History:
Chronic anemias are usually asymptomatic even at remarkably low levels
of hemoglobin. Symptoms more often relate to the underlying cause (eg, lethargy
if secondary to iron deficiency, shortness of breath if related to folic acid or
vitamin B-12 deficiency, left upper quadrant pain if due to HS and splenomegaly,
right upper quadrant pain if due to chronic hemolysis with subsequent
cholelithiasis, constipation and cold intolerance if due to hypothyroidism).
Although uncommon, there may be failure to thrive in infancy. Hemoglobin levels
as low as 5-6 g are extremely well tolerated under stable circumstances and do
not need transfusion. If the basic process is correctable, the anemia resolves
without treatment.
Inquire carefully regarding any evidence of blood loss (eg, hemoptysis,
hematochezia, melena, hematuria, menorrhagia). In endemic areas, a history of
papulovesicular skin lesions on the feet may suggest a diagnosis of hookworms.
Age is always an important consideration. Iron deficiency is seen in older
infants, toddlers, and menstruating girls. The deficiency can be surprisingly
severe, but transfusion is indicated only in the rare circumstance of impending
high-output cardiac failure.
The patient's sex must always be considered in hemolytic anemias. Severe
G-6-PD deficiency may be seen as a chronic nonspherocytic anemia in males only.
Ethnicity is a factor in the hemoglobinopathies. The hemoglobin S syndromes
usually (though not invariably) are seen in populations of central African
origin; hemoglobin C syndromes are seen in populations of western African
origin. The hemoglobin D syndromes usually are seen in northern Indian
subcontinent populations, whereas hemoglobin E syndromes are seen in populations
of southeastern Asia. The beta-thalassemias are seen in Mediterranean, Middle
Eastern, and Southeast Asian populations. The alpha-thalassemias are seen in
African and Asian populations. The thalassemias involving the beta chain are
clinically silent in the first months of life and only become apparent after 6
or 9 months due to cessation of gamma chain production.
Dietary history is important with regard to the amount and source of milk
that infants and toddlers ingest and to their risk of chronic iron deficiency.
Food aversions (eg, to leafy vegetables) can cause predisposition to folic acid
deficiency. Certain diets (eg, a vegan diet) could result in vitamin B-12
deficiency if continued over several years.
A careful review of past history is always crucial. Blood loss over an
extended period results in iron deficiency. Chronic infection, such as chronic
pyelonephritis, bacterial endocarditis, or osteomyelitis, results in the anemia
of chronic disease. Any inflammatory process, such as chronic renal failure or a
chronic collagen vascular disease, also results in the anemia of chronic
disease. Episodic pain in the chest, abdomen, or extremities may reflect a
diagnosis of sickle cell disease.
Drugs with oxidant properties trigger hemolysis due to G-6-PD deficiency, and
this may become chronic if the drugs are continued for an extended period.
Exposure to known marrow toxins, such as benzene or the antibiotic
chloramphenicol, may result in aplastic anemia months after the actual exposure.
Neonatal history may provide useful information about a possibly overlooked
congenital process that manifested after birth. Exaggerated jaundice as a
newborn may be the clue for G-6-PD deficiency in males or for HS in either sex.
Family history is critical in any hereditary anemia. Anemia occurs in
families with thalassemia syndromes. Gallstones, early cholecystectomy, and
splenomegaly are common in families with HS.
Physical:
- Vital signs are rarely abnormal in patients with chronic anemias because
adaptive mechanisms are so well developed. Tachycardia on exertion is usually
the only exception to this rule.
- Growth curves may be affected by chronic anemia, usually in a symmetric
fashion and not including head circumference.
- Dysmorphic features are seen in Fanconi anemia, which is characterized by
some or all of the following: small stature, small head, absent thumbs, and
hyperpigmented skin. Chronic hemolysis with extramedullary hematopoiesis may
result in frontal bossing and prominent cheeks.
- Pallor may be difficult to appreciate unless carefully sought. Pallor of
the conjunctivae, nail beds, palm creases, or gums may be recognized. Parents
and friends usually do not notice any difference because of the chronicity of
the problem.
