This guideline provides recommendations for the diagnosis, investigation and management of iron deficiency in patients of all ages.- Use a case-finding approach to identify individuals at risk of iron deficiency and iron deficiency anemia (Table 1). There is no indication for population-based general screening. - Determine the cause of iron deficiency. Consider age and clinical presentation when investigating for cause. - Iron deficiency by itself causes symptoms for patients, even in the absence of anemia, and warrants investigation and treatment. - Ferritin is the test of choice for the diagnosis of iron deficiency. - Ferritin values occur on a continuum. The suggested cut-offs are estimated ranges that should be interpreted using clinical judgment based on the patient's age, gender, risk profile (Table 1) and symptoms. - Serum iron, iron binding capacity, and transferrin saturation/fraction saturation are not routinely useful for investigating iron deficiency anemia. - Take a nutrition history and provide dietary education to address dietary risk factors. - Caregivers of infants and toddlers should receive guidance to prevent excessive cow's milk intake. - Prescribe oral iron supplements as first line therapy for iron deficiency. One preparation is not preferred over another; patient tolerance should be the guide. Anemia should correct in 2-4 months. Continue oral iron for 4-6 months after anemia corrects to replenish iron stores. - Consider prescribing IV iron when there is inadequate response to oral iron, intolerance to oral iron therapy, or ongoing blood loss.Iron deficiency: insufficient total body iron stores, caused by increased requirements, decreased intake, increased loss, and/or decreased absorption 1 (see Table 1). Anemia: low hemoglobin level, most frequently defined as a hemoglobin value over two standard deviations below the genderand age-adjusted mean. 1 A hemoglobin value below the local, lab-specific lower reference interval indicates anemia. Iron deficiency anemia (IDA): anemia due to insufficient body iron stores 1 . The following laboratory findings are typical for IDA: microcytic anemia, hypochromia, and decreased ferritin. IDA may be normocytic if anemia is mild or in early iron deficiency. 2# Identification of Patients at Risk for Iron Deficiency and Iron Deficiency Anemia
Screening of the general population for iron deficiency is not recommended. 3 Use a case-finding approach to identify patients at risk of iron deficiency and iron deficiency anemia (Table 1).
Common risk profiles, by age, include:
- Infants and toddlers (refer to page 7)
- Adolescents and adults: endurance athletes, regular blood donors, disordered eating - Pre-menopausal women: especially those with menorrhagia, vegetarian diet - All adults age >65 - All ages: low socioeconomic status, lack of balanced diet, inadequate nutritional intake Table 1: Common causes of and risk factors for iron deficiency and IDA in adults Note: Please refer to Iron Deficiency in Children and Iron Deficiency in Obstetrics on pages 7-8 for causes and risk factors in children, pregnancy and the perinatal period.

# Increased Requirements Decreased Intake
- Pregnancy (2nd/3rd trimester)
- Lactation - Rapid growth spurts (infants, children, adolescents)
- Low socioeconomic status - Vegetarian or vegan diet - Lack of balanced diet or poor intake - Eating disorder - Alcohol use disorder - Age > 65 4 - Recent immigration from developing regions with lower access to iron-rich foods, higher rates of infectious disease, and higher rates of multiparity 5 , especially Southeast Asia, Africa 6
Increased Loss Decreased Absorption 

# Signs and Symptoms in Adults
Even in the absence of anemia, isolated iron deficiency causes symptoms and warrants investigation and treatment. Early stage iron deficiency can exist without overt anemia, but with other non-hematological symptoms 7 due to deficiency of ironcontaining cellular enzymes and unsaturated myoglobin. Some patients may be asymptomatic.  - Children (ug/L) < 12 diagnostic of iron deficiency 12-20 possible iron deficiency
Ferritin values occur on a continuum; cut-offs are suggested and clinical interpretation is required:
- The likelihood of iron deficiency increases with lower ferritin concentrations, including those that overlap with the normal reference interval. The normal reference interval is derived from healthy outpatients without signs of iron deficiency or chronic illness. - In adults, iron deficiency is unlikely if ferritin >30 ug/L (or >70-100 in a patient with chronic inflammatory disease, 13 or >50 in the elderly 2 ) - Ferritin is an acute phase reactant and may be unreliable in patients with chronic disease, active inflammation, or malignancy. Testing ferritin is not recommended during acute infection or hospitalization. - Non-hematologic symptoms can occur when the serum ferritin is in the low normal range (< 30 ug/L)

