I. What every physician needs to know.

There is no active excretory mechanism to remove iron from the body – it is only lost through the shedding of cells via desquamation (dermal, intestinal, and genitourinary) and bleeding. As such, consideration of occult bleeding should be undertaken in adult men and post menopausal women in whom iron deficiency is discovered.

Iron deficiency is common, with resultant anemia in 2-5% of adult men and postmenopausal women in the developed world. Gastrointestinal blood loss, possibly due to gastric or colonic carcinoma or peptic ulcerative disease relating to NSAID use, and malabsorption of dietary iron due to celiac disease are the most important causes to consider and evaluate.

Iron deficiency is usually identified through the anemia that results from advanced iron deficiency, however, every living cell requires iron, and deficiency has been linked to a spectrum of signs and symptoms, not all of which clearly relate to decreased circulating hemoglobin. Tissue iron deficiency may manifest as abnormalities in host immunity, work performance, and neurological function. In severe iron deficiency, the gastrointestinal tract is particularly susceptible, with the possible development of glossitis, stomatitis, esophageal webs, and chronic gastritis and resultant malabsorption. Dermal manifestations may involve cheilosis, spoon nail deformity (koilonychia), and hair loss.

II. Diagnostic Confirmation: Are you sure your patient has Iron Deficiency?

Iron deficiency is diagnosed by measurement of the following blood tests: serum iron concentration, total iron binding capacity (TIBC, a measurement of the amount of transferrin in the blood), and the serum ferritin. The transferrin saturation is also an informative measure, calculated as follows: transferrin saturation (%) = serum iron/total iron binding capacity X 100. Among the aforementioned iron indices, serum ferritin has the greatest sensitivity and specificity for the detection of iron deficiency, and is recommended by the World Health Organization as the best indicator of iron deficiency.

Serum iron may be low or normal in iron deficiency. Low serum iron suggests iron deficiency, however, acceptance of a low serum iron as diagnostic of iron deficiency is unwarranted. Low serum iron may result from many chronic diseases and inflammatory states. Determination of the serum iron alone is of limited utility in the evaluation of iron stores and iron deficiency.

TIBC is often increased in iron-deficiency anemia, and transferrin saturation of 15% or less is typically found. Exceptions to this finding are common, however, detracting from the utility of the measurement of transferrin saturation in the diagnosis of iron deficiency.

The serum ferritin correlates directly with total body iron stores. Serum ferritin is typically less than 10 ng/mL in severe iron deficiency associated with anemia. In iron deficiency without anemia, ferritin is typically in the range of 10-20 ng/mL. A moderate increase in the serum ferritin occurs in inflammatory disorders – when an inflammatory state coexists with iron deficiency the serum ferritin is often in the normal range. Interpretation of the serum ferritin in this context becomes difficult.

In the anemia of iron deficiency, the red cells may demonstrate hypochromia and microcytosis.

A. History Part I: Pattern Recognition:

Symptoms of iron deficiency have a broad clinical spectrum – whereas some individuals with iron deficiency are asymptomatic, significant anemia due to advanced iron deficiency may cause significant morbidity with findings of pallor, fatigue, lethargy, malaise, headache, dyspnea, tachycardia, palpitations, and diminished functional capacity. Glossitis, stomatitis, and angular cheilitis may be evident. Underlying comorbidities, particularly cardiovascular and pulmonary diseases such as advanced heart failure and empysema, may lead to marked increases in the susceptibility of individuals to the clinical impact of iron deficiency given limited physiologic reserves for diminished circulating hemoglobin and tissue oxygen delivery.

A typical presentation of iron-deficiency anemia may include: a woman of menstruating age, describing recent menorrhagia and frequent NSAID use for premenstrual symptoms, who presents complaining of weeks of headache, lethargy, and malaise, who is found to be pale-appearing on physical examination with a microcytic anemia on laboratory analysis.

