Chronic anemia also called the anemia of inflammation, is a condition that can be associated with many different underlying disorders including chronic illnesses such as cancer, certain infections, and autoimmune and inflammatory diseases such as rheumatoid arthritis or lupus. Anemia can be defined as a reduction in hemoglobin (less than 13.5 g/dL in men; less than 12.0 g/dL in women) or hematocrit (less than 41.0% in men; less than 36.0% in women) or red blood cell (RBC) count. Anemia is characterized by low levels of circulating red blood cells or hemoglobin, the part of red blood cells that carries oxygen. Anemia of chronic disease is usually a mild or moderate condition. In mild cases, anemia may not be associated with any symptoms or may cause fatigue, paleness of the skin (pallor), and lightheadedness. The underlying mechanisms that cause anemia of chronic disease are complex and not fully understood.
Causes
The exact cause of anemia in chronic disease may vary. Usually, several processes are occurring concurrently. Anemia can be caused by a slight shortening of normal red blood cell survival. In addition, the production of red blood cells (erythropoiesis) or erythropoietin (a hormone that stimulates red blood cell production) may be impaired. Red blood cells carry oxygen to the body. The exact cause of anemia in chronic disease may depend upon the underlying condition. For example, cancer cells may secrete certain substances that damage or destroy immature red blood cells. In some cases, cancer cells or infectious diseases may infiltrate the bone marrow, the soft spongy material found in long bones where blood cells are formed.
Researchers have also learned that individuals with anemia or chronic disease also have an imbalance in the distribution of iron in the body and as a result, cannot effectively use iron to create new blood cells despite having sufficient or elevated levels of iron stored in the tissues. Iron is a critical mineral that is found in all cells of the body and is essential for the body to function and grow properly. Iron is found in many types of food including red meat, poultry, eggs, and vegetables. Iron levels must remain in a specific range within the body, otherwise, they can cause anemia (due to low functional iron levels) or damage to affected organs (due to abnormally high iron levels in certain tissues).
Iron is needed to produce hemoglobin, the part of a red blood cell that carries oxygen. A key finding in anemia of chronic disease is increased uptake and retention of iron within certain cells, which leads to reduced amounts of functional iron that is available for the production of hemoglobin. The lack of functional iron hinders the development of hemoglobin, which, in turn, reduces the amount of oxygen delivered throughout the body (anemia).
Researchers believe that the immune system, which remains constantly active in individuals with chronic diseases, produces substances that influence the development, storage, and transport of iron within the body. Cells in the immune system produce cytokines, specialized proteins that stimulate or inhibit the function of other immune system cells.
Hepcidin, a hormone produced in the liver that helps regulate the metabolism and transport of iron within the body, plays a significant role in the development of anemia of chronic disease. Researchers believe a specific cytokine known as interleukin-6 (IL-6) stimulates the production of hepcidin in most cases, although hepcidin can also be produced in response to inflammation by pathways that do not involve IL-6. Excess hepcidin causes too much iron to be trapped within cells, lowering the amount of iron available to produce hemoglobin, thereby resulting in anemia. Most researchers believe that hepcidin is a key factor influencing the development of anemia of chronic disease.
The etiology of chronic anemia is based on mean corpuscular volume (MCV). MCV is the average size of RBC.
Microcytic anemia (MCV less than 80 femtoliters [fL])
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Iron deficiency anemia: Most common cause of anemia
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Thalassemia
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Anemia of chronic disease
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Sideroblastic anemia
Macrocytic Anemia (MCV greater than 100 fL)
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Vitamin B12 and folic acid deficiency
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Alcoholism and liver disease
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Myelodysplastic syndromes
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Drug-induced
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Hypothyroidism
Normocytic anemia (MCV 80 to 100 fL)
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Bone marrow suppression (aplastic anemia and myelophthisic anemia)
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Anemia of chronic disease
Hemolytic anemia
Hemolytic anemia may be due to hemolytic uremic syndrome, sickle cell, mechanical heart valves, disseminated intravascular coagulation, cold hemoglobinuria, and cold agglutinin disease. Some conditions can present in more than one classification. For example, early iron deficiency can be normocytic. Anemia of chronic disease is mostly normocytic but can be microcytic too. Hemolytic anemia can cause either macrocytic or normocytic anemia.[rx]
Red blood cells are produced in bone marrow with the help of nutrients (iron, B12, folic acid), cytokines, erythroid-specific GF, and EPO (erythropoietin, produced by kidneys). Once RBCs are released into the blood, they have a lifespan of about 110 to 120 days. Approximately 1% of RBCs are removed every day from the circulation. Under normal conditions, there is a balance between the number of RBCs released into circulation by the bone marrow to the number removed from circulation. The imbalance of production and release by the bone marrow to loss of RBC leads to anemia as below.
