As noted in Chapter 3, anemia associated with various chronic diseases is usually normocytic and either normochromic or hypochromic. The serum iron and total iron-binding capacity (TIBC) are typically both decreased. In 100 consecutive patients in our hospital who had chronic disease and red cell or iron-related biochemical abnormalities, 68 had anemia with normal mean corpuscular volume (MCV), decreased serum iron, and decreased TIBC; 7 had no anemia; 9 had normal serum iron levels; 6 had normal TIBC; and 7 had decreased MCV (with normal serum ferritin levels). Others have reported that decreased MCV may occur in up to 25% of cases.
Chronic renal disease
Anemia of moderate degree is frequently found in association with uremia. Some investigators claim it is almost always present when the blood urea nitrogen (BUN) level is persistently more than twice normal, and it often appears before this level is reached. Patients with prolonged but potentially reversible azotemia (e.g., acute renal failure) often develop anemia until the kidneys recover. Transient types of azotemia usually do not produce anemia unless azotemia is prolonged or due to the underlying cause itself. The anemia of actual renal insufficiency develops regardless of the cause of the uremia.
The peripheral blood RBCs are usually normocytic-normochromic; there is often mild to moderate anisocytosis. Varying numbers of burr cells (triangular shrunken RBCs with irregular pointed projections from the surface (Chapter 2) are found in some patients. In some cases there is mild hypochromia and, occasionally, some degree of microcytosis. On the other hand, mild macrocytosis may be present in a few patients.
Bone marrow usually shows normal cellularity, although in some cases there is mild RBC hypoplasia. Marrow iron is adequate. The serum iron level is usually normal, but about 20%-30% of patients have low serum iron levels even though they do not have iron deficiency. Most of these patients also have a low or low-normal TIBC typical of chronic disease anemia (Chapter 3). Reticulocyte counts are usually normal; occasionally, they may be slightly elevated.
The pathophysiology involved is not well understood. The primary known abnormality is a lack of incorporation of iron into RBCs within the bone marrow. There is depression both of hemoglobin synthesis and of formation and release of mature RBCs into the peripheral blood. In 10%-15% of patients there is also decreased RBC survival in the peripheral blood, although the hemolytic aspect is usually not severe. There is, however, a rare condition known as the hemolytic-uremic syndrome that features a severe microangiopathic (RBC fragmentation) hemolytic anemia. Patients in the late stages of uremia may have a bleeding tendency due to coagulation defects, most commonly thrombocytopenia. Platelet function may be abnormal even with normal numbers of platelets. The effect of hemorrhage, if it occurs, is separate and additional to the anemia of chronic renal disease.
Anemia of neoplasia
Anemia develops in 60%-90% of patients with moderate or far-advanced cancer. The anemia of neoplasia is usually normocytic with normal reticulocyte counts, unless there is hemorrhage or chronic blood loss. Cytotoxic chemotherapy is accompanied by a macrocytic MCV in 30%-40% (12%-82%) of patients. A hemolytic component is present in a considerable minority of patients, but hemolysis is generally mild and is not detectable except with radioisotope RBC survival procedures. Occasionally, hemolysis may be severe, especially in patients with chronic lymphocytic leukemia and malignant lymphomas. In one series, anemia was ascribed to a combination of decreased RBC survival and decreased marrow production in 56% of patients, to blood loss in 29%, and to marrow metastases by the tumor in 13%. Thrombocytopenia may be found in certain types of leukemia and in myelophthisic anemias. Fibrinolysins appear in occasional cases of widespread malignancy, most often prostate carcinoma.
Anemia of infection
Mild to moderate anemia is frequently associated with subacute or chronic infection. The mechanism of this anemia is not well understood, but there seems to be a decreased rate of erythropoiesis, coupled in some patients with slightly shortened RBC survival time and failure to use iron normally. The anemia of infection usually does not develop unless the infection lasts 1 month or more, although it may develop rapidly in patients with severe acute infection such as septicemia. Chronic infection producing anemia generally is of at least moderate severity. Infections in which anemia is likely to develop include bronchiectasis, salpingitis, abscess of visceral organs or body cavities, and severe pyelonephritis. Anemia is a common finding in subacute bacterial endocarditis and in the granulomatous diseases such as tuberculosis and sarcoidosis. The anemia is usually normocytic and normochromic, but sometimes it is hypochromic. Reticulocyte counts are usually normal, although occasionally they may be slightly increased. Bone marrow aspiration shows either normal marrow or hyperplasia of the granulocytes. The serum iron level is usually low or low-normal, and plasma TIBC is reduced (in iron deficiency anemia the TIBC is elevated).
Aplastic anemia is a rare complication of type C (non-A, non-B) hepatitis virus infection.