# Hematology Profile (CBC)
- Hemoglobin value is required to assess severity of anemia - May suggest iron deficiency - Not diagnostic test of choice for iron deficiency
The following findings CBC and peripheral smear findings are highly suggestive of iron deficiency: - hypochromia (low mean corpuscular hemoglobin concentration (MCHC))

# - microcytosis (low mean corpuscular volume (MCV))
Patients with microcytic anemia should not be given iron supplements until iron deficiency is confirmed by testing ferritin. Low MCV in the setting of normal ferritin may indicate hemoglobinopathies such as thalassemia especially in high risk ethnic groups. Long term iron therapy is harmful for these patients.

# Refer to Appendix C: Algorithm for Investigation of Iron Deficiency in Non-Anemic Adults.
- Iron therapy may improve restless legs syndrome severity and restlessness. Iron supplementation is recommended if serum ferritin is  75 ug/L. 8,9 Additional tests for the diagnosis of iron deficiency in patients with chronic disease, inflammation or malignancy Anemia of chronic disease (ACD) may co-exist with an element of true iron deficiency. However, ferritin values may be falsely elevated in chronic disease as ferritin is an acute phase reactant. In this specific situation, ordering a fasting serum iron and transferrin saturation may be helpful to diagnose iron deficiency that may be missed by solely relying on ferritin. A typical iron deficiency profile for such patients (e.g. those with inflammatory bowel disease) is:
- low serum iron, - low or normal transferrin (i.e. total iron binding capacity), and - fasting transferrin saturation below 20%.
The clinical approach for such patients is the same as for iron deficiency in otherwise well patients (investigate for cause, supplement with iron and refer as appropriate). Patients with a true iron deficiency which co-exists with anemia of chronic disease will respond to a diagnostic trial of iron supplementation.
Guidance for the investigation and management of iron deficiency in the setting of specific chronic diseases is provided:
- Chronic Kidney Disease (CKD): Kidney Disease: Improving Global Outcomes (KDIGO) guidelines 14 recommend including CBC, absolute reticulocyte count, serum ferritin and TSAT as well as other tests (vitamin B12) in the initial evaluation of anemia in patients with CKD and anemia. Note that ferritin levels in patients with CKD may be elevated due to inflammation, and so many not accurately reflect iron status and need for supplementation. TSAT <24% is the current recommended threshold to confirm iron deficiency. In patients with CKD, if iron deficiency and other nutritional deficiencies are rectified, and anemia persists, consider erythropoiesis stimulating agents, which would require specialist referral.
- Heart Failure: Canadian Cardiovascular Society guidelines 15 recommend consideration of IV iron therapy for heart failure patients with all of the following: ejection fraction 40%, serum ferritin < 100 mg/L or between 100-299 mg/L, and TSAT <20%. If ferritin is unexpectedly elevated, in a patient without chronic disease, active inflammation, or malignancy, C-reactive protein (CRP) can help support the diagnosis of an inflammatory process. Refer to the BC Guideline: C-Reactive Protein and Erythrocyte Sedimentation Rate Testing for information on the use of CRP.

# Investigation of the Etiology of Iron Deficiency
Once iron deficiency/IDA is diagnosed, the etiology must be identified. Clinical evaluation of the cause of iron deficiency is important. It should be based upon a directed history, symptom review and physical examination.