Decreased Red Blood Cell Production
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Lack of nutrients (malnutrition and malabsorption)
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Bone marrow problems (suppression and lack of RBC precursors)
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Lack of hormones (CKD, hypothyroidism)
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Ineffective erythropoiesis (defective RBC production)
Increased Red Blood Cell Destruction (Hemolytic Anemia)
Inherited hemolytic anemia
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Sickle cell anemia
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Thalassemia
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Hereditary spherocytosis and elliptocytosis
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G6PD deficiency
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Pyruvate kinase deficiency
Acquired hemolytic anemia
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Immune hemolytic anemia
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Mechanical hemolytic anemia
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Paroxysmal nocturnal hemoglobinuria
Blood Loss
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Gastrointestinal
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Menstrual cycles (menorrhagia)
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Surgery
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Trauma
Diagnosis
A diagnosis of anemia of chronic disease is made based upon the identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests. Such tests can measure the levels of certain substances in the body including hemoglobin levels, the levels of iron in the serum, total iron-binding capacity, overall red blood cell count, or normal or increased levels of ferritin in the blood. Ferritin is a protein that binds to iron and is used as an indicator of the body’s iron stores in the blood plasma. Another test that may be performed measures transferrin saturation. Transferrin is a protein that is involved in the transport of iron from the intestines into the bloodstream. Methods to allow the reliable measurement of hepcidin in plasma have been developed but are not available or approved for use in the diagnosis of anemia of chronic disease at present.
A detailed history should include medical history, home medications, alcohol use, and family history. Ethnicity and country of origin are also helpful.
Some important questions to obtain in a history:
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Obvious bleeding- per rectum or heavy menstrual bleeding, black tarry stools, hemorrhoids
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Thorough dietary history
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Consumption of nonfood substances
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Bulky or fatty stools with foul odor to suggest malabsorption
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Thorough surgical history, with a concentration on abdominal and gastric surgeries
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Family history of hemoglobinopathies, cancer, bleeding disorders
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Careful attention to the medications taken daily
Important examination findings include:
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Pallor
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Jaundice
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Tachycardia
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Tachypnea
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Orthostatic hypotension and
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Other findings relevant to underlying etiology
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Abdominal exam:
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Splenomegaly: hemolysis, lymphoma, leukemia, myelofibrosis
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Hepatomegaly: alcohol, myelofibrosis
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Scar from gastrectomy: decreased absorptive surface with the loss of the terminal ileum leads to vitamin B12 deficiency Scar from cholecystectomy: Cholesterol and pigmented gallstones are commonly seen in sickle cell anemia are hereditary spherocytosis
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Cardiovascular:
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Tachycardia
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Systolic flow murmur
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Severe anemia may lead to high output heart failure
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Neurologic exam: Decreased proprioception/vibration: vitamin B12 deficiency
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Skin:
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The pallor of the mucous membranes/nail bed or palmar creases: suggests hemoglobin < 9 mg/dL
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Petechiae: thrombocytopenia, vasculitis
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Dermatitis herpetiformis (in iron deficiency due to malabsorption- Celiac disease)
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Koilonychia (spooning of the nails): iron deficiency
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Rectal and pelvic exam: These examinations are usually overlooked and underperformed in the evaluation of anemia. If a patient has heavy rectal bleeding, one must evaluate for the presence of hemorrhoids or hard masses that suggest neoplasm as causes of bleeding.