Rheumatoid-collagen disease group
Rheumatoid-collagen diseases are frequently associated with mild to moderate normocytic anemia. In one study 40% of males and 63% of females with rheumatoid arthritis were anemic. Active disease is more likely to produce anemia. Incidence of coexistent iron deficiency ranges from 10%-30%. Reticulocytes are usually normal, and the bone marrow is unremarkable. In many patients there apparently is decreased erythropoiesis with a slightly shortened RBC survival time, but there is some disagreement regarding frequency of decreased RBC survival. About 5%-10% of patients with rheumatoid arthritis have splenomegaly, which may be associated with cytopenias.
Chronic liver disease
The type and frequency of anemia in liver disease vary with the type and severity of hepatic dysfunction, but anemia has been reported in up to 75% of patients. It is most frequently seen in far-advanced cirrhosis. Extensive metastatic carcinoma of the liver may produce the same effect, although it is difficult to say whether the liver involvement or the neoplasm itself is the real cause. About 30%-50% (8%-65%) of patients with anemia have macrocytosis; about one third are normocytic. Some have hypochromia due to GI blood loss. Target cells in varying numbers are a frequent finding on peripheral blood smear.
Macrocytic anemia in liver disease is most often found in severe chronic liver damage; this type of anemia is not frequent in acute liver disease, even when severe, or in chronic disease of only slight or mild extent. A small but significant percentage of hepatic macrocytic anemias are megaloblastic, usually secondary to folic acid dietary deficiency, although most are not megaloblastic and are not corrected by folic acid treatment. A peripheral blood smear may be macrocytic even when there is a normal hemoglobin or hematocrit reading, and sometimes even with a normal MCV.
GI bleeding occurs in a considerable number of cirrhotic patients; often it is very slight and intermittent. Esophageal varices are present in some. Other lesions may be demonstrated in other patients. In a considerable proportion of cases the source of bleeding cannot be located.
Hypersplenism occurs in some patients with portal vein hypertension and its resulting splenic congestion. Thrombocytopenia, usually mild, is reported to occur in up to 50% of patients with cirrhosis, and other cytopenias may sometimes develop. In severe chronic (or massive acute) liver disease, coagulation problems may result from insufficient hepatic synthesis of several blood coagulation factors.
Some liver-diseased patients have shortened RBC survival demonstrated only by using radioactive isotope studies and show no evidence of GI bleeding. There is no clinical or laboratory evidence of hemolysis otherwise. About 3%-5% develop Zieve’s syndrome, a combination of hyperlipemia, cirrhosis, and microangiopathic hemolytic anemia. This hemolytic anemia is associated with reticulocytosis and the other classic features of hemolysis.
Unless blood loss is a factor, and excluding megaloblastic anemia, the bone marrow is unremarkable in liver disease and the reticulocyte count is usually close to normal. Not all cases of anemia associated with liver disease can be explained.
Hypothyroidism
Anemia is found in 30%-50% (21%-60%) of hypothyroid patients. About 15% (8%-20%) of the anemic patients have macrocytosis, most of the remainder having either normocytic-normochromic or normocytic-hypochromic indices. A small percentage have hypochromic-microcytic RBCs.
The hypochromic anemia of hypothyroidism responds to a combination of iron and thyroid hormone preparation. The iron deficiency component is frequently produced by excessive menstrual bleeding. In patients without demonstrable blood loss it is speculated that decreased intestinal iron absorption may occur, since thyroid hormone is known to affect intestinal carbohydrate absorption. Most of the macrocytic cases respond only to thyroid hormone. In these patients the bone marrow is not megaloblastic and is sometimes slightly hypocellular. The reticulocyte count is usually normal. Isotope studies reportedly show normal RBC survival time in most cases. Lack of thyroid hormone seems to have a direct effect on erythropoiesis, since thyroid hormone therapy cures both the myxedema and the anemia (unless there is superimposed iron deficiency). A minority of patients with macrocytic anemia have folic acid or vitamin B12 deficiency, presumably secondary to decreased intestinal absorption. Thyroid hormone is required in addition to folic acid or vitamin B12. About 5% have actual pernicious anemia, with megaloblastic bone marrow.
Comments on chronic disease anemia
To conclude this discussion, it should be noted that the normocytic-normochromic anemia of systemic disease has often been called“simple chronic anemia,” although the pathophysiology is far from simple. The disease categories listed in this chapter are only the most common. In many cases, the diagnosis is one of exclusion; the patient has anemia for which no definite etiology can be found, so whatever systemic disease he or she has is blamed for the anemia. Some investigators restrict the diagnosis of chronic disease anemia to those who have decreased serum iron and TIBC. Regardless, it is important to rule out treatable serious diseases. This is especially true for hypochromic anemias (in which blood loss might be occurring) and macrocytic anemias (which may be due to vitamin B12 or folic acid deficiency). A normocytic-normochromic anemia may be due to an occult underlying disease, such as malignant lymphoma or multiple myeloma.