B. History Part 2: Prevalence:

In the United States iron deficiency has the highest prevalence in adults among women of menstruating age. Women aged 16-49 have an incidence of iron deficiency of 11%, with 3% of teenaged girls (16-19y) and 5% of women (20-49y) having iron deficiency severe enough to cause anemia. Women over the age of 50 have a 5-7% prevalence of iron deficiency, with 2% suffering associated anemia.

Among men the incidence of iron deficiency and associated anemia is less than 1% between the ages of 16 and 49. Iron deficiency increases slightly among men aged 50-69 at 2%, while the prevalence of anemia of iron deficiency remains less than 1%. In men aged 70 years or older, the prevalence of both iron deficiency and anemia of iron deficiency double at 4% and 2% respectively.

These gender differences are largely due to menstruation and pregnancy; while a grown man requires only approximately 1mg of iron daily to replace physiologic losses, this daily requirement increases by 50% among women who are menstruating. Pregnancy adds significant additional demands for nutritional iron, including a daily need of 5-6 mg in the third trimester.

As there is no physiologic pathway for iron excretion, deficiency results from conditions in which dietary intake (possibly limited by insufficient dietary iron or, uncommonly, inadequate absorption) does not meet the body’s demands from either iron utilization (growth, pregnancy, epithelial reproduction, erythropoesis) or loss (bleeding, desquamation). Given this, growing children, pregnant and premenopausal women are at the greatest risk.

Worldwide, iron deficiency is usually a result of dietary insufficiency in the setting of chronic intestinal blood loss owing to parsitosis. Important causes to consider in the adult, hospitalized patient in the developed world include celiac and inflammatory bowel disease leading to inadequate absorption (and possibly occult blood loss in IBD), as well as intestinal blood loss resulting from gastritis, peptic ulcer disease, varices, carcinoma, diverticulosis, and hemorrhoids. Other sources of blood loss to consider include genitourinary blood loss from menorrhagia or metrorragia, carcinoma, and chronic infection. Excessive phlebotomy is an important potential cause not to overlook in the hospitalized patient.

C. History Part 3: Competing diagnoses that can mimic Iron Deficiency.

Most of the symptoms of iron deficiency are related to the anemia that results in advanced iron deficiency. These signs and symptoms, including lethargy, malaise, headaches, pallor, decreased activity tolerance, tachycardia, palpitations, and dyspnea on exertion may result from anemia of myriad etiologies. Other anemias that must be differentiated from the anemia of iron deficiency include thalassemia minor and sideroblastic anemias (microcytic), the anemia of chronic inflammation or disease (may be microcytic or normocytic and is the most common etiology of anemia in hospitalized patients) and the anemia of chronic kidney disease (generally normocytic/normochromic).

D. Physical Examination Findings.

Commonly, there are very limited physical exam findings in iron deficiency. In advanced iron deficiency with associated anemia, however, physical findings may include relative tachycardia with associated flow murmur in response to anemia, pallor, glossitis (smooth, red tongue), stomatitis (inflammation of oral mucosae), and angular cheilitis (inflammatory lesions at the corner of the mouth).

Koilonychia (ridging, thinning, and spoon-like deformation of the fingernails) is rarely encountered. Mucosal atrophy in the laryngopharynx may occur, resulting in the formation of a web in the post-cricoid region causing dysphagia, in a condition known as the Plummer-Vinson syndrome.

E. What diagnostic tests should be performed?

There are no physical examination findings that specifically confirm the diagnosis of iron deficiency. Associated physical exam findings such as glossitis, etc. are merely suggestive.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

CBC: evaluation for the degree of anemia; note also: iron deficiency anemia can induce thrombocytosis, through mechanisms that are not completely understood but may involve erythropoietin stimulation of thrombopoietin receptors through cross reactivity.

Red-cell indices:

MCV: in advanced iron deficiency, microcytosis is seen (MCV less than 80)

MCH: low (may manifest as hypochromic appearance on smear)

RDW: often high in iron deficiency anemia

Smear for red cell morphology: early iron deficiency involves normal appearance of red cells. As deficiency progresses, microcytosis and hypochromia develop. Anisocytosis (varied cell sizes), poikilocytosis (varied cell shapes), target cells, and pencil cells (rod-shaped) may be seen.

