicals that signal the iron regulation mechanism to adopt a defense mode.
What physicians see when the iron withholding defense system is activated is a mild drop in hemoglobin. However, what many physicians miss is that less iron is being absorbed and extra free iron is being collected by macrophages and stored in liver cells (hepatocytes). As a result serum ferritin rises. Anemia of chronic disease is not progressive. Hemoglobin values may remain in a slightly low range, but the levels can drop to as low as 7.0 g/dL depending on the severity of the inflammation and the length of time present. Other tests such as serum ferritin or C-reactive protein (CRP) can be performed to help differentiate between iron-deficiency anemia, where oral iron can be beneficial and anemia of chronic disease, where oral iron should not be given.
In a U.S. Department of Agriculture study, investigators illustrate the Iron Withholding Defense System at work. Drs. Fariba Roughead and Janet Hunt of the USDA Grand Forks Human Nutrition Research Center conducted a study of the effects of iron supplements on the body’s control of iron absorption. In a randomized, placebo-controlled trial, heme and nonheme iron absorption by healthy men and women were measured from a test meal containing a hamburger, potatoes, and milkshake. These absorption measurements were made before and after a period of twelve weeks when the 57 participants were given 50 milligrams of supplemental iron or placebo daily while they consumed their usual diets.
Serum ferritin and fecal ferritin were measured during supplementation and for a period of 6 months after supplementation was discontinued. Volunteers who took iron supplements, even those with initial ferritin less than 21 ng/mL, adapted to absorb less nonheme iron, but not less heme iron from meat.
Daily iron supplements caused these volunteers to absorb 36 percent less nonheme iron and 25 percent less total iron from food, and to have higher iron stores than those in the placebo group. The higher ferritin persisted for 6 months post supplementation, except in individuals who had low iron stores at the beginning of the study. Since iron stores were greater after iron supplementation, Drs. Roughead and Hunt’s study demonstrated that adaptation in absorption did not completely prevent differences in body iron stores.
The adaptation to reduce iron absorption even in volunteers with low iron stores may indicate a localized control system to prevent excessive iron exposure of intestinal cells. The study is consistent with two systems at work, one that regulates how much iron we must absorb for normal function, and the iron withholding defense system, which protects us from nurturing harmful pathogens with excesses of iron we don’t presently need.
In adults, anemia of chronic disease is likely due to some common ailment such as urinary tract infection, a head or chest cold, mononucleosis, tonsillitis or strep, stomach or intestinal flu, and bacterial infections such as H. pylori. ACD can also occur when an autoimmune disease is present. Most of these conditions are treatable and when the patient is cured, the anemia will be corrected. If the anemia persists once an illness is cured, the doctor will want to investigate further for a secondary underlying cause of anemia that may be more serious such as kidney disease, tumor, or cancer.
Anemia of chronic disease can be an indicator that a serious life-threatening condition is in the initial stages of development. However, when disease advances beyond this mild form of anemia, where treatment of the underlying condition cannot affect a cure, levels such as serum ferritin and transferrin iron saturation percentage change. For this reason, persons who have experienced anemia of chronic disease, where suspected underlying conditions have been addressed but the anemia persists, further investigation is needed. Blood loss, kidney function, bone marrow function, cancer, abnormal absorption or chronic hemolysis could be pursued as causes.
Anemia of chronic disease can also be present even when tissues have excessive levels of iron. Tissue iron is different from functional iron in hemoglobin. Persons with hereditary hemochromatosis can have excessively high tissue iron but develop anemia because of iron damage to the kidney, anterior pituitary, or bone marrow. The damaged kidney produces less erythropoietin, a hormone vital to red blood cell production (erythropoiesis). An inflamed or damaged anterior pituitary can result in hypothyroidism, which causes diminished erythropoiesis and mild anemia. The bone marrow is the site of red blood cell formation.
Differentiating between anemia of chronic disease and iron-deficiency anemia
Patients with anemia of chronic disease do not generally have hemoglobin values below 9.5 g/dL, although levels can go much lower. Iron-deficiency anemia is often suspected in patients with anemia of chronic disease because the two conditions have many similarities. In both conditions, the serum iron level is low. Small or microcytic cells can be present in either disorder, though this type of cell is more indicative of true iron deficiency. Transferrin, a protein that transports iron, is elevated in iron-deficiency anemia, indicating that the body needs more iron. The total iron-binding capacity (TIBC), an indirect measurement of transferrin, is low in anemia of chronic disease because there is ample iron, but it is not easily available. TIBC tends to be increased when iron stores are diminished and decreased when they are elevated. In iron-deficiency anemia, the TIBC is higher than 400–450 mcg/dL because stores are low. In anemia of chronic disease, the TIBC is usually below normal because the iron stores are elevated.
In nearly two-thirds of the patients, the serum ferritin is one test that can be used to distinguish between anemia of chronic disease and iron-deficiency anemia. Ferritin is an acute-phase reactant, which means that it can be elevated in the presence of inflammation and this factor must be taken into consideration when examining the findings. Serum ferritin can be raised to normal levels even in the presence of iron deficiency. For this reason, difficulties arise in distinguishing iron deficiency in a patient with inflammation or infection from the anemia of chronic disease. Tests for inflammation like CRP are not helpful in this case. For some cases in which both iron deficiency and anemia of chronic disease are possible, bone marrow aspiration with iron staining is the traditional means of determining that a person is iron deficient. However the serum transferrin receptor test can be used to help differentiate between iron-deficiency anemia and anemia of chronic disease. The serum transferrin receptor is much less affected by inflammation than serum ferritin; results will be high in iron-deficiency anemia and usually low to low-normal in anemia of chronic disease. The ratio of the serum transferrin receptor to the logarithm of the serum ferritin concentration is better able to distinguish anemia of chronic disease from iron deficiency than is either test alone.
The greatest risk for harm is mistaking anemia of chronic disease for iron-deficiency anemia and allowing the patient to take iron pills. This risk can be reduced or eliminated by differentiating between to the two iron disorders with serum ferritin test and by informing the patient about the differences in these two iron disorders.
There is no treatment for anemia of chronic disease except to address the underlying condition. Iron supplementation is inappropriate in these patients because the added iron can become free to nourish bacteria and cancer cells.
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