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Wintrobe's Clinical Hematology, 11th Ed

by John P. Greer (Editor), John Foerster (Editor), John N. Lukens (Editor)

Publisher: Lippincott Williams & Wilkins Publishers; 11th edition (December 2003)

Robert T.

Means, Jr.

Anemias Secondary to Chronic Disease and

Systemic DisordersANEMIA OF CHRONIC DISEASE

The anemia that is often observed in patients with infectious, inflammatory, or neoplastic

diseases that persist for more than 1 or 2 months is called anemia of chronic disease.

The characteristic feature of this syndrome is the occurrence of hypoferremia in the

presence of ample reticuloendothelial iron stores. Anemia of chronic disease is defined by

the presence of this unique combination of findings ( 1 , 2 and 3 ). As so defined, the

syndrome does not include anemias caused by marrow replacement, blood loss, hemolysis,

renal insufficiency, hepatic disease, or endocrinopathy, even when these disorders are

chronic. These other syndromes are discussed in the sections Anemia of Chronic Renal

Insufficiency, Anemia in Cirrhosis and Other Liver Diseases, and Anemias Associated with

Endocrine Disorders.

As the discussion above suggests, the designation anemia of chronic disease is far from

perfect ( 4 ). The most commonly proposed alternative, anemia of inflammation ( 4 ), also

has significant deficiencies, and the more pathophysiologically correct term

cytokine-mediated anemia ( 5 ) is not commonly used. Highly specific descriptive

designations, such as anemia of defective iron reuse ( 6 ), hypoferremic anemia with

reticuloendothelial siderosis, and thesauric hypoferremic anemia ( 7 ), are also rarely used.

Associated Syndromes

Anemia of chronic disease is extremely common and, overall, is probably more common

than any anemia syndrome other than blood loss with consequent iron deficiency. Cash

and Sears evaluated all the anemic individuals admitted to the medical service of a busy

municipal hospital during two 2-month periods in 1985 to 1986 ( 8 ). After patients with

active bleeding, hemolysis, or known hematologic malignancy were excluded, 52% of

anemic patients met laboratory criteria for anemia of chronic disease ( 8 ). The syndrome

is also observed in 27% of outpatients with rheumatoid arthritis ( 9 ) and in 58% of new

admissions to inpatient rheumatology units ( 10 ). Clinical disorders commonly associated

with anemia of chronic disease are listed in Table 47.1. However, it should be remembered

that 40% of patients in the series reported by Cash and Sears lacked one of the

traditional chronic associated disorders ( 8 ). Approximately one-third of this latter group

had renal insufficiency, in which pathophysiologic mechanisms implicated in anemia of

chronic disease are active ( 28 ).

TABLE 47.1. Conditions Associated with Anemia of Chronic Disease

Chronic infections ( 8, 13)

Pulmonary infections: abscesses, emphysema, tuberculosis, pneumonia

Subacute bacterial endocarditis

Pelvic inflammatory disease

Osteomyelitis

Chronic urinary tract infections

Chronic fungal disease

Meningitis

Human immunodeficiency virus

Chronic, noninfectious inflammations

Rheumatoid arthritis ( 14, 15, 16 and 17)

Rheumatic fever ( 18)

Systemic lupus erythematosus ( 19)

Severe trauma ( 20)

Thermal injury ( 21)

Vasculitis

Malignant diseases ( 22, 23, 24 and 25)

Carcinoma

Hodgkin disease

Lymphosarcoma

Leukemia

Multiple myeloma

Miscellaneous

Alcoholic liver disease

Congestive heart failure

Thrombophlebitis

Ischemic heart disease

Idiopathic

Clinical and Laboratory Description

Because this type of anemia occurs in association with so many diseases, the clinical

manifestations necessarily vary widely. Usually, the signs and symptoms of the underlying

disorder overshadow those of the anemia, but on rare occasions, reduction of the

hemoglobin level provides the first evidence of the existence of the primary condition.

This situation may be observed particularly in difficult-to-diagnose clinical syndromes,

such as temporal arteritis ( 29 ).

Anemia

DEVELOPMENT AND SEVERITY

Typically, anemia develops during the first 1 to 2 months of illness and thereafter does not progress ( 2 ). The hematocrit usually is maintained between 0.25 and 0.40 ( 2 , 11 , 30 ), but significantly lower values are observed in 20 to 30% of patients ( 8 , 9 ). The hemoglobin concentration and hematocrit generally provide an accurate reflection of the extent to which the circulating red cell mass is reduced, although in certain cases, expansion of the total blood volume would mean that the reduction in red cell mass is less than the hemoglobin or hematocrit indicates ( 11 ).

This is particularly likely in syndromes associated with increased levels of interleukin

(IL)-6. IL-6 produces a dilutional anemia: Expansion of the plasma volume results in a

reduced hematocrit or hemoglobin concentration without changes in the circulating red

cell mass ( 31 ). A general correlation exists between the degree of anemia and the

severity of the underlying disease ( 2 ). For example, infections accompanied by

pronounced fever, chills, and suppuration are associated with more severe anemia than

those with fewer systemic manifestations ( 32 ). In infected wounds, the degree of anemia

is related to the number of organisms present ( 32 ). Correlation has also been observed

between the severity of the anemia and the activity of rheumatoid arthritis, judged by

fever, severity of joint swelling and inflammation, and the erythrocyte sedimentation rate (

16 , 33 ). In patients with malignant disease, anemia is more severe when metastases are

widespread than when the disease is localized; however, the development of anemia does

not require neoplastic invasion of the bone marrow ( 27 , 34 ). Typically, the percentage of

reticulocytes is normal or reduced ( 2 ), although on rare occasions, it may be slightly

increased ( 32 ).

MORPHOLOGIC FEATURES

The erythrocytes usually are normocytic and normochromic;

however, hypochromia and microcytosis may be observed. In older series, microcytosis

[mean corpuscular volume (MCV)