Initial work-up
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Complete blood count: Hemoglobin, hematocrit (HCT), MCV, reticulocyte count index
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Comprehensive metabolic panel: Renal and liver function tests
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Iron studies which include serum iron, TIBC (total iron-binding capacity), and ferritin
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Serum vitamin B12, folic acid, and thyroid-stimulating hormone (TSH)
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Stool for occult blood
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Zinc protoporphyrin/heme ratio – Decreased iron supply for the formation of hemoglobin leads to increased utilization of zinc and an increase in the ZPP/H ratio; this is preferable to invasive bone marrow aspiration.[rx]
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Reticulocyte hemoglobin content – Provides an estimate of iron availability for RBC production over a few days before the test. Thus, it is a useful indicator of early iron deficiency, and sequential measurements can also help to guide response to parenteral iron therapy. Inflammation does not influence this parameter and is useful in determining iron status in patients with CKD.[rx][rx]
- Intravenous iron is available in many forms, such as ferric carboxymaltose, ferric gluconate, ferric/iron sucrose, ferumoxytol, and low-molecular-weight iron dextran. Response to intravenous iron merits observation to establish the need for further supplementation six to eight weeks after initial iron replacement.[3]
Mean corpuscular volume (MCV) is a measure of the volume occupied by a single red blood cell. Increased values are seen in macrocytic anemia (vitamin B12 deficiency, folate deficiency, alcohol use), whereas decreased values are seen in the microcytic anemia.
Mean corpuscular hemoglobin concentration reflects the average hemoglobin concentration in RBCs. Increased values are seen in spherocytosis, and low values are seen in thalassemia, iron deficiency, and macrocytic anemia. If result > 2, this suggests hemolysis or acute blood loss, while results < 2 suggests hyperproliferation.
After calculating the reticulocyte count, check the MCV.
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MCV (<80 fl)
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Iron deficiency- decreased serum iron, percent saturation of iron, with increased total iron-binding capacity (TIBC), transferrin levels, and soluble transferrin receptor
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Lead poisoning- basophilic stippling on the peripheral blood smear, ringed sideroblasts in bone marrow, elevated lead levels
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AOCD- may be normocytic
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Thalassemia- RBC count may be normal/high, low MCV, target cells, and basophilic stippling are on peripheral smear. Alpha thalassemia is differentiated from beta-thalassemia by a normal Hgb electrophoresis in alpha thalassemia. Elevated Hgb A2/HgbF is seen in the beta-thalassemia trait.
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Sideroblastic anemia- elevated serum iron and transferrin with ringed sideroblasts in the bone marrow
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MCV (90-100fl)
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Renal failure: BUN/Creatinine
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Aplastic anemia- ask for drug exposure, check for infections (EBV, hepatitis, CMV, HIV), test for hematologic malignancies and paroxysmal nocturnal hemoglobinuria (PNH)
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Myelofibrosis/myelophthisis- check bone marrow biopsy
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Multiple myeloma- serum and urine electrophoresis
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Pure red cell aplasia- test for Parvovirus B19, exclude thymoma
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MCV (>100 fl)
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B12/folate levels- B12 and folate deficiency can be differentiated by an elevated methylmalonic and homocysteine level in B12 deficiency and only an elevated homocysteine level in folate deficiency. Methylmalonic levels are relatively normal.
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MDS- hypopigmented PMNs on peripheral smear, bone marrow biopsy
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Hypothyroidism- TSH, free T4
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Liver disease- check liver function
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Alcohol- assess alcohol intake
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Drugs
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Steps to evaluate for hemolytic anemia
1) Confirm the presence of hemolysis- elevated LDH, corrected reticulocyte count >2%, elevated indirect bilirubin and decreased/low haptoglobin
2) Determine extra vs. intravascular hemolysis-
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Extravascular
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Spherocytes present
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Urine hemosiderin negative
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Urine hemoglobin negative
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Intravascular
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Urine hemosiderin elevated
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Urine hemoglobin elevated
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3) Examine the peripheral blood smear [rx]
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Spherocytes: immune hemolytic anemia (Direct antiglobulin test DAT+) vs. hereditary spherocytosis (DAT-)
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Bite cells: G6PD deficiency
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Target cells: hemoglobinopathy or liver disease
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Schistocytes: TTP/HUS, DIC, prosthetic valve, malignant HTN
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Acanthocytes: liver disease
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Parasitic inclusions: malaria, babesiosis, bartonellosis
4) If spherocytes +, check if DAT is +
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DAT(+): Immune hemolytic anemia (AIHA)
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DAT (-): Hereditary spherocytosis
Other investigations that might be warranted include esophagogastroduodenoscopy for the determination of an upper GI bleed, colonoscopy for the determination of a lower GI bleed, and imaging studies if malignancy, or internal hemorrhage is suspected. If a menstruating woman has heavy vaginal bleeding, evaluate the presence of fibroids with a pelvic ultrasound.
