Chronic Anemia 

Updated: Jan 22, 2020
Author: Christopher D Braden, DO; Chief Editor: Barry E Brenner, MD, PhD, FACEP 

Overview

Practice Essentials

Anemia is defined as an absolute reduction in the quantity of the oxygen-carrying pigment hemoglobin (Hgb) in the circulating blood. Anemia is further broadly subcategorized into acute and chronic. (See Etiology.)

Anemia usually is grouped into 3 etiologic categories: decreased red blood cell (RBC) production, increased RBC destruction, and blood loss.

Anemia is a manifestation of an underlying disease process and is not a diagnosis in itself. A wide array of diseases, including inflammations, infections, and malignancies, may at some point be associated with anemia. Common conditions associated with anemia include the following:

  • Gastritis
  • Gastric or duodenal ulcer
  • Liver or renal disease
  • Hypothyroidism
  • Sickle cell disease
  • Hypermenorrhea
  • Previous history of anemia or blood transfusions
  • Thrombocytopenia or blood coagulation disorders
  • Cancer or other chronic illness (eg, rheumatic disease)
  • Poor diet, especially iron deficiency

A disease may lead to anemia through a combination of mechanisms. For example, a gastrointestinal malignancy may cause anemia through blood loss, as well as lead to anemia of chronic disease. (See Etiology.)

Go to Anemia and Pediatric Chronic Anemia for complete information on these topics.

Patient Education

For patient education information, see Anemia.

Etiology

Microcytic hypochromic anemia

Possible causes of this condition include iron deficiency, thalassemia, sideroblasts, and lead poisoning.

Anemia of chronic disease commonly is manifested by normocytic normochromic indices; however, microcytic hypochromic indices also can be associated with anemia of chronic disease.

Macrocytic anemia

Possible causes of macrocytic anemia include vitamin B-12 deficiency, folate deficiency, liver disease, and hypothyroidism.

Normocytic anemia

Normocytic anemia is further divided into 2 broad categories: anemia with primary bone marrow involvement and anemia secondary to underlying disease.

Anemias with primary bone involvement include aplastic anemia and myelophthisic anemia.

The etiology of myelophthisic anemia involves interruption of normal hematopoiesis due to the accumulation of malignant or reactive cells or cell products. It is characterized by the appearance of immature myeloid cells and nucleated RBCs in the peripheral blood. The 3 major classes of disorders that can produce myelophthisic anemia are intrinsic bone marrow malignancies (eg, leukemia, lymphoma, myeloma), metastatic tumors (eg, neuroblastoma, melanoma), cancers that are more prone to bone marrow metastasis (eg, prostate, breast, lung, stomach, renal carcinomas), and granulomatous disease (eg, tuberculosis, sarcoidosis).

Agnogenic myeloid metaplasia, which is characterized by anemia with primary bone marrow involvement, involves gradual bone marrow fibrosis, extramedullary hematopoiesis, and splenomegaly with no known underlying systemic disorder.

Most cases of anemia in the world are secondary to an underlying disease. The marrow does not respond appropriately to microcytic anemia, leading to decreased production of RBCs. This type of anemia includes that associated with liver cirrhosis, uremia, chronic inflammation, and hypoendocrine conditions (eg, thyroid, adrenal, pituitary disorders).

Hemolytic anemia

This type of anemia includes sickle cell anemia, thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome, aortic valve prosthesis, disseminated intravascular coagulation (DIC), cold agglutinin disease, and paroxysmal cold hemoglobinuria (PCH).

Epidemiology

Occurrence in the United States and internationally

The incidence of anemia mirrors the incidence of the underlying cause. Some published studies report the incidence of anemia to be 2-15% in the United States and Great Britain.

Anemia is far more common in underdeveloped countries than in the United States. The true incidence of anemia is difficult to define because of multiple factors (eg, patient population, geographic location, normal range reference, ability to adequately screen for the disease).

