Anemia of chronic disease (anemia of chronic inflammatory disease, hypoferremia of inflammation)

I. What every physician needs to know.

Anemia of chronic disease (ACD) carries many names. ACD, also known as anemia of chronic inflammatory disease (ACID) and hypoferremia of inflammation, is an anemia that results from a secondary process. In the developed world, ACD is the second most common anemia after iron deficiency anemia.

Any chronic medical problem that results in the release of inflammatory cytokines may contribute to ACD. In the absence of a chronic, pro-inflammatory medical condition, the diagnosis of ACD should not be made. Other causes for anemia, particularly if the anemia is acute to subacute, should be considered before a diagnosis of ACD is made.

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The release of cytokines such as interleukins, tumor necrosis factor, and any resultant inflammatory cascade decrease bone marrow responsiveness to erythropoietin (EPO), down regulate EPO receptors on progenitor cells, decrease EPO expression by renal cells, and induce apoptosis of red cell precursors. New research has elucidated that molecules like hepcidin, an iron regulatory hormone, also play a role in ACD.

Produced in the liver, hepcidin is an acute phase protein that is involved in iron metabolism. It is the predominant negative regulator of iron absorption in the small intestine and iron release from macrophages. Its secondary role increases cellular internalization and degradation of ferroportin, an iron export protein. Hepcidin levels correlate with interleukin 6 (IL-6) serum concentrations and are inversely proportional to the expression of ferroportin, the iron export protein found in cell membranes. Hepcidin is also elevated in the setting of an acute infection.

The mechanisms behind ACD are:

  • The impaired reuse of iron for erythropoiesis. This process is often called the dysregulation of iron metabolism and is thought to be induced by Hepcidin. Iron is trapped in macrophages or poorly absorbed from the gastrointestinal tract and therefore cannot be used for hemoglobin (Hgb) synthesis.

  • Impaired and reduced production of and response to erythropoietin (EPO). Despite decreased production, EPO serum levels can often be elevated in ACD without subsequent increase in erythropoiesis.

  • Decrease in the life span of red cells. This results from erythrophagocytosis.

II. Diagnostic Confirmation: Are you sure your patient has anemia of chronic disease?

In order to make a diagnosis of ACD, first a diagnosis of anemia must be made. The criteria for diagnosing anemia have been described in other chapters. Briefly, the diagnosis entails Hgb below 12.0 g/dL for women and 13.5 g/dL for men. The anemia found in chronic disease is often normochromic, normocytic to microcytic and hypoproliferative.

The appearance and morphology of a patient’s red blood cells should be considered along with an iron profile (including an iron level, total iron binding capacity [TIBC], transferrin saturation and ferritin) and reticulocyte count or index. The typical result profile for a patient with ACD is low serum iron with low to normal TIBC and transferrin saturation. Ferritin is almost never low in ACD. Reticulocyte index is typically low.

A. History Part I: Pattern Recognition:

ACD is found in patients with any form of immune activation caused by many chronic disease states. The most commonly associated disease processes are infections, malignancy, autoimmune diseases, chronic kidney disease, and transplant recipients with chronic rejection. A large subset of patients with chronic obstructive pulmonary disease are also at risk for ACD because of high inflammatory or infectious states. The patient phenotypically will resemble one with the causative underlying disease. The most common symptom of ACD and other anemias is fatigue, but other common symptoms include dyspnea on exertion, shortness of breath, or weakness.

The most common pattern of lab abnormalities is described above.

The presentation of ACD is not always “chronic.” Acute events such as sepsis, major surgery or trauma can also cause a similar anemia pattern because of acute inflammation and the release of cytokines and hepcidin as described above. These acute medical problems also shorten red cell survival. For this reason, the term “anemia of inflammation” is often more appropriate than ACD.

B. History Part 2: Prevalence:

ACD is second to iron deficiency as the most common type of anemia worldwide. Any patient with a chronic inflammatory state is at increased risk of ACD, the most common inflammatory states being infections (sepsis, osteomyelitis, human immunodeficiency virus [HIV], hepatitis C), rheumatologic diseases (rheumatoid arthritis [RA], systemic lupus erythematosus [SLE]), and malignancies. More than half of patients with active autoimmune disease and estimates up to 2/3 of cancer patients have ACD.

C. History Part 3: Competing diagnoses that can mimic anemia of chronic disease.

When ACD is suspected, other causes of anemia must be considered in the differential. These anemias include iron deficiency anemia, inborn errors of Hgb synthesis such as thalassemia or sickle cell disease, and mixed anemia. Other anemias that can mimic ACD are coexisting subacute or chronic blood loss and medication effects. Please see the chapter on anemia for more assistance with an anemia differential. Once other anemias are excluded, it is vital to make every attempt to find the process causing ACD.

ACD is a normocytic hypoproliferative process and has similar findings to anemia of chronic kidney disease and anemia caused by thyroid disease, panhypopituitarism, and hyperparathyroidism. Less often, ACD can be microcytic and therefore confused with other microcytic anemias. Briefly, these can be iron deficiency anemia, thalassemias and variants of myleodysplastic syndrome (MDS). Coexisting anemias can be a diagnostic challenge and other blood tests may be considered. Please see the chapter on anemia for further discussion.