# Directed history should include:
- nutrition and physical activity history - pregnancy status and number of pregnancies - history of blood loss, including GI bleeding, hematuria, menorrhagia, and blood donation - GI symptoms including changes in bowel habits, abdominal pain, dyspepsia, and unexplained weight loss - family history including colorectal cancer 16 Menorrhagia is the most frequent cause of iron deficiency among pre-menopausal women. Consider referral to gynecologist for management of heavy menses and/or consider bleeding disorder, e.g. von Willebrand disease screening.
Testing for malabsorption is recommended if small bowel disease is clinically suspected, or if oral iron supplementation results in inadequate response despite compliance.
Iron deficiency/IDA in adult men and post-menopausal women and in pre-menopausal women without menorrhagia is more likely to have a serious underlying cause of blood loss including malignancy. 16 Consider upper/lower endoscopy.

# Investigation of overt and occult GI and GU bleeding
Primary care providers are encouraged to consult with colleagues including local gastroenterology services or the RACE line to obtain rapid advice and avoid unnecessary travel and wait times.

# FIT and FOBT Testing
FIT and FOBT testing are not indicated for investigation of overt GI bleeding and are not needed for patients being referred. Given the risk of false negatives, FIT and FOBT testing should not be used to rule out GI bleeding.

# Overt GI bleeding
Overt GI bleeding that is otherwise unexplained, new, or out of pattern requires GI evaluation. Consider referral for GI evaluation.
BC colon cancer screening guidelines recommend that patients with signs or symptoms of colon cancer (e.g. unexplained GI bleeding, unexplained iron deficiency anemia) proceed directly to specialist referral for possible endoscopic investigation. 17,18 If any doubt remains about whether to refer for GI investigations, referral is strongly encouraged due to the potentially severe consequences of delayed identification of colorectal cancer. Age-specific risk for colon and rectal cancer is elevated among those born circa 1990 compared to older cohorts. 19 

# Overt GU bleeding
Consider referral to urologist for further work-up, especially for gross painless hematuria.

# Unexplained iron deficiency/IDA
Adult males, post-menopausal females and pre-menopausal females with unexplained iron deficiency/IDA should receive:
- referral for GI investigations (upper/lower endoscopy)
- screening for GU bleeding with urinalysis - screening for celiac disease

# Management
The objective of treatment is to replenish iron stores: normalize hemoglobin levels and ferritin. 16 Target normal ferritin >100 g/L.
Iron replacement therapy should begin as soon as iron deficiency is detected, whether or not anemia is also present.
The exception is: patients with microcytic anemia should not be given iron supplements until iron deficiency is confirmed by testing ferritin. Low MCV in the setting of normal ferritin may indicate hemoglobinopathies such as thalassemia. Long term iron therapy is harmful for these patients.
Individualize disease-specific management depending on underlying cause. 20 Even when there is an apparently obvious cause the etiology may be multifactorial.

# Dietary iron intake
To help prevent iron deficiency, encourage all individuals to consume a diet with sufficient iron. This may include establishing individualized iron intake goals according to recommended daily intake based on sex, age, pregnancy status, and diet. Refer to Associated Documents for recommended daily intake values, and foods high in iron. Consider dietitian referral. Patients can also call 8-1-1 to speak to a dietitian.