Among 292 children in a low-income community in the Dominican Republic, 69.9% were found to be anemic using the World Health Organization (WHO)–recommended hemoglobin cut point of < 11.0 g/dl, and 34.6% were classified as anemic using a cut point of < 10.0 g/dl. The prevalence of microcytosis in anemic children ranged from 23.5% to 80.2%, depending on the hemoglobin and age-based mean corpuscular volume cut points used.[1]

Race-, sex-, and age-related demographics

African Americans have a higher incidence of sickle cell anemia and glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. G-6-PD is essential for RBC protection from oxidative insults and for approximately 10% of RBC energy production.

Mediterranean populations show a higher incidence of beta thalassemia.

Sex distribution varies based on the underlying cause. Overall, females have approximately twice the incidence of males of anemia.

Anemia is prevalent in all age groups. Some younger patients may have a better ability to compensate for anemia, which may delay initial diagnosis.

Prognosis

Prognosis is dependent on several factors. The underlying medical condition usually dictates the prognosis, but comorbid conditions, the chronicity of the disease, and the patient’s diet, age, and access to medical care are contributing factors.

Complications

The majority of complications in chronic anemia arise from chronic or persistent tissue hypoxia.

Pediatric patients, elderly patients, and patients who are immunocompromised are at the highest risk for complications, since they have less physiologic reserve.

Failure to comply with follow-up and treatment regimens predisposes patients with chronic anemia to complications.

 

Presentation

History

A comprehensive history and physical examination are vital in determining the cause of anemia. For example, a family history of a dominant inheritance pattern would suggest spherocytosis. In addition, knowing what medications the patient is taking is vital, as many drugs and toxins can cause anemia (eg, alcohol, isoniazid, lead).

The spectrum of symptoms manifested by anemia is dependent on many factors, including underlying medical condition, medications, rate of onset, and the individual's ability to compensate for the deficit. The hallmark of chronic anemia is the ability of patients to sustain a relatively normal level of function at significantly lower than normal Hgb levels.

Primary symptoms result from tissue hypoxia and might include the following:

  • Fatigue, weakness, irritability

  • Headache

  • Dizziness, especially postural

  • Vertigo

  • Tinnitus

  • Syncope

  • Dyspnea, especially with increased physical activity (exercise intolerance)

  • Chest pain, palpitations

  • Difficulty sleeping or concentrating

  • Thirst

  • Anorexia

  • Decreased urine output/bowel irregularity

  • Decreased libido or impotence

Physical Examination

Physical findings mirror the underlying disease process and the duration from the onset. Patients with chronic anemia usually do not manifest typical physical findings associated with acute anemia.

The usefulness of skin pallor as a sign is limited by the color of the skin, the Hgb concentration, and the fluctuation of blood flow to the skin. The color of the palmar creases is a better indicator. If they are as pale as the surrounding skin, Hgb is usually less than 7 g/dL. Patients also may exhibit purpura, petechiae, and jaundice.

Ocular findings may include the following:

  • Pale conjunctiva

  • Retinal hemorrhages

Cardiovascular findings may include the following:

  • Tachycardia

  • Orthostatic hypotension

Pulmonary findings may include the following:

  • Tachypnea

  • Rales

Abdominal findings may include the following:

  • Hepatomegaly and/or splenomegaly

  • Ascites

  • Masses

  • Positive result on Hemoccult test

Neurologic findings may include the following:

  • Peripheral neuritis/neuropathy

  • Mental status changes

 

DDx

Diagnostic Considerations

Be vigilant for acute blood loss while attributing low Hgb and hematocrit values to a chronic state.

Consider anemia as an etiologic factor in patients who present with dyspnea, headache, angina, or altered mental status.

Consider anemia as a contributing factor to jaundice (hemolytic anemia) while focusing on other conditions, such as acute hepatitis, that can present with jaundice.

Be vigilant for the presence of pancytopenia.