D. Physical Examination Findings.

The physical exam findings of a patient with ACD are similar for any anemia and should be complete. A patient’s vitals can suggest the severity or acuity of the anemia especially if there is concurrent blood loss. If a patient were orthostatic by pulse or pressure, then one would suspect severe anemia or blood loss. A patient with severe anemia may also be tachycardic or tachypnic. Common findings in anemia are skin pallor, pale conjunctiva, a flow murmur in severe anemia caused by high cardiac output. Patients may exhibit poor exercise tolerance or generalized weakness on exam. Unless there is a secondary process such as blood loss or hemolysis, these exam findings do not typically develop acutely or with evidence of shock. An acute change in a patient with suspected ACD should prompt an investigation into other causes of anemia. The other physical exam findings in ACD will mimic that of the underlying pro-inflammatory process. For example, a patient with ACD secondary to rheumatoid arthritis may have joint and skin abnormalities related to rheumatoid arthritis.

The exam alone cannot differentiate between different anemic states, but may provide clues about underlying disease states that can cause ACD.

E. What diagnostic tests should be performed?

Other than the physical exam described above and laboratory test described in the next section, no other initial diagnostic tests are recommended.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Common studies that are sent to distinguish between the anemias include Hgb, reticulocyte count, iron studies including total iron level, ferritin, transferrin saturation, and total iron binding capacity (TIBC). Most patients with ACD alone have a mild anemia and Hgb levels around 10-11g/dl. ACD is usually normocytic and normochromic, but after a prolonged time it may become microcytic and hypochromic.

The laboratory profile of a patient with ACD alone is low to normal serum iron, normal to high ferritin, low TIBC and transferrin saturation, and a reduced reticulocyte index. Iron stores are typically normal in ACD, but poorly mobilized. This profile can be used to differentiate ACD from other common anemias. Iron deficiency anemia is characterized by low serum iron, transferrin saturation, and ferritin and high TIBC. Total body iron stores are low in iron deficiency. A presentation of thalassemia, by comparison, should have a normal iron profile, but the red blood cells are usually microcytic and hypochromic.

Ferritin is a poor measure of iron stores in a patient with an active inflammatory process (ferritin is an acute phase reactant). Therefore, a normal or elevated ferritin is non-diagnostic for ACD, but a low ferritin would make the diagnosis of ACD less likely.

A small percentage of ACD cases have Hgb closer to 8g/dl. In these severe cases, the reticulocyte count is usually low, below 25,000/microL. In addition, 20% of cases will have low serum iron levels and transferrin saturation in the range of iron deficiency in an individual with normal iron stores. This is believed to be caused by the abundance of iron trapped in and unreleased by macrophages because of down-regulated ferroportin.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

No imaging studies are indicated in diagnosing ACD; this is a serologic diagnosis.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

If a systematic approach is used to evaluate and diagnose anemia, unnecessary tests and treatment delays can be avoided. Please see the chapter on anemia for a comprehensive and systematic approach to diagnosing anemia. Often an overly comprehensive approach is taken and laboratory tests like fibrinogen, vitamin B12, folate, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are ordered before the results of earlier tests are carefully considered. Without clinical context, these tests can be non-specific and not extremely useful.

Always consider the result of the CBC (Hgb, HCT and red cell morphology) and reticulocyte index before ordering additional tests in an anemic patient. B12 and folate deficiency are associated with macrocytic anemia and should not be ordered in the setting of a normocytic to microcytic anemia common in ACD. Because ACD occurs in the setting of a pro-inflammatory state, ESR and CRP may be elevated. ESR and CRP will not aid in diagnosis of ACD, however, and should not be routinely obtained unless the result is needed to treat an underlying disease. Unless there is concern for a confounding hemolytic process, a fibrinogen level will not be useful in the diagnosis of ACD.

EPO levels vary broadly among many of the anemias and often are not diagnostic. An EPO level should only be obtained if a patient exhibits poor response to management of the underlying pro-inflammatory state.

Although examining the bone marrow can be instructive, especially to evaluate an anemia accompanied by other cytopenias or when there is uncertainty about a patient’s iron stores, it is an invasive and time consuming test. Without a strong suspicion for malignancy, a bone marrow exam is likely excessive.

III. Default Management.

The management of ACD should be focused on the causative inflammatory state.

A. Immediate management.

Acute management in ACD is only required if concurrent blood loss or hemolysis is suspected or if hemoglobin measurements are low enough to cause symptoms of decreased oxygen delivery. When ACD coexists with blood loss anemia you must immediately manage the anemia that is leading to blood loss.

B. Physical Examination Tips to Guide Management.

See above.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Once a diagnosis of ACD is made and treatment of the underlying pro-inflammatory condition is begun, the laboratory tests to follow are complete blood count (CBC), iron, ferritin and transferrin saturation as described below in long-term management.

D. Long-term management.

As above, the long term management of ACD should focus on the underlying inflammatory state. A stable patient who is not undergoing changes to therapy does not need routine laboratory testing more frequent than 3 months.