# Treatment with Oral Iron
Oral iron replacement is almost always preferred to intravenous (IV) therapy. Refer to Appendix A: Oral Iron Formulations and Adult Doses for a list of commonly used oral iron preparations, doses, and costs.
Advise patients that iron can be toxic to children and should always be safely stored.
Oral iron intolerance is very common:
- Oral iron preparations may cause nausea, vomiting, dyspepsia, constipation, diarrhea or dark stools.
- Strategies to minimize these effects include: 21 o start at a lower dose and increase gradually after 4 to 5 days (to reach target dose in a few weeks) o give divided doses o give the lowest effective dose o take supplements with meals (note: iron absorption is enhanced when supplements are taken on an empty stomach; however, tolerance and adherence may be improved when iron is taken with meals) o try a different iron preparation o try alternative dosing schedules such as every other day dosing 22 (resolution of symptoms and replenishment of iron stores may take longer)
Iron absorption can be decreased by various medications and supplements such as multivitamins, calcium, or antacid tablets.
Space administration by at least 2 hours apart. Avoid taking iron supplements with tea, coffee or milk.
Iron absorption from iron salts can be enhanced by taking them on an empty stomach (at least 1 hour before or 2 hours after eating), or with 600-1200 mg vitamin C. This does not apply to other types of iron preparations such as polysaccharides or polypeptides whose absorption is not affected by food.
Monitoring Response to Oral Iron 1. The frequency of subsequent monitoring depends upon the severity of the anemia, the underlying cause of the iron deficiency, and the clinical impact on the patient. Reassess patients with moderate to severe anemia by testing CBC as early as 2-4 weeks. Hemoglobin should increase by 10-20 g/L by 4 weeks. It may take up to 6 months to replenish iron stores. 2. Hemoglobin will correct within 2 to 4 months if appropriate iron dosages are taken as prescribed and underlying cause of iron deficiency is corrected. 3. Continue iron therapy an additional 4 to 6 months (adults) after correction of anemia to replenish the iron stores. 23 Ferritin should be re-checked 3 to 6 months after normalization of hemoglobin in anemic patients, or after initiation of iron supplementation in non-anemic patients. Target normal ferritin >100 g/L. 4. If ferritin and hemoglobin are not responding as anticipated, consider adherence, ongoing bleeding, malabsorption, or alternate diagnosis. 5. If the patient's clinical status is compromised by moderate to severe anemia, consider blood transfusion. Once the patient is stable, iron replacement can commence.

# IV Iron Therapy
IV iron should not be considered a routine treatment. Access to IV iron and the processes to order it depend on local availability and protocols. Refer to Appendix B: Intravenous Iron Formulations and Adult Doses for a list of commonly used parenteral iron formulations and doses.
Intravenous therapy may be initiated when there is:
- complete or partial failure of oral iron therapy trial (in compliant patients)
- intolerance to oral iron therapy - inadequate iron absorption - continued blood loss - urgent surgery in an iron-deficient patient/pre-operative indication - chronic kidney disease, including dialysis patients 24 Maximum hemoglobin response to IV iron usually occurs within 2 to 3 weeks of the last dose.

# Intramuscular (IM) Therapy
IM iron therapy is not generally recommended because risks include unpredictable absorption, anaphylaxis, and local complications (e.g., pain, permanent staining of the skin, sarcoma formation). 25 IM iron therapy may be appropriate in certain contexts and clinical judgment is required.

# Iron supplementation: ongoing care
Once anemia has corrected and iron stores have normalized, a low maintenance dose may be prescribed if there is an ongoing need for additional iron (e.g., menorrhagia, rapid growth, regular blood donation, vegetarian diet). Consider similar supplementation for patients who have iron deficiency but not anemia. Ensure adequate dietary intake is established and maintained (refer to Associated Documents and consider dietitian referral; patients can also call 8-1-1 for dietitian services).

# Iron Deficiency and IDA in Infants, Children and Adolescents
Iron deficiency and IDA in children are associated with motor and cognitive deficits which may be irreversible. 26 

# Common causes and risk factors
- All ages: Increased requirements due to growth, low socioeconomic status, lack of balanced diet, (including ethnic groups with low iron high fibre/phytates diet e.g., Asians), celiac disease, bleeding from any source, e.g., frequent nosebleeds, GI diseases including short gut syndrome, cow's milk protein colitis - Infants 750 mL/day, bottle use beyond 12-15 months, picky eating (insufficient intake or diversity of solid food), obesity 27 - Adolescents: menorrhagia, disordered eating, vegetarian diet (refer to Vegetarian and Vegan Diets on page 9), extreme physical exercise/endurance athletes, low body weight

# Signs and symptoms
- Some patients may be asymptomatic - All ages: tiredness, restless legs, inattention, poor school performance, irritability/depression, growth retardation, unexplained cognitive and intellectual impairment, breath-holding spells, developmental delay, pica/pagophagia - Infants: poor feeding, lethargy, failure to thrive, cardiomegaly, tachypnea - Adolescents: presyncope, syncope, headache, irritability, fatigue, exercise intolerance, restless legs