Serum iron indices:

Iron (may be low or normal; influenced by many pathologic and physiologic states limiting its diagnostic utility when interpreted in isolation)

Total iron binding capacity (TIBC) = the unsaturated or latent iron-binding capacity + serum iron (TIBC is typically elevated, however, there are many exceptions to this finding, limiting the diagnostic utility of the TIBC when interpreted in isolation)

Transferrin saturation = Iron:TIBC (usually low, at less than 15% in iron deficiency)

Ferritin: usually low in iron deficiency. Less than 10 is virtually diagnostic of iron deficiency anemia, while levels between 10 and 20 are suggestive. Ferritin is an acute phase reactant, and levels are increased in the setting of inflammation. The serum ferritin level may be in the normal range despite concomitant iron deficiency in this circumstance.

When patients with iron deficiency anemia were compared against those with anemia of chronic inflammation, a cutoff point of serum ferritin = 32 ng/mL resulted in a sensitivity of 79% and a specificity of 97% in distinguishing the two conditions. If a chronic inflammatory state is present, it may be possible to take this into account in the interpretation of the ferritin level as a correlate of body iron stores – for example, in anemic patients with rheumatoid arthritis, a serum ferritin level less than 60 ng/mL is suggestive of iron deficiency. Despite active inflammation, levels of greater than 150-200 ng/mL argue against iron deficiency.

Testing of the stool for occult blood in cases of confirmed or suspected iron deficiency in all patients (even in reproductive-aged women with ongoing menses).

Tests to consider:

Reticulcyte %: for calculation of the absoulte reticulocyte count and the reticulocyte production index (RPI). RPI will be less than 2 in iron deficiency.

Although serum ferritin remains a cost-effective and valuable screening test for iron deficiency, a limitation of serum ferritin is that normal levels may be found despite iron deficiency in many common clinical conditions including chronic infection or inflammation, chronic liver disease, and malignancy. In the differentiation of the anemia of iron deficiency from anemia of chronic disease of inflammation, the soluble serum transferrin receptor (sTfR) level has proven informative.

Serum transferrrin receptor levels are directly correlated with the total erythropoietic state in the body, and are elevated in iron deficiency and normal in the anemia of chronic disease and inflammation. Using a cutoff value of 29.5 nmol/L, sTfR measurement has a high diagnostic accuracy and predictive value (sensitivity 93%, specificity 84%, PPV of 88%, NPV of 90%) in distinguishing between these two conditions. It should be noted, however, that the area under the curve for the receiver operating characteristic between TIBC alone and sTfR in distinguishing between iron deficiency anemia and anemia of chronic disease was not statistically different when using a cutoff value of 3.15 mg/L for TIBC.

Urinalysis: evaluation for hematuria (overt or occult), hemoglobinuria.

Bone marrow biopsy with prussian blue staining for evaluation of iron stores: absent in iron deficiency anemia – the gold standard test for iron deficiency (although this is costly and invasive and has largely been supplanted by measurement of the serum ferritin in screening for evidence of iron deficiency).

Helicobacter pylori serologies, staining on gastric or small bowel biopsy, or demonstration through urea breath testing: may indicate an etiology for chronic gastrointestinal blood loss through associated ulcerative disease and gastritis.

Gastric and or small bowel biopsy: for the diagnosis of atrophic gastritis or celiac sprue to explain iron deficiency from reduced iron absorption.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

There are no imaging studies that establish the diagnosis of iron deficiency. If iron deficiency is diagnosed, however, further evaluative studies to elucidate the etiology are warranted, most notably of the gastrointestinal tract for a condition to explain blood loss. This process should be undertaken even in premenopausal women if they have abdominal symptoms, evidence of occult gastrointestinal bleeding, a hemoglobin less than 10 g/dL, or if they fail to respond to a trial of iron replacement therapy. It is unwise to assume iron deficiency results only from menopausal bleeding in this population, although it is the most common cause. As many as 12% of premenopausal women may have a significant gastrointestinal condition, possibly including carcinoma, that is contributing to iron deficiency through blood loss.

