Postgraduate Medicine
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Determining the cause of anemia Robert G. Brown MD To cite this article: Robert G. Brown MD (1991) Determining the cause of anemia, Postgraduate Medicine, 89:6, 161-170, DOI: 10.1080/00325481.1991.11700925 To link to this article: http://dx.doi.org/10.1080/00325481.1991.11700925
Published online: 17 May 2016.
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20 Download by: [La Trobe University]
Date: 17 June 2016, At: 21:22
-@CME credit article Determining the cause of anemia General approach, with emphasis on microcytic hypochromic anemias Robert G. Brown, MD
Downloaded by [La Trobe University] at 21:22 17 June 2016
Preview Anemia Is a common problem encountered in primary care medicine. The possible causes are so numerous that many practitioners adopt a shotgun approach to diagnosis. Dr Brown outlines a systematic, cost-effective approach In which morphologic classification by cell size and hemoglobin content serves as the starting point for differential diagnosis.
Anemia is defined as a reduction in either the red blood cell volume (hematocrit) or the concentration of hemoglobin in the blood. Normal values for red blood cell measurements vary with age (table 1). In general, values more than 2 SD below the mean warrant investigation. However, relying strialy on a numerical definicion of anemia may obscure significant pathologic features.
For example, a woman who has chronic lung disease and a hemoglobin level of 13.5 gldL may need a more detailed workup, especially if her hemoglobin level had been 17.5 gldL Similarly; a patient with moderate to severe dehydration and normal hematocrit and hemoglobin values may need to undergo further examination, and these values would most certainly have to be measured again after rehydration. In contrast, a patient with significant fluid overload due to congestive heart failure might appear to be anemic from findings on the initial hemogram, but values may rerum to normal after diuresis. Anemias are classified as micro-
eyrie hypochromic, normocytic, or macrocytic according to the size and hemoglobin content of the red blood cells. Differential diagnosis within each class is guided by the patient history; physical examination results, red cell morphologic findings, and reticulocyte count.
History and physiml examination A family history of anemia suggests an inherited red cell disorder, as does a patient history of anemia and intermittent jaundice early in life. A history of chronic blood loss is also important. Women of reproductive age should be asked specific questions about the frequency; duration, and heaviness of menstrual flow. Since patients will report any urinary or pulmonary bleeding, truly occult blood loss is almost always from the gastrointestinal traCt. Many drugs and toxins can cause anemia (table 2). The possibility of alcohol-related bone marrow toxicity is often overlooked in patients who "don't look alcoholic." Most chronic inflammatory diseases and malignant diseases are accompanied by a characteristic mild to moderate ane-
VOL 89/NO 6/MAY 1, 1991/POSTGRADUATE MEDICINE • . - A
mia (the anemia of chronic disease), and a thorough systems review usually points to the diagnosis. Patients who have diminished hepatic, renal, or thyroid function are often anemic, and the classic signs and symptoms of these conditions should be sought. A complete physical examination, along with the patient history; narrows the differential diagnostic considerations in anemia Signs of chronic rheumatologic disease, liver disease, and endocrinopathies should be sought. Generalized lymphadenopathy suggests infection, lymphoma, or leukemia. Pelvic and rectal examinations are essential, and the breasts and abdomen should be examined for evidence of malignant disease. Scleral icterus and an enlarged spleen suggest a hemolytic anemia. Diminished vibration and proprioceptive sensation suggest a deficiency of vitamin B12 rather than folate when a complete blood cell count reveals macrocytic anemia and hypersegmented neutrophils. IUd cd1 structure Morphologic classification of anemia is based on the red cell indexes and examination of a peripheral blood smear. MEAN CORPUSCULAR VOWME-
The most useful of the red cell indexes is the mean corpuscular volume (MCV). The normal range for adults is about 78 to 98 fL; it is somewhat lower for infants and chilcontinued 161
Most chronic inflammatory and malignant diseases are accompanied by a mild to moderate anemia.
