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Anemia

Anemia of chronic disease

Serum iron is often low in patients with chronic conditions. Reduced serum iron, which deprives bacteria of an essential nutrient necessary for growth and replication, is an immune system strategy for defending the body during infection. This maneuver is mediated cytokines such as interleukin1 (IL1). IL1 stimulates the liver to release transferrin and lactoferrin. These compounds bind with iron in the blood and transfer it to the liver, thereby reducing the amount of iron in the blood.

 

Anemia of chronic disease is not due to iron deficiency and will not be helped by iron supplements. In fact, iron supplements are counterproductive because iron will help L-form bacteria multiply.

According to the textbook “An Introduction to Human Disease: Pathology and Pathophysiology Correlations” by Leonard V. Crowley, "Many conditions may depress bone marrow functions. Chronic diseases of all types may impair hematopoiesis [the formation of blood cells] and lead to mild or moderate anemia, which is called the anemia of chronic disease. The most common cause of this type of anemia is chronic infection, but other chronic diseases and some malignant tumors may also be responsible."

Anemia and Inflammation Therapy

It is very common for hemoglobin and hematocrit to dip with Inflammation Therapy (IT). This is caused by at least three mechanisms. One is that herxing can kill affected red blood cells. Another is that Benicar dilates the blood vessels and creates a larger total volume of blood circulating, so the existing blood has to be diluted with serum (mostly water) and that lowers the lab results. The third mechanism is that Benicar can decrease the production of new blood cells somewhat.

Anemia of chronic disease pathogenesis

A number of bacterial pathogens have developed a mechanism for acquiring iron directly from the (human) host in order to hoard iron for their own use (instead of the human's benefit). Bacteria use several mechanisms to successfully compete for available iron in the host, and their increased supply of iron may enhance bacterial pathogenicity.

See Lactoferrin receptors in gram-negative bacteria: insights into the iron acquisition process.

The human body has limited defense mechanisms to limit the availability of iron to bacteria, thus blocking their growth. Once this iron-restricted erythropoiesis and the 'anemia of chronic disease' has developed, iron supplementation is not useful.

Iron transport and anemia are related to cytokines that are produced in inflammatory and infectious diseases, such as Tumor Necrosis Factor alpha and Interferon Gamma. The cytokines associated with Th1/Th17 immune response are sensitive to intracellular iron concentration. The regulation of iron transport by cytokines is a key mechanism in the pathogenesis of anemia of chronic disease.

In sarcoidosis, granulomas sequester ferritin and iron, and the low assay is closely tied to the presence of inflammatory granulomas. Serum ferritin may be high in sarcoidosis, especially if the liver is involved.

One of the potential 'benefits' of the anemia of chronic disease is that bacteria are being starved of the iron essential for their proliferation. When intracellular bacteria are eliminated, iron stores will be available once again.

Hepcidin

The discovery of hepcidin provides a thread that ties together the perplexing triad of decreased serum iron, increased macrophage iron and chronic inflammation. See Hepcidin: Inflammation's Iron Curtain

Diagnosing Anemia

GI bleeding

Anemia is often caused by subclinical gastrointestinal bleeding. A simple outpatient stool test (hemoccult test) should be done to rule out concerns pertaining to bleeding into the gastrointestinal tract.

Fatigue

Fatigue from chronic disease is a common symptom and is often seen in patients without anemia. Fatigue is not usually related to anemia unless the anemia is severe. It usually resolves gradually as Th1 inflammation resolves on IT but it it is often one of the longer-lasting symptoms.

Testing

Hemoglobin, hematocrit and serum ferritin are the most common ways to test for anemia but they do not differentiate between Iron Deficiency Anemia (IDA) and anemia of chronic disease. alt

Normal hemoglobin results vary, but in general are:

  •          Male: 13.8 to 17.2 gm/dL (140-174g/l)
  •          Female: 12.1 to 15.1 gm/dL (123-157g/L)

Hematocrit is a blood test that measures the number of red blood cells and the size of red blood cells. It gives a percentage of red blood cells found in whole blood. Most automated cell counters measure the hemoglobin directly, but the hematocrit is calculated. Generally, therefore, it is probably more reliable to base clinical decisions on the hemoglobin concentration.

Mean corpuscular volume (MCV)

MCV measures the size of the red blood cells. Larger or smaller than normal red blood cells may indicate anemia.
Ref. Range 80 - 97

Mean corpuscular volume is decreased in anemia of chronic disease.

Iron supplements are usually well tolerated by patients, so many doctors don’t bother to definitively diagnose iron deficiency anemia. They use iron supplements as a therapeutic probe and retest Hgb and Hct to see if they are effective. Before agreeing to take an iron supplement, patients should talk with their doctor about further testing.

Identifying iron deficiency anemia versus anemia of chronic disease with the correct lab tests

To identify iron deficiency anemia, hemoglobin must be measured together with more selective measurements of iron status. The following tests are needed for a differential diagnosis:

  • serum ferritin
  • serum iron
  • total iron binding capacity (TIBC; an indirect reflection of the transferrin level)
  • percent transferrin saturation (calculated from the serum iron and the TIBC)
  • soluble transferrin receptor (sTfR)

All of these tests reflect slightly different aspects of internal iron metabolism and give the most complete picture of the iron status of the patient.