EPO as a treatment for ACD is controversial. Administering EPO may overcome the hyporesponsiveness of endogenous EPO that characterizes ACD. With the co-morbidities of cancer, rheumatoid arthritis or HIV, repleting EPO for a serum level below 500 mU/mL may be helpful.

EPO treatment is started with dosages of 100 to 150 units/kg subcutaneously 3 times a week. Augmentation is dependent on a change in Hgb. An increase in Hgb of 0.5g/dL in 4 weeks is expected. If an appropriate response is not achieved, therapy can be increased to 300 units/kg. Weekly subcutaneous dosing may be more convenient for the patient at a dose of 30,000 to 40,000 units. If no response is seen in 12 weeks, treatment with EPO should be suspended.

EPO should be stopped if hemoglobin levels climb above above 12g/dL. In order to maintain EPO treatment success, iron stores must be maintained.

Supplemental iron can be given to maintain transferrin saturation above 20% and ferritin above 100 ng/mL. Iron supplements may augment treatment with EPO, especially in patients on dialysis or patients on chemotherapeutic agents causing marrow suppression. Oral iron should be attempted first and, if no response, parenteral iron can be administered. Transfusion can be considered for symptomatic anemia or Hgb less than 7g/dL. A detailed discussion on transfusion guidelines is discussed in another chapter.

E. Common Pitfalls and Side-Effects of Management

The focus of management should be the underlying inflammatory condition and not the anemia itself. Similarly, other causes for anemia, especially in the acute setting, should be considered in the differential. Any acute change in Hgb of a patient with known ACD should prompt a re-investigation of secondary causes of anemia to prevent delays in care.

Blood transfusions are often over-used in ACD. Blood transfusions should be reserved for symptomatic patients with severe anemia (less than 7g/dL) in which both treating the underlying condition and erythropoiesis-stimulating agents have been tried and failed. The side effects of transfusions should not be underestimated.

Side effects from treatment of EPO in ACD have not be fully investigated.

IV. Management with Co-Morbidities

Because managing ACD requires managing the underlying co-morbidity, there is usually no change in the standard of care for that primary disease process.

A. Renal Insufficiency.

No change in standard management.

B. Liver Insufficiency.

No change in standard management.

C. Systolic and Diastolic Heart Failure

No change in standard management.

D. Coronary Artery Disease or Peripheral Vascular Disease

No change in standard management.

E. Diabetes or other Endocrine issues

No change in standard management.

F. Malignancy

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc).

No change in standard management.

H. Primary Lung Disease (COPD, Asthma, ILD)

No change in standard management.

I. Gastrointestinal or Nutrition Issues

No change in standard management.

J. Hematologic or Coagulation Issues

No change in standard management.

K. Dementia or Psychiatric Illness/Treatment

No change in standard management.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

This is a chronic disease and usually does not require daily in-patient surveillance. However, an acute change in Hgb should not automatically be attributed to ACD. As discussed before, ACD does not cause acute anemia.

B. Anticipated Length of Stay.

ACD alone should not impact length of stay. It is the inflammatory disease state that will most often determine the length of stay and failure to treat this underlying medical problems can lead to delays in discharge.

C. When is the Patient Ready for Discharge.

The patient with ACD is ready for discharge when the underlying disease process is under stable control.

D. Arranging for Clinic Follow-up

Most primary care physicians can manage and monitor ACD. Referral to specialists may be needed to manage the underlying pro-inflammatory medical problem.

1. When should clinic follow up be arranged and with whom.

A patient with ACD should be followed by a primary care provider and the specialty managing the underlying cause of ACD. If a patient was admitted for a lupus flare and found to have worsening of his/her anemia, then this patient should see both his/her primary care provider as well as a Rheumatologist.

The time interval for follow-up is based on the severity of the anemia and underlying disease process. Keep in mind that ACD may take weeks to respond to treatment. If the anemia is suspected to be ACD, but not fully confirmed when the patient is stable for discharge, then the patient may need to see a Hematologist after discharge as well.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

Once a diagnosis of ACD is made, no additional tests are needed before clinic follow up.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

Depending on the elapsed time since the last laboratory tests, CBC, ferritin, iron levels, and transferrin saturation may be helpful to monitor for stability or response to treatment. In stable patients, routine labs are not needed more frequently than every 3 months.

E. Placement Considerations.

The underlying disease in ACD will determine placement considerations.

F. Prognosis and Patient Counseling.

The underlying disease in ACD will impact prognosis and patient counseling.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.

The underlying disease in ACD will impact the documentation of core indicators.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

The underlying disease in ACD will influence appropriate measures to prevent readmission need to be taken. The patient should be educated about their anemia and symptoms that may indicate worsening anemia. With close follow up after discharge and adherence to treatment, many readmissions can be avoided.

VII. What's the Evidence?

Nemeth, E, Ganz, T. “Anemia of inflammation”. Hematol Oncol Clin North Am. vol. 28. 2014 Aug. pp. 671-81.

Weiss, G. “Anemia of Chronic Disorders: New Diagnostic Tools and New Treatment Strategies”. Semin Hematol. vol. 52. 2015 Oct. pp. 313-20.

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