Iron Deficiency Anemia Clinical Presentation

Author: James L Harper, MD; Chief Editor: Emmanuel C Besa, MD more...

Updated: Feb 3, 2012

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History
Physical Examination
Complications
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History

Whereas iron deficiency anemia is a laboratory diagnosis, a carefully obtained history can facilitate its recognition. The history can be useful in establishing the etiology of the anemia and, perhaps, in estimating its duration.

Iron deficiency in the absence of anemia is asymptomatic. One half of patients with moderate iron deficiency anemia develop pagophagia. Usually, they crave ice to suck or chew. Occasionally, patients are seen who prefer cold celery or other cold vegetables in lieu of ice. Leg cramps, which occur on climbing stairs, also are common in patients deficient in iron.

Often, patients can provide a distinct point in time when these symptoms first occurred, providing an estimate of the duration of the iron deficiency.

Fatigue and diminished capability to perform hard labor are attributed to the lack of circulating hemoglobin; however, they occur out of proportion to the degree of anemia and probably are due to a depletion of proteins that require iron as a part of their structure.

Increasing evidence suggests that deficiency or dysfunction of nonhemoglobin proteins has deleterious effects. These include muscle dysfunction, pagophagia, dysphagia with esophageal webbing, poor scholastic performance, altered resistance to infection, and altered behavior.

Dietary history

A dietary history is important. Vegetarians are more likely to develop iron deficiency, unless their diet is supplemented with iron. National programs of dietary iron supplementation are initiated in many portions of the world where meat is sparse in the diet and iron deficiency anemia is prevalent. Unfortunately, affluent nations also supplement iron in foodstuffs and vitamins without recognizing the potential contribution of iron to free radical formation and the prevalence of genetic iron overloading disorders.

Elderly patients, because of poor economic circumstances, may try to survive on a “tea and toast” diet because they do not wish to seek aid. They may also be hesitant to share this dietary information. This group is far more likely to develop protein-calorie malnuturition before they develop iron deficiency anemia.

A fundamental concept is that after age 1 year, dietary deficiency alone is not sufficient to cause clinically significant iron deficiency and a source of blood loss should always be sought as part of the management of a patient with iron deficiency anemia. Infants and toddlers are the primary risk groups for dietary iron deficiency anemia. Neonates who double their birthweight are a special risk group. Also see Pediatric Acute Anemia and Pediatric Chronic Anemia.

Pica is not a cause of iron deficiency anemia; pica is a symptom of iron deficiency anemia. It is the link between iron deficiency anemia and lead poisoning, which is why iron deficiency anemia should always be sought when a child is diagnosed with lead poisoning. Hippocrates recognized clay eating; however, modern physicians often do not recognize it unless the patient and family are specifically queried. Both substances decrease the absorption of dietary iron. Clay eating occurs worldwide in all races, though it is more common in Asia Minor. Starch eating is a habit in females of African heritage, and it often is started in pregnancy as a treatment for morning sickness.

History of hemorrhage

Two thirds of body iron is present in circulating red blood cells as hemoglobin. Each gram of hemoglobin contains 3.47 mg of iron; thus, each mL of blood lost from the body (hemoglobin 15 g/dL) results in a loss of 0.5 mg of iron.

Bleeding is the most common cause of iron deficiency, either from parasitic infection (hookworm) or other causes of blood loss. Patients report a history of bleeding from most orifices (hematuria, hematemesis, hemoptysis) before they develop chronic iron deficiency anemia; however, gastrointestinal bleeding may go unrecognized, and excessive menstrual losses may be overlooked.

Patients often do not understand the significance of a melanotic stool. Unless menstrual flow changes, patients do not seek medical attention. If they do, they report that their menses are normal in response to inquiry for self-evaluation. Because of the marked differences among women with regard to menstrual blood loss (10-250 mL per menses), query the patient about a specific history of clots, cramps, and the use of multiple tampons and pads. For more information, also see Menorrhagia.

Physical Examination

Anemia produces nonspecific pallor of the mucous membranes. A number of abnormalities of epithelial tissues are described in association with iron deficiency anemia. These include esophageal webbing, koilonychia, glossitis, angular stomatitis, and gastric atrophy.

