Less Common Anemias: Beyond Iron Deficiency

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Less Common Anemias: Beyond Iron Deficiency

Blackwell, MHS, PA-C, and C. Hendrix, MHS, PA-C

[Clinician Reviews 11(4):57-65, 2001. © 2001 Clinicians Publishing

Group]

Introduction

When iron deficiency fails to account for your patient's anemia, data

from the history, clinical setting, and basic blood work can make

classification of the anemia possible. Patients with chronic infection,

inflammation, or cancer are prone to anemia of chronic disease -- a

normocytic anemia initially, but a microcytic anemia when advanced.

Renal failure and dialysis are associated with a

normochromic-normocytic anemia; treatment often includes recombinant

human erythropoietin. The most common macrocytic anemias, associated

with vitamin B12 or folate deficiencies, are characterized by

reticulocytopenia and usually may be rectified by repletion of these

nutrients. The hallmark of hemolytic anemias is reticulocytosis in the

absence of bleeding.

Anemia -- abnormally low hemoglobin concentration or inadequate red

blood cell (RBC) population -- can be the result of blood loss,

deficient erythropoiesis, or excessive RBC hemolysis. Anemia is

demonstrated on the complete blood cell (CBC) count (see Table 1). The

most common form of anemia encountered in primary care is iron

deficiency anemia; the most frequent cause is blood loss. No matter how

mild, anemia is a significant clinical finding, and the cause should be

sought in every case.

Classification of anemia, general evaluation of anemic patients, and

diagnosis and treatment of iron deficiency anemia have been discussed in

a previous article (Blackwell S, Hendrix PC. Common Anemias: What Lies

Beneath. Clinician Reviews. 2001;11[3]:52-64). This second article will

outline the evaluation and management of patients with anemia of chronic

disease, anemia of renal failure, and anemias of vitamin B12 and folate

deficiencies -- all of which are associated with deficient

erythropoiesis (marrow failure). It will also address several of the

more common hemolytic anemias.

Anemia of Chronic Disease

Anemia of chronic disease is an iron-reutilization anemia that occurs

with underlying chronic disorders such as infections, inflammatory

disorders, and malignancy.[1-13] After iron deficiency anemia, it is the

second most common form of anemia worldwide. Early in its course, anemia

of chronic disease is mormochromic-normocytic, but eventually it becomes

microcytic.[2]

Pathophysiology

Patients with infections, inflammation, or malignancies have an

overexpression of inflammatory cytokines that blunt both production of

erythropoietin and the ability of erythroid progenitor cells to respond

to erythropoietin. In addition, there may be a defect in mobilization of

reticuloendothelial iron for use in hemoglobin synthesis. Whatever the

degree of anemia, anemic cancer patients produce less erythropoietin

than do patients with uncomplicated iron deficiency anemia.[14]

Diagnosis

The underlying cause often is more important than the anemia itself, and

pathophysiologic contributors to anemia arise in infectious and

inflammatory conditions that are not necessarily chronic.[2] In these

cases, anemia is typically mild and gradual in onset, and the hematocrit

remains in the vicinity of 30% (although in 10% of patients, anemia is

more severe). The absolute reticulocyte count is often decreased but may

be normal. Clinical features typically reflect those of the underlying

cause.

Anemia of chronic disease may be suspected in patients with chronic

infection or inflammation, especially those with tuberculosis, lung

abscess, rheumatoid arthritis, systemic lupus erythematosus, polymyalgia

rheumatica, inflammatory bowel disease, and malignant disease.[1-13,15]

It is also a consideration following major trauma or surgery. Not all

chronic conditions cause this form of anemia, however. Asthma,

congestive heart failure, hypertension, ischemic heart disease, and

uncomplicated diabetes mellitus are not associated with anemia of

chronic disease.

The diagnosis of anemia of chronic disease is often one of exclusion,

once iron deficiency, anemia of renal disease, and deficiencies of

vitamin B12 and folate have been ruled out. RBC size and shape are more

consistent in anemia of chronic disease than in iron deficiency anemia.

The most consistent features of anemia of chronic disease are low serum

iron levels and normal or increased iron binding levels with normal or

increased iron stores. This anemia can coexist with iron deficiency

anemia and anemia of renal failure.[16]

The serum ferritin assay is the most useful screening test. The result

is normal or elevated unless the patient is iron deficient, but it is

not diagnostic in the low end of the normal range (20 µg/L to 150 µg/L).