- Petechiae and excessive bruises may indicate thrombocytopenia due to
marrow aplasia or replacement by malignant cells. Less commonly, the same
findings may reflect vasculitis due to infection or collagen vascular
disease.
- Papulovesicular lesion(s) on the feet may suggest a hookworm
infestation.
- Systolic murmur may be apparent and is usually loudest along the left
sternal border as appropriate for any flow murmur.
- Gallop rhythm, cardiomegaly, and hepatic enlargement may indicate early
congestive heart failure.
- Splenomegaly may indicate chronic hemolysis as in HS or elliptocytosis; it
also may indicate a replacement process as in myeloid metaplasia or
malignancy.
Causes:
- The chronic anemias, as with the acute anemias, are separated into the
following 3 main categories:
- Decreased red cell production
- Marrow aplasia: This may involve a single cell line, as in
Diamond-Blackfan anemia (ie, pure red cell aplasia, erythrogenesis
imperfecta), or it may involve all cell lines as in the aplastic anemias.
Fanconi anemia (ie, congenital aplastic anemia) is usually hereditary
(autosomal recessive) and is associated with other phenotypic
abnormalities as described above. Acquired aplastic anemia is seen at any
age in an otherwise healthy patient.
- Marrow replacement: This may involve tumor cells, fibrous tissue, or
granulomas. Leukemia is the most common malignancy in childhood and
occasionally presents as "smoldering leukemia" over several months. This
is just as likely to occur with acute lymphatic leukemia as with acute
monocytic leukemia. Chronic myelocytic leukemia, though more rare, also
may present as a chronic anemia.
Tumor cells also may metastasize to the bone marrow, though, by that
time, the underlying diagnosis usually has been established. The most
common malignancies that behave in this manner are Hodgkin disease,
non-Hodgkin lymphomas (though extensive involvement of the marrow results
in a change of definition to leukemia), neuroblastoma, rhabdomyosarcoma,
and primary bone tumors. Fibrous tissue may invade the marrow in an
uncontrolled fashion in myelofibrosis with myeloid metaplasia; this is one
of the conditions within the myeloproliferative spectrum of
premalignancies. Granulomas may occur with any of the TORCH
(toxoplasmosis, other infections, rubella, cytomegalovirus infection,
herpes simplex) infections in neonates or in miliary tuberculosis at any
age.
- Impaired erythropoietin production occurs as seen in the anemia of
chronic disease.
- Nutritional deficiency occurs as seen in iron deficiency or in folic
acid or vitamin B-12 deficiency. Protein-energy malnutrition also is
associated with chronic anemia.
- Hemoglobinopathies of the underproduction type occur as seen in the
heterozygous thalassemia syndromes. Normal hemoglobin is underproduced
because of mutations affecting production of alpha- or beta-globin chains.
- Suppression of DNA synthesis occurs as seen in long-term maintenance
chemotherapy.
- Dysplastic erythropoiesis occurs as seen in congenital
dyserythropoietic anemias (types I, II, and III), all characterized by
abnormal-appearing red cell precursors in the bone marrow.
- Increased red cell destruction (hemolysis)
- Extracorpuscular causes include (1) mechanical injury (chronic
disseminated intravascular coagulopathy [DIC], giant hemangioma
[Kasabach-Merritt syndrome]); (2) cardiac valve defects (usually
prosthetic); (3) antibodies (chronic autoimmune hemolysis [warm or cold]);
(4) infections, drugs, and toxins; and (5) hypersplenism (secondary to
splenomegaly of any cause).
- Intrinsic causes include (1) red cell membrane defects (HS,
elliptocytosis, stomatocytosis, acanthocytosis, paroxysmal nocturnal
hemoglobinuria), (2) red cell enzyme abnormalities (G-6-PD deficiency,
pyruvate kinase deficiency), and (3) hemoglobinopathies (homozygotes of
hemoglobins S, C, D, E or the thalassemias, or double heterozygotes of the
above).
- Anemia due to blood loss
- Occult bleeding, usually in unrecognizable quantities via the GI tract
- Loss through the lungs (eg, idiopathic pulmonary hemosiderosis)
- Loss through the kidneys (eg, paroxysmal nocturnal hemoglobinuria)
- Excessive menstrual blood loss due to a coagulopathy (eg, von
Willebrand disease)