Downloaded by [La Trobe University] at 21:22 17 June 2016
Table 1. Normal hematologic values, by age Age
Hemoglobin (gldl) Mean (-2 SO)
Hematocrit (%} Mean (-2 SO)
Mean (-2 SO)
MCV (fl}
18.0 (14.0) 12.0 (10.5)
54 (42) 36 (32)
108 (95) 78 (70)
14.5 (13.0) 14.0 (12.0)
43 (38) 41 (36)
86 (77) 88 (78)
15.5 (13.5) 14.0 (12.0)
47 (40) 41 (36)
88 (78) 88 (78)
dren (table 1). On the basis of the MCV, anemias can be classified as microcytic (low MCV), normocytic (normal MCV), or macrocytic (high
MCV). 1-3 days 6 mo-2 yr 12-18 yr Male Female Adult Male Female
Figure 1. Microcytes.
Figura 2. Oval macrocytes, as seen in megaloblastic anemia.
Figura 3. Mechanical hemolytic anemia. Schistocytes (arrow), normal cells, large "shift cells," and a nucleated red blood cell are present.
Figura 4. Normal red blood cells.
Since the MCV represents an automated averaging of the size of all red cells in a blood sample, it is a reliable means of classifYing anemias only when the red cell population is fairly homogeneous. The red cell distribution width (RDW) is a calculated index; values above the normal range (11.5% to 14.5%) correlate with anisocytosis (variability of red cell size). Thus, when the RDW is significantly elevated, the MCV is less reliable. In such situations, careful examination of a well-prepared peripheral blood smear is especially helpful. On microscopic examination, a normal red blood cell is about the size of the nucleus of a small lymphocyte. With this as a guideline, cell size can be estimated in absolute terms (figures 1 and 2) and the marked heterogeneity of cells can be appreciated on a blood smear. A patient whose MCV is normal may be found to have many red cell fragments (schistocytes, which lower the MCV); some normal-sized cells; and many large polychromatophilic cells ("shift cells," which on supravital staining are shown to be reticulocytes and which raise the MCV). Thus, the diagnosis of a mechanical hemolytic anemia can be made (figure 3).
162
AIIIBIIA • VOL 89INO 6/MAY 1, 1991/POSTGRADUATE MEDICINE
The mean corpuscular volume is a reliable means of classifying anemias only when the red cell population is fairly homogeneous.
Downloaded by [La Trobe University] at 21:22 17 June 2016
Table 2. Drugs that can cause anemia Drugs causing marrow hypoplasia or aplasia
Drugs causing hemolytic anemia
Antineoplastic drugs • Antimetabolites: mercaptopurine (Purinethol), azathioprine (lmuran), fluorouracil (Adrucil), hydroxyurea (Hydrea), cytarabine (Cytosar-U) • Alkylating agents: cyclophosphamide (Cytoxan, Neosar), chlorambucil (Leukeran), busulfan (Myleran), melphalan (Aikeran) Antimicrobial drugs: chloramphenicol (Chloromycetin), quinacrine (Atabrine) hydrochloride, streptomycin sulfate, sulfas Anticonvulsant drugs: trimethadione (Tridione), phenytoin sodium (Dilantin), primidone (Mysoline), carbamazepine (Tegretol) Anti-inflammatory drugs: phenylbutazone (Butazolidin), gold salts, aspirin, colchicine Oral hypoglycemics: chlorpropamide (Diabinese), tolbutamide (Orinase) Tranquilizers: chlordiazepoxide (Ubrium), meprobamate (Equanil, Miltown) Major tranquilizers/antiemetics: chlorpromazine (Thorazine), prochlorperazine (Compazine) Antihistamines: chlorpheniramine, tripelennamine hydrochloride (PBZ) Miscellaneous: alcohol, acetazolamide (Diamox), potassium perchlorate (Perchloracap)
In G6PO deficiency • Antimicrobial drugs: sulfas, primaquine phosphate, quinacrine, nitrofurantoin (Furadantin), nalidixic acid (Neg Gram Caplets) • Others: phenazopyridine hydrochloride (Baridium, Pyridium) In immune hemolytic anemia Penicillin, sulfas, quinine, quinidine sulfate, methyldopa (Aidomet), para-aminosalicylic acid, mefenamic acid (PonsteQ, levodopa (Dopar, Larodopa) Folate antagonists
Methotrexate (Rheumatrex Dose Pack, Folex) Pyrimethamine (Daraprim) Sulfadoxine and pyrimethamine (Fansidar) Trimethoprim and sulfamethoxazole Triamterene (contained in Dyazide, Maxzide) Porphyrin/heme synthesis antagonists
Alcohol Isoniazid Drugs causing gastrointestinal blood loss
Aspirin Nonsteroidal anti-inflammatory agents Alcohol
G6PD, glucose-6-phosphate dehydrogenase.