The exact relationship of these epithelial abnormalities to iron deficiency is unclear and may involve other factors. For example, in publications from the United Kingdom, esophageal webbing and atrophic changes of the tongue and the corner of the mouth are reported in as many as 15% of patients with iron deficiency; however, they are much less common in the United States and other portions of the world.

Splenomegaly may occur with severe, persistent, untreated iron deficiency anemia. This is uncommon in the United States and Europe.

Complications

Iron deficiency anemia diminishes work performance by forcing muscles to depend on anaerobic metabolism to a greater extent than they do in healthy individuals. This change is believed to be attributable to deficiency in iron-containing respiratory enzymes rather than to anemia.

Severe anemia due to any cause may produce hypoxemia and enhance the occurrence of coronary insufficiency and myocardial ischemia. Likewise, it can worsen the pulmonary status of patients with chronic pulmonary disease.

Defects in structure and function of epithelial tissues may be observed in iron deficiency. Fingernails may become brittle or longitudinally ridged, with the development of koilonychia (spoon-shaped nails). The tongue may show atrophy of the lingual papillae and develop a glossy appearance. Angular stomatitis may occur with fissures at the corners of the mouth.

Dysphagia may occur with solid foods, with webbing of the mucosa at the junction of the hypopharynx and the esophagus (Plummer-Vinson syndrome); this has been associated with squamous cell carcinoma of the cricoid area. Atrophic gastritis occurs in iron deficiency with progressive loss of acid secretion, pepsin, and intrinsic factor and development of an antibody to gastric parietal cells. Small intestinal villi become blunted.

Cold intolerance develops in one fifth of patients with chronic iron deficiency anemia and is manifested by vasomotor disturbances, neurologic pain, or numbness and tingling.

Rarely, severe iron deficiency anemia is associated with papilledema, increased intracranial pressure, and the clinical picture of pseudotumor cerebri. These manifestations are corrected with iron therapy.

Impaired immune function is reported in subjects who are iron deficient, and there are reports that these patients are prone to infection; however, because of the presence of other factors, the current evidence is insufficient to establish that this impairment is directly due to iron deficiency.

Children deficient in iron may exhibit behavioral disturbances. Neurologic development is impaired in infants and scholastic performance is reduced in children of school age. The intelligence quotients (IQs) of schoolchildren deficient in iron are reported to be significantly lower than those of their nonanemic peers. Behavioral disturbances may manifest as an attention deficit disorder. Growth is impaired in infants with iron deficiency. The neurologic damage to an iron-deficient fetus results in permanent neurologic injury and typically does not resolve on its own. Iron repletion stabilizes the patient so that his or her status does not further decline.

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Contributor Information and Disclosures

Author

James L Harper, MD Associate Professor, Department of Pediatrics, Division of Hematology/Oncology and Bone Marrow Transplantation, Associate Chairman for Education, Department of Pediatrics, University of Nebraska Medical Center; Assistant Clinical Professor, Department of Pediatrics, Creighton University School of Medicine; Director, Continuing Medical Education, Children's Memorial Hospital; Pediatric Director, Nebraska Regional Hemophilia Treatment Center

James L Harper, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Federation for Clinical Research, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Council on Medical Student Education in Pediatrics, and Hemophilia and Thrombosis Research Society

Disclosure: Nothing to disclose.

Coauthor(s)

Marcel E Conrad, MD Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine

Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, and Southwest Oncology Group

Disclosure: No financial interests None None

Chief Editor

Emmanuel C Besa, MD Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Clinical Oncology, American Society of Hematology, and New York Academy of Sciences

Disclosure: Nothing to disclose.

Additional Contributors

Ronald A Sacher, MB, BCh, MD, FRCPC Professor, Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Ronald A Sacher, MB, BCh, MD, FRCPC is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society of Blood Transfusion, International Society on Thrombosis and Haemostasis, and Royal College of Physicians and Surgeons of Canada

Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; Talecris Honoraria Board membership

Paul Schick, MD Emeritus Professor, Department of Internal Medicine, Jefferson Medical College of Thomas Jefferson University; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital

Paul Schick, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Society of Hematology, International Society on Thrombosis and Haemostasis, and New York Academy of Sciences

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: eMedicine Salary Employment