The reticulocyte count reflects the presence of nonnucleated immature red blood cells in the bone marrow. Increased levels are seen when there is accelerated erythropoiesis, following anemia, hemorrhage, pregnancy, or splenectomy. Decreased levels indicate lower production and can be a result of aplastic anemia, radiation exposure, or chronic infection.
Differentiation of microcytic anemias based on iron studies
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Iron deficiency anemia: Low serum iron, high TIBC, and low ferritin.
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Anemia of chronic disease: Low serum iron, low TIBC, and high ferritin.
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Sideroblastic anemia: High serum iron, normal TIBC, and high ferritin.
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Thalassemia: Normal serum iron, normal TIBC, and normal ferritin.
Peripheral smear, hemoglobin electrophoresis, and bone marrow examination if needed. Further testing would include esophagogastroduodenoscopy (EGD) and colonoscopy if gastrointestinal (GI) bleeding is suspected and imaging studies if malignancy is suspected.
Treatment
The treatment of anemia of chronic disease is geared toward the underlying disease. If the treatment of the underlying disease is successful, anemia usually improves or resolves completely without direct treatment of its own.
Chronic anemia is managed predominantly in outpatient settings. They need hospitalization if:
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Patient is symptomatic
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There is a significant drop in hemoglobin/HCT
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Transfusion is needed
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Extensive investigations are needed
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If hemoglobin is less than 7 g/dL or if a patent is symptomatic, transfusion of packed red blood cells (PRBC) is indicated. Transfusions should be performed with caution in patients with volume overload status like end-stage renal disease (on hemodialysis) and congestive heart failure (CHF).
Anemia due to acute blood loss – Treat with IV fluids, crossmatched packed red blood cells, and oxygen. Always remember to obtain at least two large-bore IV lines for the administration of fluid and blood products. Maintain hemoglobin of > 7 g/dL in a majority of patients. Those with the cardiovascular disease require a higher hemoglobin goal of > 8 g/dL.
Anemia due to nutritional deficiencies: Oral/IV iron, B12, and folate.
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Oral supplementation of iron is by far the most common method of iron repletion. The dose of iron administered depends on the patient’s age, calculated iron deficit, the rate of correction required, and the ability to tolerate side effects. The most common side effects include metallic taste and gastrointestinal side effects such as constipation and black tarry stools. For such individuals, they are advised to take oral iron every other day, in order to aid in improved GI absorption. The hemoglobin will usually normalize in 6-8 weeks, with an increase in reticulocyte count in just 7-10 days.
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IV iron may be beneficial in patients requiring a rapid increase in levels. Patients with acute and ongoing blood loss or patients with intolerable side effects are candidates for IV iron.
- Recombinant human erythropoietin and darbepoetin alfa are the two ESAs generally used in the management of anemia in CKD. They are fairly similar in efficacy and side effect profile, except for the longer half-life of darbepoetin alfa, thus allowing for less frequent dosing.[rx][rx]In these patients, erythropoietin (50 to 100 units/kg IV or SC) is usually given every 1 to 2 weeks, and darbepoetin alfa dosing is every 2 to 4 weeks.
Other treatments include treating underlying conditions as below.
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Iron deficiency anemia: Intravenous (IV) iron versus oral iron
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Vitamin B12 and folic acid deficiency with B12 and folic acid supplementation
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Treating underlying bone marrow disorders
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EPO injections in chronic kidney disease patients
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Synthroid in patients with hypothyroidism
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Avoiding any culprit medications
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Treatment of GI causes of blood loss (PPI for gastritis and PUD)
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Regulation of menstrual cycles in patients with menorrhagia
Efforts to treat the anemia by correcting the iron imbalance in the body with therapies such as oral iron supplements or vitamins have generally proven ineffective. Such efforts can have a negative impact on overall health. For example, iron supplementation is controversial because certain diseases such as cancer use iron to grow and spread and certain infections use iron as nourishment. More research is necessary to understand the complex mechanisms that ultimately result in anemia of chronic disease and what role if any, traditional therapies for anemia and iron imbalance have in the treatment of affected individuals.
References