Management

Treatment of the underlying condition is important. The use of

recombinant human erythropoietin (RrHuEPO) may reverse anemia,

eliminating the need for transfusion in some patients. However, this

treatment option remains investigational at present.[17]

Anemia of Renal Failure

Anemia is among the most characteristic manifestations of chronic renal

failure.[1,2,18] Anemia of renal failure is a hypoproliferative anemia

characterized by normochromic-normocytic RBCs.

Pathophysiology

Anemia develops in patients with renal disease for several reasons.

First, failure of renal excretory function leads to increased hemolysis,

and RBC life span is decreased. Second, patients who undergo intensive

dialysis experience blood loss. Third, uremia suppresses erythroid

progenitor cells, decreasing erythropoietin production in proportion to

the degree of excretory impairment.

Diagnosis

Anemia generally occurs when the creatinine clearance falls below 45

mL/min. The absolute reticulocyte count is not elevated, and patients

with anemia of renal failure may have peripheral reticulocytopenia.[1,2]

Other mechanisms of anemia may be operating, however, and a serum

ferritin level below 60 µg/L suggests iron deficiency, even in the

patient with renal insufficiency.[1] Less frequent reasons for anemia in

patients with renal disease include folate deficiency, aluminum

toxicity, hypersplenism, and microangiopathic hemolytic anemia.

In anemia of renal failure, serum iron levels and serum total iron

binding capacity are low or normal and the serum ferritin concentration

is increased. Echinocytes (also known as burr cells) and acanthocytes

(spur cells) may be seen on the peripheral blood film.

Management

Successful therapy directed at the underlying kidney disease corrects

the anemia. For patients who require dialysis and those whose renal

function cannot be fully restored, RrHuEPO is the mainstay of

therapy.[19-22] It may be administered intravenously or subcutaneously

and is well tolerated.[23] The induction dosage is 50 U/kg to 100 U/kg,

three times weekly. A maintenance dosage (approximately half that) can

be given once anemia has been corrected. Patients require iron

supplementation.

CBC count indexes of anemia should increase to normal or near normal

within 12 weeks. Most patients experience significant improvement in

hematocrit, energy level, and overall performance status. Transfusion,

however, may be necessary for the patient in whom cardiopulmonary

manifestations of anemia develop.

Common Macrocytic Anemias

The macrocyte, seen on the peripheral blood film, is an abnormally large

erythrocyte; a megaloblast is a large and immature progenitor of an

abnormal erythrocyte. The macrocytic anemias comprise the megaloblastic

anemias (including those caused by vitamin B12 and folate deficiencies)

and the nonmegaloblastic macrocytic anemias (eg, those associated with

chronic alcoholism, liver disease, hypothyroidism, and use of certain

cytotoxic medications; see Table 2, page 60).[1,2]

Macrocytosis alone does not imply deficient erythropoiesis. Macrocytosis

without associated anemia can occur in alcoholism, hypothyroidism, liver

disease, and hemolytic or bleeding disorders.

Pathophysiology

In the megaloblastic state, DNA synthesis is defective while RNA

synthesis continues, with a consequent increase in cytoplasmic mass and

maturation. Deficiencies of vitamin B12 (cobalamin) or folate are the

most common causes of macrocytic anemia (see Table 3). Anemia caused by

vitamin B12 deficiency is frequently called pernicious anemia, although

the term originally referred only to anemia in which intrinsic factor

(which is required for vitamin B12 absorption in the terminal ileum) is

not secreted by the parietal cells of the gastric mucosa.

Vitamin B12 deficiency leads to secondary deficiency of folate when the

activity of all enzymes that require folate is impaired.[2] Vitamin B12

deficiency does not become apparent for some time. Normally, liver

stores are sufficient to provide for physiologic demand for vitamin B12

for several years when intrinsic factor is absent, and for as long as a

year when enterohepatic reabsorption capacity is limited.

Folate itself is essential for synthesis of DNA, RNA, and proteins.