MEAN CORPUSCUlAR HFMOGI.OBIN CONCENTRATION-Red blood cells are also characterized morpho-
logically by hemoglobin content. The mean corpuscular hemoglobin concentration (MCHC) is a derived red cell index. Values within the normal range (32 to 36 gld.L) indicate normochromia, and values below this range, hypochromia. Only in
spherocytic disorders is the MCHC increased, and automated cell counters are relatively insensitive to this. As with the MCV, the MCHC must be considered in conjunction with examination of a peripheral blood smear. On a well-stained blood smear the area of central pallor in a normal red blood cell has a diameter about one third that of the
VOL 89/NO 6/MAY 1, 1991/POSTGRAOUATE MEDICINE • AN. .IA
entire cell (figure 4). When the central pallor far exceeds this, the red blood cells are considered hypochromic. Again, since the MCHC represents an average, it does not reflect the marked heterogeneity in red cell hemoglobin concentration that may be present in a particular patient. Idiopathic sideroblastic anemia is an extreme example in which excontinued
163
Downloaded by [La Trobe University] at 21:22 17 June 2016
Many anemias are characterized by specific aberrations in red cell structure that are easily recognized on a peripheral blood smear.
Figura 5. Sickled cells in patient with hemoglobin SS disease.
Figura 6. Spherocytes in patient with hereditary spherocytosis.
Figura 7. Teardrop cells in patient with myelofibrosis.
Figura a. Target cells and microcytes in patient with thalassemia trait.
Figura 9. Burr cell.
Figura 10. Bite cells. Notched-out deformities remain after expulsion of Heinz bodies, as in glucose-6-phosphate dehydrogenase deficiency.
amination of a peripheral blood smear reveals two populations of red blood cells, one entirely normal and o~e macrocytic and quite hypochro-
When none of these abnormalities are present, the morphologic classification of anemias by cell size and hemoglobin content can be used to determine the underlying cause.
rmc.
Figura 11. Elliptocytes in patient with hereditary elliptocytosis.
164
ABERRATIONs-Many anemias are charaaerized by rather specific aberrations in red cell structure (figures 5 through 11). These are easily recognized on a peripheral blood smear and include sickled cells, spherocytes, teardrop cells, schistocytes, target cells, burr cells, bite cells, and elliptocytes (table 3).
Miaocytic hypochromic anemias Microcytic hypochromic anemias can result from iron deficiency, chronic disease, thalassemias, hemoglobin E disorders, and lead toxicity (table 4). An algorithm for diagnosis of such anemias is presented in figure 12. continued
ANDIIA • VOL 89/NO 6/MAY 1, 1991/POSTGRAOUATE MEDICINE
Response to a trial of iron therapy is useful in diagnosing iron deficiency when a patient's serum ferritin level is normal.
Downloaded by [La Trobe University] at 21:22 17 June 2016
Table 3. Morphologic findings on peripheral blood smear in anemia
Findings Sickled cells Spherocytes Teardrop cells Schistocytes Target cells Burr cells Bite cells Elliptocytes
Disorders Sickle cell anemia Sickle cell-hemoglobin C disease Sickle cell-thalassemia syndromes Hereditary spherocytosis lgG autoimmune hemolytic anemia Myelophthisic anemias Myelofibrosis Mechanical hemolytic anemias Hemoglobin C and E syndromes (predominant cell type) Hypochromic anemias (present in smaller numbers) Uremia Heinz body-positive anemias, most commonly G6PD deficiency Hereditary elliptocytosis (predominant cell type) Iron deficiency (present in smaller numbers)
G6PD, glucose-6-phosphate dehydrogenase.