Conditions to consider in the differential diagnosis of anemia, along with those in the next section, include the following:

  • Hemophilia, type A

  • Hemophilia, type B

  • Hemorrhoids

  • Henoch-Sch ö nlein purpura

  • Inflammatory bowel disease

  • Malaria

  • Methemoglobinemia

  • Mononucleosis

  • Mycoplasma pneumonia

  • Cushing syndrome

  • Alcohol and substance abuse

  • Coccidioidomycosis

  • Dengue fever

  • Disseminated intravascular coagulation

  • Dysfunctional uterine bleeding

  • Dysmenorrhea

  • Sarcoidosis

  • Systemic lupus erythematosus

Differential Diagnoses

 

Workup

Approach Considerations

The following laboratory measurements are critical in the workup of anemia:

  • Measurement of red blood cell (RBC) indices

  • Examination of peripheral blood smear

  • Bone marrow examination (not necessary in all patients)

Additional laboratory tests that allow differentiation of anemias based on RBC index information include the following:

  • Serum iron concentration

  • Total iron-binding capacity (TIBC)

  • Serum vitamin B-12

  • Serum folate

  • Serum bilirubin

  • Liver function tests (LFTs)

  • Thyroid panel

  • Hgb electrolytes

  • Heavy metal studies

The ultimate diagnosis of chronic anemia is based on results of blood studies. In the initial emergency department (ED) evaluation, a prudent choice of labs includes the following:

  • Complete blood count (CBC) with leukocyte differential and peripheral smear

  • RBC indices

  • Reticulocyte count

  • Bilirubin

Based on the RBC indices, further blood work may be initiated in the ED. Iron studies may be performed. These can include ferritin, TIBC, total iron, and percent saturation. Typically, iron studies are helpful in the diagnosis of microcytic and normocytic anemias.

Serum vitamin B-12, folate levels, and the red cell folate level are useful in evaluating macrocytic anemias. Order concurrent liver and thyroid function studies for patients with macrocytic anemia.

Hgb electrophoresis may delineate sickle cell anemia and thalassemias.

Heavy metal studies (eg, serum lead level) may be considered when a high level of suspicion is present, historically and clinically, for heavy metal poisoning.

Imaging studies

No specific imaging tests exist for chronic anemia; however, several imaging modalities can be used in examining the underlying etiology (eg, computed tomography [CT] scanning for abdominal mass, chest radiography for histoplasmosis/coccidioidomycosis).

Bone marrow examination

Bone marrow examination may be diagnostic in cases in which workup is otherwise nonspecific. This is not a procedure performed in the acute setting.

Common Lab Studies

Hematocrit

Hematocrit also is known as the packed cell volume (PCV) and indicates the percentage of RBCs in a volume of whole blood. Increased values occur with severe dehydration, erythrocytosis, polycythemia, severe burns, and shock, and in people living in high altitudes, males, and infants.

Decreased values occur with anemia and the many differential diagnoses that encompass anemia (eg, hyperthyroidism, leukemia, liver disease, hemolytic reactions). Other causes of decreased hematocrit values include female sex, advanced age, and pregnancy. Hematocrit value is not reliable immediately after blood loss or blood transfusions.

Hgb concentration

Hgb concentration is expressed in grams per 100 mL of blood. Each gram of Hgb has a carrying capacity of 1.34 mL of oxygen.

Increased Hgb values can indicate severe dehydration, erythrocytosis, polycythemia, severe burns, shock, chronic obstructive pulmonary disease (COPD), or congestive heart failure (CHF). Increased values also occur in people living in high altitudes, people consuming drugs such as gentamicin or methyldopa, and infants.

Decreased values indicate anemia and the many differential diagnoses that encompass anemia (eg, hyperthyroidism, leukemia, liver disease, hemolytic reactions). Other possible causes of decreased Hgb values include the following:

  • Overhydration
  • Pregnancy
  • Drugs (eg, acetaminophen, antineoplastic agents, chloramphenicol, hydralazine, monamine oxidase inhibitors [MAOIs], nitrites, penicillin, tetracycline, sulfonamide)

Mean corpuscular volume

Mean corpuscular volume (MCV) is the hematocrit divided by the RBC count. It is a measurement of the volume occupied by a single RBC and is an indicator of individual cell size. Increased values indicate differentials that encompass macrocytic anemia (eg, vitamin B-12 or folate deficiency, liver disease, alcoholism), while decreased values indicate microcytic anemia (ie, iron deficiency, thalassemia, anemia of chronic blood loss). This is the most important of the RBC indices. A normal value can appear when a wide variety of cell sizes is present (ie, macrocyte, microcyte).