Serum ferritin

The ferritin test measures the level of a blood plasma protein that stores iron for later use by the body. Serum ferritin represents the iron stores in the body. Serum ferritin is also an acute phase reactant and will rise rapidly in the face of inflammation. Serum ferritin may be high in anemia of chronic disease, especially if the liver is involved.

However, low serum ferritin does not prove iron deficiency anemia.

Lab ranges for serum ferritin:

Male: 12-300 ng/mL
Female: 12-150 ng/mL

Serum Iron

Iron is closely associated with Th1 immune activity. Macrophages, the Th1 phagocytes, accrete ferritin. Ferrodoxin is also oxidized and reduced when 25-D is converted to 1,25-D.

The iron level test measures the amount of iron in the blood serum that is being carried by a protein (transferrin) in the blood plasma.

Serum iron (60-170 mcg/dl) on its own provides no useful information. Serum iron has a diurnal variation that can be as much as 30% within a single individual; it is sensitive to the day's dietary iron intake and is affected by many confounding diseases. A low serum iron picked up as an incidental finding has a very low specificity for iron deficiency.

Total iron-binding capacity (TIBC) or Unsaturated iron-binding capacity (UIBC)

Total iron binding capacity (TIBC) is a blood test that shows if there is too much or too little iron in the blood. This test helps measure the ability of a protein called transferrin to carry iron in the blood. Normal range 240-450 mcg/dl

TIBC is typically measured along with serum iron to evaluate patients suspected of having either iron deficiency or iron overload. The iron concentration divided by TIBC gives the transferrin saturation, which is a more useful indicator of iron status than iron or TIBC alone.

The TIBC test measures the amount of iron the blood would carry if the transferrin were fully saturated. Since transferrin is produced by the liver, the TIBC can be used to monitor liver function and nutrition.

Transferrin

The transferrin test is a direct measurement of transferrin--which is also called siderophilin--levels in the blood. Some laboratories prefer this measurement to the TIBC. The saturation level of the transferrin can be calculated by dividing the serum iron level by the TIBC.

It is customary to test for transferrin (instead of TIBC) when evaluating a patient's nutritional status or liver function. Because it is made in the liver, transferrin will be low with liver disease. Transferrin levels also drop when there is not enough protein in the diet, so this test can be used to monitor nutrition.

Transferrin saturation

Normal transferrin saturation is 20-50%. As an index of iron transport rather than storage, this measure (calculated from serum iron and TIBC) is an alternative to serum ferritin. However, as it’s affected by the same confounding factors it will not add much additional information regarding iron deficiency if a serum ferritin test has already been ordered. A serum transferrin saturation of >55% can be a very useful indication of possible iron overload. On the other hand, if serum ferritin is elevated but transferrin saturation is low, the patient is unlikely to have iron overload.

Serum (soluble) transferrin receptor

A new test called serum transferrin receptor (sTfR) is a good way to verify anemia of chronic disease because it is not affected by inflammation. sTfR refers to the presence of a cleaved portion of the transferrin receptor present in serum. In a patient with a preexisting inflammatory state, an investigating physician should test for sTfR to identify whether an anemia is an iron deficiency anemia, in which sTfR is elevated, or is due to anemia of chronic disease.

sTfR increases in iron deficiency anemia and is usually unaffected by chronic disease states.

lab testing chart

Iron Deficiency Anemia versus Anemia of Chronic Disease

Anemia of chronic disease and iron deficiency anemia, the most common forms of anemia, are differentiated primarily by estimates of iron status. Standard measures of iron status, such as ferritin, total iron-binding capacity, and serum iron are directly affected by chronic disease.

A new test called serum transferrin receptor (sTfR) is a good way to verify anemia of chronic disease because it is not affected by chronic disease.

The sTfR is elevated in iron deficiency but is not appreciably affected by chronic disease.

In general, to increase sensitivity and specificity, the measurement of sTfR should be performed in combination with other tests of iron status, including ferritin, total iron-binding capacity (TIBC) and serum iron.

AnemiaChart

In summary

Anemia of chronic disease equals:

  • ferritin normal or high
  • iron low
  • normal to low soluble transferrin receptor (sTfR)
  • normal to low total iron-binding capacity (TIBC)

Herxheimer reaction

Inflammation Therapy will treat the underlying disease (bacterial pathogens) and the cytokines associated with infection and inflammation to resolve anemia of chronic disease. During treatment, however, it is expected that anemia might temporarily worsen because of the immune system reaction.

Iron supplements

iron supplementsDon't take iron supplements in an effort to increase hemoglobin and hematocrit unless iron-deficiency anemia has been accurately diagnosed.

Iron is a key nutritional element required for the growth of almost all bacteria. (PMID:17916327 and PMID:11018148) Iron supplements will help intracellular bacteria multiply. Increasing iron in the diet would also be counterproductive.

If iron deficiency anemai is diagnosed and supplementation is advised, frequent retesting is suggested to maintain the serum ferritin level at the bottom of the normal range.

Male: 12-300 ng/mL
Female: 12-150 ng/mL

The struggle for iron - a metal at the host-pathogen interface.
"This review summarizes our current knowledge on the combat of host cells and pathogens for the essential nutrient iron focusing on the immune-regulatory roles of iron on cell-mediated immunity necessary to control intracellular microbes, the host's mechanisms of iron restriction and on the counter-acting iron-acquisition strategies employed by intracellular microbes."