INTRODUCTION	Section 2 of 10
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Background: Chronic anemia has no precise definition. Anemia that persists for 6 months or more (eg, hereditary spherocytosis [HS]) is clearly chronic; however, anemia that lasts only 2 months (eg, iron deficiency that is being treated) should also be considered chronic anemia, and other explanations must be sought.

Pathophysiology: Chronic anemia can be primary or secondary.

Primary chronic anemia

Primary chronic anemias are the true chronic anemias, in which anemia (defined as a hemoglobin level more than 2 standard deviations below the mean reference value for age) is part of the basic disease process. The basic disease process is hematologic (eg, sickle cell disease, HS), and the degree of anemia is often acceptable.

Secondary chronic anemia

Secondary chronic anemias are chronic anemias that may provide a diagnostic clue to a chronic disease. Chronic anemia is defined as anemia persisting longer than 2-6 months. Secondary chronic anemias are the consequence of a nonhematologic problem (eg, chronic osteomyelitis).

Frequency:

• Internationally: Overall prevalence of chronic anemia varies in proportion to the ethnic group studied. Worldwide, undiagnosed iron deficiency is probably the most common cause of isolated chronic anemia, especially in children aged 1-5 years and in teenagers. This may reflect inadequate nutritional iron and/or the effects of chronic parasitic infections (eg, hookworm). Anemia is also seen in persons with generalized malnutrition states but not as an isolated finding.

  In Mediterranean and Middle Eastern populations, b-thalassemia trait is an important consideration in the differential diagnosis of chronic anemia at any age. a Thalassemia is seen more commonly in other areas (eg, Southeast Asia).

Mortality/Morbidity:

• Death resulting from chronic anemia is extremely uncommon because of the adaptive ability of the cardiovascular system.

• Morbidity is also uncommon and is usually related to the primary disease process rather than the anemia per se. Shortness of breath and easy fatigability are unpredictable because some children tolerate extremely low hemoglobin concentrations, in the range of 4-5 g/dL, without any problem, while other children are symptomatic with values at 2 times that concentration. No evidence suggests that such low hemoglobin concentrations pose any systemic problems, but low concentrations can be distressing to children and families. In situations of true red blood cell aplasia, the anemia eventually reaches a point at which compensatory mechanisms are no longer adequate, and congestive heart failure or syncope can result.

Race: Certain racial groups are much more likely than others to have inherited anemias. Hemoglobin S syndromes are usually (although not invariably) seen in populations of Central African origin; hemoglobin C syndromes are seen in populations of Western African origin. Hemoglobin D syndromes are usually seen in populations of Northern India, and hemoglobin E syndromes are seen in populations of Southeast Asia. b Thalassemias are seen in Mediterranean, Middle Eastern, and Southeast Asian populations. a Thalassemias are seen in African and Asian populations. G-6-PD deficiency is more likely in individuals of Mediterranean or Southeast Asian origin.

Sex: Males are much more likely to have G-6-PD deficiency than are females. Immune hemolytic anemias are more common in females because of the higher prevalence of collagen vascular diseases. Chronic anemia may be hastened or exacerbated by menstrual blood loss.

Age: Onset of Diamond-Blackfan anemia is usually in early infancy. Onset of homozygous or doubly heterozygous hemoglobinopathies is in later infancy. Chronic iron deficiency anemia first manifests in later infancy and the second year of life. The toddler years are the period of lead poisoning. Onset of menses leads to susceptibility to iron deficiency.

	CLINICAL	Section 3 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

History: Patients with chronic anemia are usually asymptomatic, even with remarkably low levels of hemoglobin. Symptoms more often relate to the underlying cause, for example, lethargy if secondary to iron deficiency, shortness of breath if related to folic acid or vitamin B-12 deficiency, left upper quadrant pain if the result of HS and splenomegaly, right upper quadrant pain if the result of chronic hemolysis with subsequent cholelithiasis, and constipation and cold intolerance if the result of hypothyroidism. Although uncommon, failure to thrive may occur in infancy. Hemoglobin levels as low as 5-6 g/dL are extremely well tolerated under stable circumstances, and patients do not require transfusion. If the basic process is correctable, anemia resolves without treatment.

The following considerations may be relevant:

• 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 hookworm infection.

• 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.

• Hemoglobin S syndromes are usually (although not invariably) seen in populations of Central African origin.

• Hemoglobin C syndromes are seen in populations of Western African origin.

• Hemoglobin D syndromes are usually seen in the population of Northern India.

• Hemoglobin E syndromes are seen in populations of Southeast Asia.

• b Thalassemias are seen in Mediterranean, Middle Eastern, and Southeast Asian populations. Thalassemias involving the b chain are clinically silent in the first months of life and become apparent only after 6-9 months because of cessation of g-chain production.

• a Thalassemias are seen in African and Asian populations.

• Dietary history is important with regard to the amount and source of milk ingested by infants and toddlers and to their risk of chronic iron deficiency. Food aversions (eg, to leafy vegetables) can cause predisposition to folic acid deficiency. Certain diets (eg, vegan diet) can 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 because of G-6-PD deficiency, and hemolysis 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 actual exposure.

• Neonatal history may provide useful information regarding a possibly overlooked congenital process that manifested after birth. Exaggerated jaundice as a newborn may be a clue for G-6-PD deficiency in males or for HS in females or males.

• 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 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, although head circumference is not affected.

• Dysmorphic features are seen in Fanconi anemia, which is characterized by some or all of the following features: 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 sought carefully. Pallor of the conjunctivae, nailbeds, palm creases, or gums may be recognized. Parents and friends usually do not notice any difference because the problem is chronic.

• Petechiae and excessive bruises may indicate thrombocytopenia resulting from marrow aplasia or replacement by malignant cells. Less commonly, the same findings may reflect vasculitis resulting from infection or collagen vascular disease.

• Papulovesicular lesion(s) on the feet may suggest hookworm infestation.

• Systolic murmur may be apparent and usually is loudest along the left sternal border, as is appropriate in 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. Splenomegaly also may indicate a replacement process, as in myeloid metaplasia or malignancy.

Causes: As with acute anemia, chronic anemia is classified into the following 3 primary categories:

• Decreased red cell production

• Marrow aplasia 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 aplastic anemia. Fanconi anemia (ie, congenital aplastic anemia) usually is 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 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, which is just as likely to occur with acute lymphatic leukemia as with acute monocytic leukemia. Chronic myelocytic leukemia, although rarer, also may present as a chronic anemia.

  • Tumor cells also may metastasize to bone marrow, although, 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 (although 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 patients of any age with miliary tuberculosis.

• 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 heterozygous thalassemia syndromes. Normal hemoglobin is underproduced because of mutations affecting production of a- or b-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 of hemolysis 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 of hemolysis 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

• Blood loss through the lungs (eg, idiopathic pulmonary hemosiderosis)

• Blood loss through the kidneys (eg, paroxysmal nocturnal hemoglobinuria)

• Excessive menstrual blood loss resulting from a coagulopathy (eg, von Willebrand disease)