IRON DEFICIENCY-This condition is the most common cause of anemia throughout the world and by far the most common cause of microcytic hypochromic anemia (figure 13). In most cases of iron deficiency the serum ferritin concentration, which reflects total body iron stores, is low (
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Determining the cause of anemia Robert G. Brown MD To cite this article: Robert G. Brown MD (1991) Determining the cause of anemia, Postgraduate Medicine, 89:6, 161-170, DOI: 10.1080/00325481.1991.11700925 To link to this article: http://dx.doi.org/10.1080/00325481.1991.11700925
Published online: 17 May 2016.
Submit your article to this journal
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20 Download by: [La Trobe University]
Date: 17 June 2016, At: 21:22
-@CME credit article Determining the cause of anemia General approach, with emphasis on microcytic hypochromic anemias Robert G. Brown, MD
Downloaded by [La Trobe University] at 21:22 17 June 2016
Preview Anemia Is a common problem encountered in primary care medicine. The possible causes are so numerous that many practitioners adopt a shotgun approach to diagnosis. Dr Brown outlines a systematic, cost-effective approach In which morphologic classification by cell size and hemoglobin content serves as the starting point for differential diagnosis.
Anemia is defined as a reduction in either the red blood cell volume (hematocrit) or the concentration of hemoglobin in the blood. Normal values for red blood cell measurements vary with age (table 1). In general, values more than 2 SD below the mean warrant investigation. However, relying strialy on a numerical definicion of anemia may obscure significant pathologic features.
For example, a woman who has chronic lung disease and a hemoglobin level of 13.5 gldL may need a more detailed workup, especially if her hemoglobin level had been 17.5 gldL Similarly; a patient with moderate to severe dehydration and normal hematocrit and hemoglobin values may need to undergo further examination, and these values would most certainly have to be measured again after rehydration. In contrast, a patient with significant fluid overload due to congestive heart failure might appear to be anemic from findings on the initial hemogram, but values may rerum to normal after diuresis. Anemias are classified as micro-
eyrie hypochromic, normocytic, or macrocytic according to the size and hemoglobin content of the red blood cells. Differential diagnosis within each class is guided by the patient history; physical examination results, red cell morphologic findings, and reticulocyte count.
History and physiml examination A family history of anemia suggests an inherited red cell disorder, as does a patient history of anemia and intermittent jaundice early in life. A history of chronic blood loss is also important. Women of reproductive age should be asked specific questions about the frequency; duration, and heaviness of menstrual flow. Since patients will report any urinary or pulmonary bleeding, truly occult blood loss is almost always from the gastrointestinal traCt. Many drugs and toxins can cause anemia (table 2). The possibility of alcohol-related bone marrow toxicity is often overlooked in patients who "don't look alcoholic." Most chronic inflammatory diseases and malignant diseases are accompanied by a characteristic mild to moderate ane-
VOL 89/NO 6/MAY 1, 1991/POSTGRADUATE MEDICINE • . - A
mia (the anemia of chronic disease), and a thorough systems review usually points to the diagnosis. Patients who have diminished hepatic, renal, or thyroid function are often anemic, and the classic signs and symptoms of these conditions should be sought. A complete physical examination, along with the patient history; narrows the differential diagnostic considerations in anemia Signs of chronic rheumatologic disease, liver disease, and endocrinopathies should be sought. Generalized lymphadenopathy suggests infection, lymphoma, or leukemia. Pelvic and rectal examinations are essential, and the breasts and abdomen should be examined for evidence of malignant disease. Scleral icterus and an enlarged spleen suggest a hemolytic anemia. Diminished vibration and proprioceptive sensation suggest a deficiency of vitamin B12 rather than folate when a complete blood cell count reveals macrocytic anemia and hypersegmented neutrophils. IUd cd1 structure Morphologic classification of anemia is based on the red cell indexes and examination of a peripheral blood smear. MEAN CORPUSCULAR VOWME-
The most useful of the red cell indexes is the mean corpuscular volume (MCV). The normal range for adults is about 78 to 98 fL; it is somewhat lower for infants and chilcontinued 161
Most chronic inflammatory and malignant diseases are accompanied by a mild to moderate anemia.
