A look at why iron deficiency anemia should be on a differential diagnosis list for all patients with unexplained microcytic anemia, how to diagnose the cause of this anemia, and how to treat these iron-deficient patients.
In healthy animals, 98% of oxygen is carried by hemoglobin, with the remainder dissolved in blood. It is the four iron atoms within each molecule of hemoglobin that permit its remarkable oxygen-carrying capacity. Without adequate hemoglobin, oxygen delivery is profoundly compromised.1,2
Anemia, defined simply as a decrease in circulating erythrocyte mass, may be due to several different processes. These may be broadly classified by etiology into a) blood loss, b) hemolysis, or c) ineffective erythropoiesis. Iron deficiency anemia (IDA) bridges two of these categories, as it is a classic cause of ineffective erythropoiesis but is usually due to chronic blood loss.
The clinical signs of IDA are related to decreased red blood cell (RBC) mass and oxygen-carrying capacity. The onset may be insidious, with progressive lethargy, fatigue, and exercise intolerance. On physical examination, mucous membranes will be variably pale. Patients may have a high resting heart rate and tachypnea, with a low-grade systolic heart murmur.
Unusual food cravings, or pica, may be reported. Both dogs and cats may eat soil or rocks; indoor cats may ingest litter. This behavior often resolves when iron stores are replenished.
The hallmark of IDA is microcytic hypochromic anemia, which is indicated by a low mean corpuscular volume and a low mean corpuscular hemoglobin or hemoglobin concentration.1,2 The RBC distribution width is often increased and simply reflects substantial variation in erythrocyte sizes; it may be reported by a technologist as anisocytosis.
Microcytosis is an otherwise uncommon finding, and IDA should be considered in every patient with microcytic anemia. Small RBCs, without anemia, are sometimes noted in Akitas and other Japanese dog breeds. That is normal for these dogs and does not need to be investigated. The other well-recognized cause of microcytosis, with or without anemia, is portosystemic shunting.3-6 The reason for this is unclear. It appears to reflect abnormal iron metabolism but is not associated with true iron deficiency.
It is a common misconception that IDA is a nonregenerative process. In fact, reticulocyte production is variable and may be fairly robust. Iron deficiency should not be discounted just because the absolute reticulocyte count is > 60,000/μl.2
Many IDA patients have increased platelet numbers. The cause of this thrombocytosis is unknown. Thrombocytopenia has been occasionally reported in dogs with IDA.
Serum iron concentrations can be inexpensively determined by using ferrozine-based methods. Samples must be collected carefully to avoid ex vivo hemolysis, which may affect accuracy. However, low serum iron concentrations have poor specificity for IDA. In many patients with chronic inflammatory, infectious, or neoplastic conditions, iron is sequestered in the bone marrow and reticuloendothelial organs, and serum concentrations may fall below the reference range despite adequate iron stores.
This process appears to be triggered, at least in part, by increased hepcidin concentrations. This peptide hormone is produced by the liver and plays a key role in iron homeostasis, uptake, and distribution.7 It is thought that inflammatory cytokines promote production of hepcidin.
Concurrent determination of total iron-binding capacity along with serum iron concentrations is necessary to confirm IDA.2 If iron is truly scarce, total iron-binding capacity usually increases and percent saturation falls to < 20%.
Serum ferritin concentrations are a more accurate way to assess iron status and are not affected by hemolysis. Ferritin is an intracellular protein that stores iron in a nontoxic form and then releases it as needed. Under steady state conditions, serum ferritin concentrations correlate reliably with total body iron stores.2 Species-specific ferritin assays are routinely offered by reference laboratories but are likely to cost more than the measurement of serum iron concentrations.
In people, decreased reticulocyte volumes and subnormal reticulocyte hemoglobin concentrations have been shown to indicate iron deficiency. These parameters have not been looked at extensively in veterinary patients, although one study in dogs suggests that they may be a useful method to assess iron status in this species.8 Reference laboratories may be able to supply this information upon request.
Iron stores within the bone marrow can be readily assessed on examination of an aspirate or biopsy sample using special stains such as Prussian blue. However, unless there is another reason to evaluate the bone marrow, noninvasive tests are preferable.
Iron supplementation and blood transfusion can rapidly affect the laboratory diagnosis of IDA. These therapies should be withheld until appropriate samples have been collected.
There are essentially only three causes of IDA: inadequate intake, compromised absorption, and chronic blood loss. Of these, chronic blood loss is the most common cause of IDA in companion animals.
Because of growth and increased erythropoiesis, neonates have a higher need for dietary iron than adults do.1 Milk contains relatively little iron, so juveniles with even moderate parasitism may rapidly become iron-deficient. Adult animals receiving unbalanced homemade diets, particularly vegetarian or vegan diets, are vulnerable to IDA. A life-stage-appropriate diet approved by the Association of American Feed Control Officials should contain adequate amounts of iron to meet routine needs.