References

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Goddard AF, James MW, McIntyre AS, Scott BB. Guidelines for the management of iron deficiency anaemia. Gut. Oct 2011;60(10):1309-16. [Medline].
Koutroubakis IE, Oustamanolakis P, Karakoidas C, Mantzaris GJ, Kouroumalis EA. Safety and efficacy of total-dose infusion of low molecular weight iron dextran for iron deficiency anemia in patients with inflammatory bowel disease. Dig Dis Sci. Aug 2010;55(8):2327-31. [Medline].
Fernandez-Gaxiola AC, De-Regil LM. Intermittent iron supplementation for reducing anaemia and its associated impairments in menstruating women. Cochrane Database Syst Rev. Dec 7 2011;12:CD009218. [Medline].
De-Regil LM, Jefferds ME, Sylvetsky AC, Dowswell T. Intermittent iron supplementation for improving nutrition and development in children under 12 years of age. Cochrane Database Syst Rev. Dec 7 2011;12:CD009085. [Medline].
Beutler E, Lichtman MA, Coller BS. Williams Hematology. 6^th ed. New York, NY: McGraw-Hill Book Co; 2001:295-304, 447-70.
Bothwell TH, Charlton RW, Cook JD. Iron Metabolis in Man. 1979:1-77.
Conrad ME, Umbreit JN. Iron absorption and transport-an update. Am J Hematol. Aug 2000;64(4):287-98. [Medline].
Hoffman R, Benz EJ Jr, Shattil SJ. Hematology: Basic Principles and Practice. Vol 3. New York, NY: Churchill Livingston; 1998:397-427.
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McLoughlin MT, Tham TC. Long-term follow-up of patients with iron deficiency anaemia after a negative gastrointestinal evaluation. Eur J Gastroenterol Hepatol. Aug 2009;21(8):872-6. [Medline].

The sequence of events (left to right) that occur with gradual depletion of body stores of iron. Serum ferritin and stainable iron in tissue stores are the most sensitive laboratory indicators of mild iron deficiency and are particularly useful in differentiating iron deficiency from the anemia of chronic disorders. The percentage saturation of transferrin with iron and free erythrocyte protoporphyrin values do not become abnormal until tissue stores are depleted of iron. Subsequently, a decrease in the hemoglobin concentration occurs because iron is unavailable for heme synthesis. Red blood cell indices do not become abnormal for several months after tissue stores are depleted of iron.

Sequential changes in laboratory values following blood loss are depicted. A healthy human was bled 5 L in 500-mL increments over 45 days. A moderate anemia ensued, initially with normal cellular indices and serum iron. Subsequently, the mean corpuscular volume (MCV) increased as iron was mobilized from body stores and reticulocytosis occurred. The serum iron decreased, followed by an increase in the total iron-binding capacity. Gradual decreases in the red blood cell indices occurred, with maximal microcytosis and hypochromia present 120 days after bleeding. Values returned to normal approximately 250 days after blood loss. At the end of the experiment, iron was absent from body stores (marrow) because hemoglobin has a first priority for iron. Iron-59 absorption was increased after all values returned to normal in order to replenish the body store with iron. This suggests that the serum iron, total iron-binding capacity, hemoglobin concentration, and indices were not the primary regulators of iron absorption.

The total body iron in a 70-kg man is about 4 g. This is maintained by a balance between absorption and body losses. Although the body only absorbs 1 mg daily to maintain equilibrium, the internal requirement for iron is greater (20-25 mg). An erythrocyte has a lifespan of 120 days so that 0.8% of red blood cells are destroyed and replaced each day. A man with 5 L of blood volume has 2.5 g of iron incorporated into the hemoglobin, with a daily turnover of 20 mg for hemoglobin synthesis and degradation and another 5 mg for other requirements. Most of this iron passes through the plasma for reutilization. Iron in excess of these requirements is deposited in body stores as ferritin or hemosiderin.

Dietary iron contains both heme and nonheme iron. Both chemical forms are absorbed noncompetitively into duodenal and jejunal mucosal cells. Many of the factors that alter the absorption of nonheme iron have little effect upon the absorption of heme iron because of the differences in their chemical structures. Iron is released from heme within the intestinal absorptive cell by heme oxygenase and then transferred into the body as nonheme iron. Factors affecting various stages of iron absorption are shown in this diagram. The simplest model of iron absorption must consider intraluminal, mucosal, and corporeal factors.