Downloaded by [La Trobe University] at 21:22 17 June 2016
Table 1. Normal hematologic values, by age Age
Hemoglobin (gldl) Mean (-2 SO)
Hematocrit (%} Mean (-2 SO)
Mean (-2 SO)
MCV (fl}
18.0 (14.0) 12.0 (10.5)
54 (42) 36 (32)
108 (95) 78 (70)
14.5 (13.0) 14.0 (12.0)
43 (38) 41 (36)
86 (77) 88 (78)
15.5 (13.5) 14.0 (12.0)
47 (40) 41 (36)
88 (78) 88 (78)
dren (table 1). On the basis of the MCV, anemias can be classified as microcytic (low MCV), normocytic (normal MCV), or macrocytic (high
MCV). 1-3 days 6 mo-2 yr 12-18 yr Male Female Adult Male Female
Figure 1. Microcytes.
Figura 2. Oval macrocytes, as seen in megaloblastic anemia.
Figura 3. Mechanical hemolytic anemia. Schistocytes (arrow), normal cells, large "shift cells," and a nucleated red blood cell are present.
Figura 4. Normal red blood cells.
Since the MCV represents an automated averaging of the size of all red cells in a blood sample, it is a reliable means of classifYing anemias only when the red cell population is fairly homogeneous. The red cell distribution width (RDW) is a calculated index; values above the normal range (11.5% to 14.5%) correlate with anisocytosis (variability of red cell size). Thus, when the RDW is significantly elevated, the MCV is less reliable. In such situations, careful examination of a well-prepared peripheral blood smear is especially helpful. On microscopic examination, a normal red blood cell is about the size of the nucleus of a small lymphocyte. With this as a guideline, cell size can be estimated in absolute terms (figures 1 and 2) and the marked heterogeneity of cells can be appreciated on a blood smear. A patient whose MCV is normal may be found to have many red cell fragments (schistocytes, which lower the MCV); some normal-sized cells; and many large polychromatophilic cells ("shift cells," which on supravital staining are shown to be reticulocytes and which raise the MCV). Thus, the diagnosis of a mechanical hemolytic anemia can be made (figure 3).
162
AIIIBIIA • VOL 89INO 6/MAY 1, 1991/POSTGRADUATE MEDICINE
The mean corpuscular volume is a reliable means of classifying anemias only when the red cell population is fairly homogeneous.
Downloaded by [La Trobe University] at 21:22 17 June 2016
Table 2. Drugs that can cause anemia Drugs causing marrow hypoplasia or aplasia
Drugs causing hemolytic anemia
Antineoplastic drugs • Antimetabolites: mercaptopurine (Purinethol), azathioprine (lmuran), fluorouracil (Adrucil), hydroxyurea (Hydrea), cytarabine (Cytosar-U) • Alkylating agents: cyclophosphamide (Cytoxan, Neosar), chlorambucil (Leukeran), busulfan (Myleran), melphalan (Aikeran) Antimicrobial drugs: chloramphenicol (Chloromycetin), quinacrine (Atabrine) hydrochloride, streptomycin sulfate, sulfas Anticonvulsant drugs: trimethadione (Tridione), phenytoin sodium (Dilantin), primidone (Mysoline), carbamazepine (Tegretol) Anti-inflammatory drugs: phenylbutazone (Butazolidin), gold salts, aspirin, colchicine Oral hypoglycemics: chlorpropamide (Diabinese), tolbutamide (Orinase) Tranquilizers: chlordiazepoxide (Ubrium), meprobamate (Equanil, Miltown) Major tranquilizers/antiemetics: chlorpromazine (Thorazine), prochlorperazine (Compazine) Antihistamines: chlorpheniramine, tripelennamine hydrochloride (PBZ) Miscellaneous: alcohol, acetazolamide (Diamox), potassium perchlorate (Perchloracap)
In G6PO deficiency • Antimicrobial drugs: sulfas, primaquine phosphate, quinacrine, nitrofurantoin (Furadantin), nalidixic acid (Neg Gram Caplets) • Others: phenazopyridine hydrochloride (Baridium, Pyridium) In immune hemolytic anemia Penicillin, sulfas, quinine, quinidine sulfate, methyldopa (Aidomet), para-aminosalicylic acid, mefenamic acid (PonsteQ, levodopa (Dopar, Larodopa) Folate antagonists
Methotrexate (Rheumatrex Dose Pack, Folex) Pyrimethamine (Daraprim) Sulfadoxine and pyrimethamine (Fansidar) Trimethoprim and sulfamethoxazole Triamterene (contained in Dyazide, Maxzide) Porphyrin/heme synthesis antagonists
Alcohol Isoniazid Drugs causing gastrointestinal blood loss
Aspirin Nonsteroidal anti-inflammatory agents Alcohol
G6PD, glucose-6-phosphate dehydrogenase.