Folate deficiency reduces all forms of intracellular folate, leading to

impaired growth and development of bone marrow cells and other cells

that grow rapidly.[24] Attempts by the cell to repair abnormal DNA

result in further DNA fragmentation, exacerbating the abnormalities in

cell growth and maturation that are associated with folate deficiency.

Diagnosis

The correct etiologic diagnosis of a megaloblastic anemia is crucial.

For example, chemotherapy given erroneously for suspected myelodysplasia

can be fatal to a patient with a vitamin B12 deficiency that could have

been managed with cobalamin therapy.[24]

The most common cause of vitamin B12 deficiency is poor absorption

(which places patients who have undergone total gastrectomy at risk, for

example). Vitamin B12 deficiency also results from inadequate intake due

to poor diet or strict vegetarianism. It can arise when vitamin B12

requirements are increased, as in pregnancy or hyperthyroidism.

Signs and symptoms of vitamin B12 deficiency are legion, and the

deficiency is often more severe than symptoms suggest.[2] The clinical

picture may include abdominal discomfort, glossitis, weight loss, mood

changes, irritability, color blindness, and neurologic findings such as

peripheral loss of sensation, spasticity, ataxia, and loss of taste and

smell.

The evaluation begins with a serum vitamin B12 assay. The Schilling test

or an assay for anti-intrinsic factor antibody in serum should be

ordered when a patient has a low serum cobalamin level. The Schilling

test involves giving the patient a small amount of radioactive vitamin

B12, which is later measured in the urine; this test is the standard

method for evaluating intrinsic factor status and demonstrating

malabsorption.[25] The peripheral blood film shows RBCs of widely

varying size (anisocytosis) and shape (poikilocytosis), with echinocytes

and acanthocytes present. The absolute reticulocyte count is low.

Signs and symptoms of folate deficiency are similar to those of

cobalamin deficiency, except there is no neurologic involvement. The two

deficiencies are indistinguishable by peripheral blood and marrow

findings. In addition, because these nutrients function intracellularly

rather than in plasma, deficiencies may not be reflected in serum

levels.

To distinguish between vitamin B12 and folate deficiencies, serum assays

for methylmalonic acid and homocysteine are helpful.[1] The serum

methylmalonic acid level is elevated in most patients with vitamin B12

deficiency but not in patients with folate deficiency. In both cobalamin

and folate deficiency, homocysteine levels are elevated.

Management

Treatment of choice for vitamin B12 deficiency due to pernicious anemia

is intramuscular or subcutaneous injection of cyanocobalamin or

hydroxocobalamin. Patients may receive 1,000 µg once weekly for eight

weeks, then once a month for life.[24] Lower doses (as low as 100 µg)

may be adequate,[26] but due to concern about replenishing vitamin B12

stores and minimizing neurologic manifestations (and in the absence of

any toxicity), the 1,000-µg dose is commonly recommended.

In one study of vitamin B12-deficient patients, investigators

demonstrated that 2 mg/d of oral cyanocobalamin ( " a preparation of

proven bioavailability " ) was as effective as 1 mg per month,

administered intramuscularly, in correcting vitamin B12

deficiency-associated hematologic and neurologic abnormalities.[27]

Bone marrow and RBC morphology usually return to normal within 24 to 48

hours of initiation of therapy for vitamin B12 and/or folate deficiency.

If iron stores are adequate, anemia is corrected within four to eight

weeks. Poor therapeutic response may be an indication of iron deficiency

(which is common in patients with cobalamin and folate deficiencies).

Vitamin B12 deficiency can occasionally occur secondary to dietary

deficiency. A typical diet should include between 5 ng/d (the minimum

daily requirement for an adult) and 30 ng/d of vitamin B12. Since meat

and dairy products are particularly high in this nutrient, patients who

follow strict vegetarian or vegan diets or who have poor nutritional

habits should take oral vitamin B12 supplements.

Whenever possible, folate deficiency is treated by adding folic

acid-rich foods to the diet. These include legumes, leafy green

vegetables, fruits, and liver. Oral folic acid supplementation, at a

dosage of 1.0 mg/d, may also be given.