After a diagnosis of iron deficiency anemia is made, evaluation of the gastrointestinal system is warranted, as most cases of iron deficiency anemia are the result of occult gastrointestinal bleeding. The decision to proceed with upper or lower gastrointestinal evaluation initially should be based on clinician judgement and consideration of the presenting symptoms (if any). In patients describing dysphagia, gastritic symptoms, nausea, vomiting, or upper abdominal pain upper GI lesions should be suspected. Patients complaining of diarrhea or constipation, hematochezia, or lower abdominal pain should raise suspicion for a lower GI lesion. If no clear symptoms are evident, evaluation of the lower gastrointestinal tract should be the initial diagnostic approach.

Upper endoscopy is the evaluation of choice for the upper GI tract. Upper GI radiographic series are often initially pursued, although these may miss smaller mucosal lesions or vascular ectasia. Subtle lesions, such as mild esophagitis, should not be assumed to be the sole lesion explaining chronic blood loss, and further evaluation of the GI tract (lower) should follow.

Lower endoscopy (colonoscopy) is again favored over radiographic imaging in the evaluation of the lower GI tract given the higher sensitivity in identification of smaller mucosal lesions (i.e. colitis) of this modality. If no likely causative lesion is identified on either upper or lower endoscopy (as occurs in up to 52% of patients with iron deficiency anemia), further evaluation of the GI tract is warranted, possibly including: repeat upper and lower endoscopy, and evaluation of the small bowel through: enteroscopy, small bowel follow through radiographs, small bowel biopsy (to evaluate primarily for malabsorption of iron owing to celiac disease), or capsule endoscopy.

If the above evaluation is completed and has not revealed a likely etiology to explain the anemia of iron deficiency through evidence of chronic blood loss, consideration should be given to whether the diagnosis of iron deficiency is indeed accurate – with repeat evaluation for other anemic ‘mimics’ of iron deficiency including thallesemia, sideroblastic anemia, or the anemia of chronic disease or inflammation. A nongastrointestinal source of blood loss should also be considered (uterine, GU, pulmonary), as well as the possibility of nutritional deficits for iron either due to inadequate intake or absorption (gastrectomy status, celiac disease), or increased demands (most commonly due to menstruation and pregnancy).

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

None

III. Default Management.

1. Evaluation of the severity of anemia, associated symptoms, and effect on comorbidities (if present), in order to rapidly identify the need for blood transfusion.

2. Establishment of cause through evaluation of the gastrointestinal tract for evidence of a lesion or lesions to explain blood loss:

In patients describing dysphagia, gastritic symptoms, nausea, vomiting, or upper abdominal pain upper GI lesions should be suspected. Patients complaining of diarrhea or constipation, hematochezia, or lower abdominal pain should raise suspicion for a lower GI lesion. If no clear symptoms are evident, evaluation of the lower gastrointestinal tract should be the initial diagnostic approach.

Lower endoscopy (colonoscopy) is again favored over radiographic imaging in the evaluation of the lower GI tract given the higher sensitivity in identification of smaller mucosal lesions (i.e. colitis) of this modality. If no likely causative lesion is identified on either upper or lower endoscopy (as occurs in up to 52% of patients with iron deficiency anemia), further evaluation of the GI tract is warranted, possibly including repeat upper and lower endoscopy, and evaluation of the small bowel through enteroscopy, small bowel follow through radiographs, small bowel biopsy (to evaluate primarily for malabsorption of iron owing to celiac disease), or capsule endoscopy.

3. Initiation of appropriate therapy

A. Immediate management.

Evaluation of extent of anemia and indications (if any) for blood transfusion. Hb less than 7 and hemodynamic instability are clear indications for blood transfusion. In the setting of symptomatic anemia, active and ongoing bleeding, or concurrent coronary artery disease or ACS, higher transfusion thresholds may be warranted.