Mean corpuscular Hgb concentration

Mean corpuscular Hgb concentration (MCHC) is the Hgb divided by the hematocrit. It represents the average concentration of Hgb in the red blood cells. The value is expressed as a percentage. Increased values point to spherocytosis (eg, congenital hemolytic anemia), and decreased values indicate iron deficiency, thalassemia, or macrocytic anemia.

Mean corpuscular Hgb

Mean corpuscular Hgb (MCH) is the Hgb divided by the RBC count. It represents the average weight of Hgb in the RBCs and serves to confirm the accuracy of MCV value. Increased values occur in macrocytic anemia, newborns, and infants. Decreased values indicate microcytic anemia.

Reticulocyte count and index

The first question a clinician must address is whether the anemia is due to a decreased production of RBCs or to increased destruction or loss of RBCs. The reticulocyte count is the most valuable test in answering this question.

A reticulocyte is a nonnucleated, immature RBC formed in the bone marrow. Increased values indicate accelerated erythropoiesis and can be present following treatment of anemia, after splenectomy, 3-4 days following hemorrhage, in sickle cell disease hemolytic anemia, during pregnancy, or in infants. Decreased values indicate decreased RBC production by the bone marrow and can be a result of aplastic anemia, chronic infection, or radiation therapy. A persistent reticulocyte deficiency is a poor prognostic sign.

The reticulocyte index (RI) is defined as the percent reticulocyte count divided by 2 and then multiplied by the ratio of the patient's hematocrit (or Hgb) to normal hematocrit (or Hgb). Good marrow response is defined as an RI value of 2-6.

 

Treatment

Approach Considerations

EDs rarely treat anemia beyond the emergent needs. Discharging the patient on iron, vitamin B-12, or folate may mask other problems and cloud the correct diagnosis.

Unless cardiopulmonary or cerebrovascular disease is present, transfusion is rarely needed in patients who have chronic anemia with an Hgb greater than 7 g/dL.

The American College of Obstetricians and Gynecologists has guidelines available on the treatment of anemia in pregnancy.[2]

Emergent Care of Chronic Anemia

Most patients presenting with chronic anemia are not in distress.

Prehospital care most often is initiated for patients in extremis. Attention to ABCs is most appropriate. All such patients should have intravenous (IV) placement, fluid resuscitation, and airway management as necessary.

The initial status and appearance of the patient may hold useful information and should be elicited from prehospital personnel.

Patients with chronic anemia usually do not require intervention in the ED. Ultimate treatment requires investigation into the etiology of the anemia and correction of the underlying cause.

Records of previous hospitalizations or ED visits are invaluable in many aspects of patient management. Such patients frequently have undergone previous workup, and previous Hgb or hematocrit trends indicate the time course of the illness.

Admission considerations

Patients with chronic anemia requiring admission include the following:

  • Patients presenting with hypovolemia, active bleeding, angina, tachypnea, altered mental status, transient ischemic attack (TIA), or exacerbation of congestive heart failure (CHF)[3]

  • Patients who demonstrate a considerable drop in Hgb and hematocrit values when compared with previous values or who have new-onset or worsening pancytopenia

  • Patients with an initial Hgb of less than 10 g/dL or a hematocrit of less than 30%

  • Patients who may not comply with follow-up or those in whom the clinician anticipates the need for an extensive workup

Patients can be admitted to a ward bed, a monitored bed, or an intensive care unit (ICU) bed, depending on their condition.

Go to Anemia and Emergent Management of Acute Anemia for complete information on these topics.