Generally, folic acid supplements are recommended for patients who are

pregnant, who require dialysis, or who receive long-term anticonvulsant

therapy. However, before folic acid is given, vitamin B12 deficiency

must be ruled out. This is because in the cobalamin-deficient patient,

folic acid would alleviate anemia but not progressive neurologic

damage.[2]

Common Hemolytic Anemias

Hemolytic anemia is characterized by anemia with a normal or high

absolute reticulocyte count in the absence of bleeding -- indicating

that erythropoiesis is adequate, but destruction of erythrocytes is

excessive.

Pathophysiology

The causes of hemolytic anemias are classified as either intrinsic or

extrinsic. Intrinsic red cell defects include hemoglobinopathies, enzyme

deficiencies, and membrane skeletal protein abnormalities. Extrinsic red

cell defects include mechanical fragmentation, antibody-mediated

destruction, and hypersplenism.[2,28]

The actual site of hemolysis is usually extravascular, occurring in

phagocytic cells of the spleen, bone marrow, and liver.[2] The spleen

and liver destroy abnormal RBCs, and the spleen is also capable of

sequestering normal and abnormal RBCs. In particular, warm-antibody

hemolysis occurs in the spleen when phagocytes ingest immunoglobulin

G-coated RBCs. By contrast, intravascular hemolysis occurs when RBCs are

destroyed within the circulation, either due to intrinsic RBC defects

(such as glucose-6-phosphate dehydrogenase deficiency), or as a result

of RBC fragmentation (as seen in microangiopathic hemolytic anemia).

Diagnosis

The clinical setting and history point to risk factors for hemolytic

anemia, and certain medications, infections, and inflammatory disease

are closely associated with it (see Table 2, page 60, and Table

4).[1,2,29] The signs and symptoms of hemolytic anemias are similar to

those of anemia in general. In acute, severe hemolysis, the patient may

experience chills, fever, abdominal and back pain, prostration, shock,

splenomegaly, hepatomegaly, and jaundice. There may be hemoglobinuria

and hemosiderinuria, indicating intravascular hemolysis. Reticulocytosis

is present.

The definitive diagnostic test is measurement of RBC life span using a

nonreusable radiolabel, such as chromium 51, but this is seldom

necessary.[2] Diagnosis is possible in most patients using the Coombs

direct antiglobulin test and the peripheral blood film. The Coombs test

is useful for evaluating patients with autoimmune hemolytic anemia.

Spherocytosis, fragmentation of RBCs, and erythrophagocytosis are

apparent on the peripheral film. Spherocytes are reliable indicators of

hemolysis; fragmented RBCs, such as schistocytes (helmet cells) and

triangular cells, indicate traumatic or infectious RBC destruction.

Presence of immature nucleated cells suggests bone marrow hyperactivity

intended to compensate for shortened RBC survival.

Management

Treatment of patients with warm-antibody autoimmune hemolytic anemia

depends on cause.[1,2,29-31] If the condition is drug-induced,

discontinuation of the drug will reduce the rate of hemolysis. Some

agents, such as sulfonamides and cytotoxic anticancer drugs, also cause

aplastic anemia.[30,31]

If the diagnosis is idiopathic, warm-antibody autoimmunme hemolytic

anemia, corticosteroid therapy with oral prednisone (as much as 100

mg/d) is recommended. After the hematocrit has stabilized, dosing may be

tapered. Patients who do not respond to corticosteroid therapy usually

require splenectomy. Transfusion should be avoided because it may

accelerate hemolysis.

Patients with cold-antibody hemolytic anemia need to avoid exposure to

cold.[2] Splenectomy is of no value. Immunosuppressive drugs may be

helpful.

Therapy for hemolytic anemias caused by infection and RBC trauma

consists of transfusion (when anemia is severe) and treatment of the

underlying disease. Iron supplementation may be necessary.

Conclusion

Anemic patients in whom iron deficiency anemia has been ruled out must

next be evaluated for the anemias caused by inadequate RBC production

(erythropoiesis) or excessive RBC destruction (hemolysis). Only by

identifying the correct form of anemia can clinicians select and

administer appropriate therapy -- which may be as simple as correcting a

nutrient deficiency or as involved as transfusion or even splenectomy.

~~~~~~~~~~~~~~~~~~~~~~~~~

For a related article, Common Anemias: What Lies Beneath

http://www.medscape.com/CPG/ClinReviews/2001/v11.n03/c1103.03.blac/c1103.03.blac\

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