B. Physical Examination Tips to Guide Management.

In initial management, evaluation of the patient with symptomatic anemia that is felt to likely be due to iron deficiency given a history of recent and/or ongoing bleeding should include examination of clinical stability through vital sign assessment and physical examination and history-taking for evidence of end organ injury (i.e. anginal symptoms or anginal equivalent such as dyspnea in a patient with known significant coronary disease and a history of similar angina and MI who presents pale and tachycardic describing a history of weeks of hematochezia) which may suggest the possible need for rapid blood transfusion.

Evaluation of fecal occult blood or overt lower GI bleeding and or culprit rectal lesions through digital rectal examination and direct visualization of the stool for melena or hematochezia followed by fecal occult blood (guaiac) testing may rapidly suggest anemia of iron deficiency as well as the likely source.

Once a diagnosis of iron deficiency with or without anemia has been confirmed and appropriate iron replacement therapy initiated, evaluation of other physical examination findings during ongoing surveillance to evaluate the efficacy of therapy may include monitoring for the resolution of any associated physical examination findings that may have been referable to the iron deficiency and present on initial examination. For example, resolution of pallor with correction of anemia, clinical resolution of glossitis, stomatitis, and angular cheilitis, if present, may be observed with appropriate and effective iron replacement therapy.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Reticulocytosis (reticulocyte production index > 3) may be observed as early as 4 days after the initiation of appropriate therapy and will become evident within 7-10 days of ongoing effective treatment. There is little response in the serum hemoglobin in the first 2 weeks of appropriate therapy, however, there is typically correction of the hemoblobin by 50% of its deficit within 4-5 weeks and full correction to normal within 2 months of therapy, provided that the patient is fully compliant with the appropriate prescription.

A failure of this expected response to appropriate therapy should prompt the treating clinician to consider: whether the patient has been ideally compliant with therapy (are there intolerable side effects?); whether the underlying etiology (bleeding) has been appropriately managed and controlled; whether the duration and dose of iron replacement has been appropriate for valid interpretation of the success or failure of therapy; whether there underlying comorbidities that may blunt the expected response to therapy (most notably chronic inflammatory diseases which impair the utilization of iron for hematopoesis in the body, or inflammatory or other disorders of the gastrointestinal mucosa which impair iron absorption); and, are there other etiologies to explain the anemia (is the diagnosis of iron deficiency correct?).

D. Long-term management.

Iron repletion should continue until hemoglobin levels have normalized. Following this, the effective iron supplementation dose should continue for a further 3 months of therapy to fully replete body iron stores. Subsequent surveillance for recurrence of iron deficiency anemia should involve measurement of the complete blood count every 3 months for one year and then yearly thereafter.

Most important, however, is the identification and appropriate management of the underlying cause of iron deficiency. As there is no physiologic mechanism for iron excretion, clinicians must assume that the cause is blood loss, and the most likely source (second to menstruation) is gastrointestinal bleeding, possibly due to a gastrointestinal carcinoma. Evaluation of the gastrointestinal tract with endoscopy (lower, upper, or both, possibly including evaluation of the small bowel by enteroscopy or capsule endoscopy) is warranted based on clinician judgement, presenting symptoms, and findings on step-wise endoscopic evaluation as detailed above.

E. Common Pitfalls and Side-Effects of Management.

The differentiation of iron deficiency anemia from other anemias, particularly the anemia of chronic disease or inflammation, can be challenging as both conditions are common, with the anemia of chronic disease being the most common anemia in hospitalized patients. Further confusing this distinction is the fact that although the anemia of chronic disease and inflammation is usually normocytic, microcytosis is present in 20-30% of patients, and other red cell and iron indices may overlap at different stages and presentations of these two conditions. Iron deficiency anemia and the anemia of chronic disease and inflammation may also occur together.

Anemia of chronic disease and inflammation is most commonly associated with connective tissue diseases, chronic infections, malignancies, chronic liver disease, and endocrinologic disorders (most commonly thyroidal). Laboratory findings that may help to differentiate between these conditions include:

-RDW: commonly high in IDA and normal in ACD.

-TIBC: commonly increased in IDA and decreased in ACD.