Ultrastructural studies of the rat duodenum from iron-deficient (top), healthy (middle), and iron-loaded (bottom) animals are shown. They were stained with acid ferrocyanide for iron, which is seen as black dots in the specimens. No staining was seen with acid ferricyanide. This indicates that iron was in the ferric redox state. Respectively, the specimens showed no iron, moderate deposits, and increased deposits with ferritin (arrow).Incubation of the specimens with iron-nitrilotriacetic acid to satiate iron-binding proteins with iron provided specimens with equal iron staining, except that the iron-loaded specimens contained ferritin. The quantity of iron in the cell is derived from both the diet and body stores. It probably is important in the regulation of the quantity of iron accepted by the absorptive cell from the gut lumen. The authors postulate that the iron either satiates iron-binding proteins with iron, up-regulates iron regulatory protein, or does both to diminish iron uptake by the absorptive cell. The consequences of these findings are depicted in the flow charts.

Mucosal cells in the proximal small intestine mediate iron absorption. Intestinal cells are born in the crypts of Lieberkuhn and migrate to the tips of the villi. The cells are sloughed into the intestinal lumen at the end of their 2- to 3-day lifespan. Absorptive cells remain attuned to the body requirement for iron by incorporating proportionate quantities of body iron into the absorptive cells. This iron and recently absorbed iron decrease uptake of iron from the gut lumen by satiation of iron-binding proteins with iron, by stimulating an iron regulatory element, or both. The incorporation of iron into these cells in quantities proportional to body stores of iron also provides a limited method of increasing iron excretion in individuals replete in iron.

Both nonheme iron and heme iron have 6 coordinating bonds; however, 4 of the bonds in heme bind pyrroles, making them unavailable for chelation by other compounds. Therefore, ascorbic acid chelates nonheme iron to enhance absorption but has no effect upon heme iron. Many dietary components, such as phytates, phosphates, oxalates, and tannates, bind nonheme iron to decrease nonheme iron absorption. They do not affect heme. This explains why heme is so effectively absorbed with foods containing these chelators. Iron hemoglobin structure.

Three pathways exist in enterocytes for uptake of food iron. In the United States and Europe, most absorbed iron is derived from heme. Heme is digested enzymatically free of globin and enters the enterocyte as a metalloporphyrin. Within the cell iron is released from heme by heme oxygenase to pass into the body as inorganic iron. Most dietary inorganic iron is ferric iron. This can enter the absorptive cell via the integrin-mobilferrin pathway (IMP).Some dietary iron is reduced in the gut lumen and enters the absorptive cell via the divalent metal transporter-1 (DMT-1/DCT-1/Nramp-2). The proteins of both pathways interact within the enterocyte with paraferritin, a large protein complex capable of ferrireduction. Excess iron is stored as ferritin to protect the cell from oxidative damage. Iron leaves the cell to enter plasma facilitated by ferroportin and hephaestin, which associate with an apotransferrin receptor. The enterocyte is informed of body requirements for iron by transporting iron from plasma into the cell using a holotransferrin receptor.

A 70-year-old man who is 4 years post-Whipple surgery for pancreatic adenocarcinoma had been in good health with no evidence of recurrence until he had a maroon-colored stool that was heme positive. Physical examination was unrevealing. Laboratory study values showed a WBC of 9000 cells/µL, a hemoglobin of 11.5 g/dL, a mean corpuscular volume (MCV) of 95 fL, a mean corpuscular hemoglobin concentration (MCHC) of 34 g/dL, a platelet count of 250,000 cells/µL, a creatinine level of 0.9 mg/dL, a BUN level of 27 mg/dL, a total bilirubin level of 0.4 mg/dL, a serum iron level of 160 µg/dL, a total iron-binding capacity (TIBC) of 280 µg/dL, and a ferritin level of 85 ng/mL. A peripheral smear is shown.

A 26-year-old white man was referred with a microcytic anemia that failed to respond to treatment with ferrous sulfate over 6 months. Physical examination showed only mild pallor of mucous membranes. His stool was dark but heme negative. The CBC count showed a WBC of 6000 cells/µL, a hemoglobin level of 11 g/dL, a mean corpuscular volume (MCV) of 70 fL, a mean corpuscular hemoglobin concentration (MCHC) of 33 g/dL, a platelet count of 234,000 cells/µL, a hemoglobin electrophoresis AA, a hemoglobin A₂ value of 3.8%, and a fetal hemoglobin value of 2.0%.

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