Transfer considerations

Patients with chronic anemia seldom require transfer to another facility for definitive care. Transfers are only acceptable if the patient is hemodynamically stable.

Transfusions

One conspicuous exception in the treatment of chronic anemia is the use of transfusion therapy. Unless cardiopulmonary or cerebrovascular disease is present, transfusion is rarely needed in patients who have chronic anemia with an Hgb greater than 7 g/dL. Multiple situations that may require transfusion include angina, chronic heart failure, transient ischemic attack (TIA), and signs of tissue hypoxia.

It is important to weigh the risks and benefits of blood transfusion.

Many adverse reactions are associated with transfusion therapy. Most frequently encountered is a febrile nonhemolytic reaction. Patients who have had previous transfusion or patients who are pregnant are at greatest risk. Treatment is supportive with antipyretics. The clinician should maintain a high level of suspicion for a hemolytic reaction, because fever may the first symptom.

Many patients fear infection.[4] Hepatitis C occurs in 1 of 103,000 transfusions, hepatitis B occurs in 1 of 200,000 transfusions, and human immunodeficiency virus (HIV) occurs in 1 of 490,000 transfusions.

In a retrospective study of patients with chronic refractory anemia who were transfusion-dependent for more than 1 year, 10 of the 13 patients had abnormal liver function. The CT Hounsfield units in the liver were proportional to serum ferritin levels and were increased significantly in 11 patients. In the nine patients with serum ferritin >3,500 ng/mL, eight of whom died, skin pigmentation, liver dysfunction, and endocrine dysfunction were observed. Serum ferritin levels did not decrease significantly in the nine patients treated with 15-60 days of iron-chelating therapy.[5]

Graft versus host reaction

The graft versus host reaction is rare but is especially dangerous in patients who are immunocompromised. It carries a mortality rate of greater than 90%. Pathogenesis in this reaction involves donor T lymphocytes attacking host human leukocyte antigens (HLA). High fever, erythematous rash, diarrhea, and abnormal LFTs associated with recent or concurrent transfusion may herald the severe reaction. Symptoms may not appear until 8 days after transfusion, and death occurs in 3-4 weeks.

Using irradiated blood can decrease the incidence of graft versus host reaction and should be considered in all patients deemed immunocompromised, as well as in fetuses receiving intrauterine transfusions, patients receiving units from a blood relative, and patients transplanted with marrow. Care should be taken when transfusing patients with CHF. Preferably, transfusion should occur over 3-4 hours in the sitting position.

Follow-Up

Patients with chronic anemia most often are treated in the outpatient setting. Clear instructions must be given to the patient regarding proper follow-up.

Consideration of the patient’s financial situation and ability to comply with follow-up care is imperative. The key to minimizing complications from chronic anemia is ongoing reassessment and patient compliance with proposed medical therapy.

All efforts should be made to arrange for follow-up. When all avenues for outpatient evaluation fail, patients should be instructed to return to the ED for reassessment in 2-3 weeks.

Upon discharge, instruct the patient to watch for signs and symptoms of worsening anemia. The patient should be advised to return to the ED if such symptoms develop.

Consultations

Generally, patients with chronic anemia can be treated on an outpatient basis, and referral to a primary care provider is appropriate.

Consultation with the patient's primary care provider or an available internist should begin in the ED.

Symptomatic patients with an underlying medical condition that requires surgical consultation, such as chronic GI bleeding from colon cancer, should be evaluated by a surgeon in the ED.

 

Medication

Medication Summary

Documentation of the etiology of anemia is essential in the selection of therapy. Not all microcytic anemias are caused by iron deficiency; some are iron-overloading disorders. Similarly, not all megaloblastic anemias are associated with either vitamin B-12 deficiency or folic acid deficiency.

Iron Products

Class Summary

Mineral supplements are used to provide adequate iron for hemoglobin synthesis and to replenish body stores of iron. Iron is administered prophylactically during pregnancy because of the anticipated requirements of the fetus and the losses that occur during delivery.