-Ferritin: low in IDA, elevated in ACD – ferritin is an acute phase reactant and thus elevated in inflammatory states. Despite this, ferritin levels of greater than 150-200 suggest there is no iron deficiency even in states of inflammation.

-Serum soluble transferrin receptor (sTfR): high in IDA, normal in ACD.

Initial therapy

Initial treatment of the markedly anemic and symptomatic hospitalized patient suffering from a Hb of less than 7 should prompt consideration of blood transfusion – and higher hemoglobin thresholds for appropriate transfusion may be warranted in hospitalized patients with significant and symptomatic comorbidities (i.e. anginal symptoms attributable to anemia in the patient with known significant coronary disease).

The initial management of iron deficiency anemia involves not only repletion of the iron stores, but also the identification of the cause of iron deficiency, which is most commonly due to bleeding. Evaluation for the etiology of bleeding is paramount, most notably including evaluation of the gastrointestinal tract for culprit lesion(s), which may include carcinoma as outlined above.

Iron replacement therapy should be initiated with oral iron supplementation. Ferrous iron salts are preferable due to their solubility and bioavailability at the pH of the duodenum where iron is absorbed. Standard therapy for adults involves administration of 300 mg of ferrous sulfate (which contains 60 mg of elemental iron) three to four times daily. Lower doses may be as effective and better tolerated. Gastritic symptoms, heartburn, nausea, vomiting, and diarrhea may occur with oral iron repletion. If this is encountered, taking the tablets with meals, lowering the dose, or changing to a formulation to a preparation containing less elemental iron (i.e. ferrous gluconate tablets) may be effective in minimizing adverse effects and optimizing compliance. Ideally, the daily intake of elemental iron provided should amount to 150-200 mg in iron deficient adults.

Parenteral iron therapy may be appropriate for patients who have demonstrated intolerance to oral iron preparations despite the above modifications in oral dosage and formulation, patients with known poor absorption of oral iron (due to gastrectomy status, celiac disease, inflammatory bowel disese), patients with severe anemia with ongoing blood loss resulting in iron deficits that cannot be overcome adequately through the enteral route, patients with chronic kidney disease or anemia associated with chemotherapy who are receiving erythropoeitin to manage their anemia (see below). Parenteral therapy involves significantly greater cost and potential toxicities and adverse drug events (depending on the formulation), and as such the choice of this route of therapy must be considered carefully.

Intravenous iron dextran is the most commonly administered formulation for parenteral iron therapy in the United States, and it has been associated with severe adverse drug reactions including anaphylaxis and death – up to 2% of patients receiving this therapy have severe adverse drug reactions, and 0.6% of reactions are described as anaphylactoid.

Intravenous ferric gluconate has been demonstrated to be safe and effective in the treatment of iron deficiency anemia in non-hemodialysis patients. In a study of a total of 639 infusions in 74 adult, non-hemodialysis patients by Miller et al in 2007 involving 125 mg of ferric gluconate infused over a 10 minute IV push or diluted in 100 mL of isotonic saline and infused over intervals ranging from 30 to 60 minutes, no significant adverse reactions requiring hospitalization or categorized as severe or anaphylactic were reported. Only 9 infusions resulted in mild symptoms such as pruritis, nausea, or headache for which the infusion was stopped only temporarily and then completed without incident, and 2 reactions involving dyspnea and urticaria required cessation of the infusion, yet did not require further observation or hospitalization.

IV. Management with Co-Morbidities.

A. Renal Insufficiency.

Chronic kidney disease is a pro-inflammatory state, and in the clinical evaluation of iron stores by serum ferritin and TIBC in patients with chronic kidney disease, absolute iron deficiency is diagnosed when the serum ferritin is less than 100 mg/mL and the TIBC is less than 20%. The treatment of anemia in chronic kidney disease using erythropoietin has been shown to improve quality of life, and for reasons that are poorly understood, patients with chronic kidney disease being treated with erythropoietin often do not respond adequately to oral iron replacement and therefore require parenteral iron therapy to treat the iron deficiency that frequently accompanies chronic kidney disease, and to ensure adequate iron stores for optimal hematopoiesis during erthyropoietin therapy.