MEAN CORPUSCUlAR HFMOGI.OBIN CONCENTRATION-Red blood cells are also characterized morpho-
logically by hemoglobin content. The mean corpuscular hemoglobin concentration (MCHC) is a derived red cell index. Values within the normal range (32 to 36 gld.L) indicate normochromia, and values below this range, hypochromia. Only in
spherocytic disorders is the MCHC increased, and automated cell counters are relatively insensitive to this. As with the MCV, the MCHC must be considered in conjunction with examination of a peripheral blood smear. On a well-stained blood smear the area of central pallor in a normal red blood cell has a diameter about one third that of the
VOL 89/NO 6/MAY 1, 1991/POSTGRAOUATE MEDICINE • AN. .IA
entire cell (figure 4). When the central pallor far exceeds this, the red blood cells are considered hypochromic. Again, since the MCHC represents an average, it does not reflect the marked heterogeneity in red cell hemoglobin concentration that may be present in a particular patient. Idiopathic sideroblastic anemia is an extreme example in which excontinued
163
Downloaded by [La Trobe University] at 21:22 17 June 2016
Many anemias are characterized by specific aberrations in red cell structure that are easily recognized on a peripheral blood smear.
Figura 5. Sickled cells in patient with hemoglobin SS disease.
Figura 6. Spherocytes in patient with hereditary spherocytosis.
Figura 7. Teardrop cells in patient with myelofibrosis.
Figura a. Target cells and microcytes in patient with thalassemia trait.
Figura 9. Burr cell.
Figura 10. Bite cells. Notched-out deformities remain after expulsion of Heinz bodies, as in glucose-6-phosphate dehydrogenase deficiency.
amination of a peripheral blood smear reveals two populations of red blood cells, one entirely normal and o~e macrocytic and quite hypochro-
When none of these abnormalities are present, the morphologic classification of anemias by cell size and hemoglobin content can be used to determine the underlying cause.
rmc.
Figura 11. Elliptocytes in patient with hereditary elliptocytosis.
164
ABERRATIONs-Many anemias are charaaerized by rather specific aberrations in red cell structure (figures 5 through 11). These are easily recognized on a peripheral blood smear and include sickled cells, spherocytes, teardrop cells, schistocytes, target cells, burr cells, bite cells, and elliptocytes (table 3).
Miaocytic hypochromic anemias Microcytic hypochromic anemias can result from iron deficiency, chronic disease, thalassemias, hemoglobin E disorders, and lead toxicity (table 4). An algorithm for diagnosis of such anemias is presented in figure 12. continued
ANDIIA • VOL 89/NO 6/MAY 1, 1991/POSTGRAOUATE MEDICINE
Response to a trial of iron therapy is useful in diagnosing iron deficiency when a patient's serum ferritin level is normal.
Downloaded by [La Trobe University] at 21:22 17 June 2016
Table 3. Morphologic findings on peripheral blood smear in anemia
Findings Sickled cells Spherocytes Teardrop cells Schistocytes Target cells Burr cells Bite cells Elliptocytes
Disorders Sickle cell anemia Sickle cell-hemoglobin C disease Sickle cell-thalassemia syndromes Hereditary spherocytosis lgG autoimmune hemolytic anemia Myelophthisic anemias Myelofibrosis Mechanical hemolytic anemias Hemoglobin C and E syndromes (predominant cell type) Hypochromic anemias (present in smaller numbers) Uremia Heinz body-positive anemias, most commonly G6PD deficiency Hereditary elliptocytosis (predominant cell type) Iron deficiency (present in smaller numbers)
G6PD, glucose-6-phosphate dehydrogenase.
IRON DEFICIENCY-This condition is the most common cause of anemia throughout the world and by far the most common cause of microcytic hypochromic anemia (figure 13). In most cases of iron deficiency the serum ferritin concentration, which reflects total body iron stores, is low (