Dietary iron is absorbed in the proximal small intestine through a protein called ferroportin. Uptake is adjusted to match need through hepcidin.7 When iron is abundant, hepcidin prevents enterocyte secretion of absorbed iron into the portal circulation. This surplus iron is then simply lost from the body through normal enterocyte turnover. IDA has been reported in dogs with severe inflammatory bowel disease, although it is unclear if iron deficiency in these patients was due to compromised iron absorption, occult gastrointestinal (GI) blood loss, or a combination of both.9
Chronic blood loss can occur through the skin (e.g. severe flea infestation) or respiratory, urinary, or GI tracts. In general, patients with respiratory or urinary loss are likely to have overt clinical signs, such as coughing, nasal discharge, dysuria, or gross hematuria, and are presented for medical attention before IDA occurs. Animals with GI blood loss may experience vomiting, diarrhea, or hyporexia but are often apparently well before signs related to anemia are noted.
Melena, characterized by a dark tarry stool, is a reliable indicator of blood loss through the GI tract but is only noted when a substantial volume of blood enters the GI tract at one time. Studies have shown that about 500 mg/kg of hemoglobin must enter the GI tract before melena is noted; that equates to about 100 ml of blood in a medium-sized dog.10 A patient with gradual-but-persistent loss from an ulcerative lesion may never have melenic stools.
The first step in the investigation of a patient with IDA is to verify iron intake. If the animal is eating a balanced, age-appropriate diet, chronic blood loss should be assumed. The source may be evident based on the history or physical examination results. If not, a logical diagnostic approach is necessary (see the sidebar "Case report: A 5-year-old golden retriever with IDA").
In juvenile animals, hookworm infection (Ancylostoma caninum in dogs; Ancylostoma tubaeforme in cats) is the most likely cause of IDA.2 A fecal examination will usually confirm parasitism, but we recommend that young patients be treated with an appropriate anthelmintic even if fecal examination results are negative. IDA secondary to parasitism is less common in adult dogs but should still be considered in high-risk geographic areas, particularly if routine parasite prevention efforts are inadequate.
In adults, a serum chemistry profile and urinalysis should be performed. GI bleeding is suggested by a blood urea nitrogen:creatinine ratio > 25.11 Bear in mind that blood that is coughed and swallowed from the respiratory tract will also increase this value. Blood loss from the urinary system can be intermittent but is strongly suggested by gross hematuria. Ultrasonography with or without cystoscopy may be needed to identify the cause.
Fecal occult blood tests can confirm blood loss at volumes 2% to 5% of those associated with melena. However, diets with high hemoglobin content are associated with false positive results, and patients should be fed white foods (e.g. rice, tofu, fish) for several days before testing.12-14 If the GI tract appears to be the most likely source of blood loss, both primary GI disease (e.g. neoplastic, inflammatory, infectious, foreign body) and extra-GI tract disorders (e.g. medications, paraneoplastic syndromes) should be considered.
Any medications associated with GI bleeding, such as nonsteroidal anti-inflammatory agents, should be discontinued. Glucocorticoids, such as prednisone and dexamethasone, are rarely associated with chronic GI hemorrhage but should be tapered if possible.15 Patients should be checked carefully for cutaneous mast cell tumors, and any undefined masses should be examined cytologically.
Abdominal ultrasonography may help identify lesions within the GI tract or tumors of the pancreas (e.g. gastrinoma) or spleen (e.g. mast cell tumor), which may be associated with paraneoplastic gastric ulceration. Upper GI endoscopy with or without exploratory laparotomy may be necessary to identify the source of blood loss in some patients.
Iron can be administered orally as ferrous sulfate (50 to 300 mg total dose every 24 hours; available over the counter)16 or parenterally as iron dextran (10 mg/kg intramuscularly every three or four weeks).17 Ferrous sulfate may cause mild GI upset and can darken the feces. It should be given an hour before feeding to maximize intestinal uptake and should not be administered with antacids, such as calcium carbonate.
Confusion can arise with over-the-counter products, as some are labeled with elemental iron content rather than ferrous sulfate content. Overdose can be fatal, so the appropriate dosage should be clarified for owners. Iron dextran injection can be painful, and anaphylactoid reactions have been reported in pigs. The drug is slowly absorbed over one to three weeks. Many clinicians give one dose and then follow up with oral ferrous sulfate.
It may take many weeks of treatment to replenish body iron stores. Iron supplementation should be provided until RBC number and indices are within the reference ranges.
Iron deficiency should be considered in any patient with unexplained microcytic anemia and confirmed with appropriate testing. If the cause for IDA is not immediately apparent, a stepwise diagnostic approach is necessary. In the interim, parenteral or oral iron supplementation should be administered.
Audrey K. Cook, BVM&S, MRCVS, DACVIM, DECVIM-CA, DABVP (feline), Department of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843.
Heather L. Kvitko-White, DVM, DACVIM, Veterinary Medical Center of Central New York, 5841 Bridge St., Suite 200, East Syracuse, NY 13057.
To view the references for this article, visit dvm360.com/IDARefs.