Ferrous sulfate (Fer-In-Sol, Fer-Iron, Slow Iron, Slow-Fe)

Ferrous sulfate is the mainstay treatment for treating patients with iron deficiency anemia. It should be continued for about 2 months after correction of the anemia and its etiologic cause in order to replenish body stores of iron. Ferrous sulfate is the most common and cheapest form of iron used. Tablets contain 50-60 mg of iron salt. Other ferrous salts are used and may cause less intestinal discomfort because they contain a smaller dose of iron (25-50 mg). Oral solutions of ferrous iron salts are available for use in pediatric populations.

Carbonyl iron (Feosol, Iron Chews, Ircon)

Carbonyl iron is used as a substitute for ferrous sulfate. It has a slower release of iron and is more expensive than ferrous sulfate. The slower release affords the agent greater safety if ingested by children. On a milligram-for-milligram basis, it is 70% as efficacious as ferrous sulfate. Claims are made that there is less gastrointestinal (GI) toxicity, prompting use when ferrous salts are producing intestinal symptoms and in patients with peptic ulcers and gastritis.

Iron dextran (Infed)

Dextran-iron replenishes depleted iron stores in the bone marrow, where it is incorporated into hemoglobin. Parenteral use of iron-carbohydrate complexes has caused anaphylactic reactions, and its use should be restricted to patients with an established diagnosis of iron deficiency anemia whose anemia is not corrected with oral therapy.

The required dose can be calculated (3.5 mg iron/g of hemoglobin) or obtained from tables in the Physician's Desk Reference. For intravenous (IV) use, this agent may be diluted in 0.9% sterile saline. Do not add to solutions containing medications or parenteral nutrition solutions.

Iron sucrose (Venofer)

Iron sucrose is used to treat iron deficiency (in conjunction with erythropoietin) due to chronic hemodialysis. Iron deficiency is caused by blood loss during the dialysis procedure, increased erythropoiesis, and insufficient absorption of iron from the GI tract. Iron sucrose has shown a lower incidence of anaphylaxis than other parenteral iron products.

Ferric gluconate (Ferrlecit)

Ferric gluconate replaces iron found in hemoglobin, myoglobin, and specific enzyme systems. It allows transportation of oxygen via hemoglobin.

Ferric maltol (Accrufer)

An oral iron replacement that delivers iron for uptake across the intestinal wall and transfer to transferrin and ferritin. It is indicated for iron deficiency in adults.

Ferric derisomaltose (Monoferric)

Complex of iron (III) hydroxide and derisomaltose, an iron carbohydrate oligosaccharide that releases iron. Iron binds to transferrin for transport to erythroid precursor cells to be incorporated into hemoglobin. Ferric derisomaltose is administered IV and is indicated for iron deficiency anemia in adults who are intolerant to or have had unsatisfactory response to oral iron.

Vitamins

Class Summary

Vitamins are used to meet necessary dietary requirements and are used in metabolic pathways, as well as in DNA and protein synthesis.

Cyanocobalamin (vitamin B-12) and folic acid are used to treat megaloblastic and macrocytic anemias secondary to deficiency. Both vitamin B-12 and folic acid are required for the synthesis of purine nucleotides and the metabolism of some amino acids. Each is essential for normal growth and replication. Deficiency of either cyanocobalamin or folic acid results in defective DNA synthesis and cellular maturation abnormalities. Consequences of deficiency are most evident in tissues with high cell turnover rates (eg, hematopoietic system).

Vitamin K deficiency causes elevation of prothrombin time and is commonly seen in patients with liver disease.

Cyanocobalamin (Nascobal)

Deoxyadenosylcobalamin and hydroxocobalamin are active forms of vitamin B-12 in humans. Microbes synthesize vitamin B-12, but humans and plants do not. Vitamin B-12 deficiency may result from intrinsic factor (IF) deficiency (pernicious anemia), partial or total gastrectomy, or diseases of the distal ileum.

Folic acid (FA-8)

Folic acid is an essential cofactor for enzymes used in the production of red blood cells (RBCs).