# Diagnosis
- Serum ferritin is the diagnostic test of choice for iron deficiency. The ferritin cut-offs for children are different from the ferritin cut-offs for adults. Refer to - Take a thorough dietary history: o Infants < 6 months: should consume breastmilk or formula. Animal milk (cow, goat, etc.) should not be consumed before 9-12 months. 29 o Infants 6-9 months: first foods should be iron-rich foods, offered at least twice a day. 29 o Infants 0-12 months who are not exclusively receiving breastmilk and are at risk of iron deficiency may benefit from formula with higher iron levels. o Toddlers 12-24 months should not consume more than 750 mL per day of cow's milk 30 because its volume can displace other iron rich foods. o Refer to BC Pediatric Nutrition Guidelines for more information on children age six months to six years. 29 o Refer to Associated Documents for age and sex-specific recommended daily iron intake and a list of iron-rich foods.

# Treatment
- Advise patients that iron can be toxic to children and should always be safely stored.
- Provide dietary counselling. Dietitian referral is recommended. Patients and caregivers can also call a dietitian at 8-1-1.
Refer to Associated Documents on page 11 for recommended dietary intake and a list of foods high in heme and non-heme iron. - Recommend infants and toddlers with iron deficiency begin treatment with liquid oral iron salts. Refer to Appendix B: Liquid Iron Formulations and Pediatric Doses for recommended treatment doses, strengths and bottle sizes of liquid iron products for use in children, and guidance on tolerability. - Blood transfusion is very rarely required for iron deficiency anemia in children because onset of anemia is gradual allowing for physiologic compensation and the response to iron supplementation is prompt. Judicious transfusion is indicated for very severe anemia in the setting of hemodynamic compromise/severe signs of anemia requiring emergent correction.
In this case, transfused blood should be administered in small aliquots of 5 mL/kg over 4 hours with close monitoring, for prevention of fluid overload/cardiac failure.

# Monitoring response
- Refer to adult Monitoring Response section for guidance.
- If hemoglobin is correcting by 4 weeks, continue oral iron and check CBC and ferritin at three months.

# Iron Deficiency and Obstetrics
There is an increase in iron requirement (about 1000 mg total) during pregnancy, parturition and lactation. 31,32 Iron is essential for normal fetal development. It is important to prevent iron deficiency in the fetus by preventing iron deficiency in pregnant women. 33 Assess risk of iron deficiency among women planning pregnancy, especially women in high-risk groups (Table 1).

# Iron supplementation for non-anemic pregnant women
Most pregnant women need to take a supplement to get enough iron. 34 An increase in iron consumption by about 15-30 mg elemental iron/day is recommended for non-anemic women, an amount readily met by most prenatal vitamin formulations. Health Canada recommends that pregnant women take a daily multivitamin that includes B12, 0.4mg of folic acid, and 16-20 mg of iron. 34 IDA in pregnant women IDA is the most frequent form of anemia in pregnant women. Refer to Appendix A: Oral Iron Formulations and Adult Doses. Anemia in pregnancy is defined as:  - 1st trimester: hemoglobin < 110 g/L - 2nd and 3rd trimester: hemoglobin < 105 g/L Treatment with oral iron has been recommended when ferritin is less than 30 ug/L. Refer to Treatment with Oral Iron on page 6 for strategies to improve tolerance and compliance. Hemoglobin increase after two weeks indicates empirical confirmation of the diagnosis and response to treatment. 38 Ferritin decreases by approximately 50% in all pregnant women by the second trimester. This is a functional decrease that does not indicate iron deficiency.
If necessary, intravenous iron is considered to be safe for the second and third trimester (refer to Appendix B: Intravenous Iron Formulations and Adult Doses). 33 

# Iron Deficiency in the Elderly
Anemia in the elderly is a common clinical finding, often multifactorial, and has significant impact on quality of life, functional decline, and mortality. Treatment of iron deficiency and its underlying cause(s) may improve outcomes. Iron deficiency is the second most common cause of anemia after anemia of chronic disease (the reverse is true for younger patients).
The diagnosis of absolute iron deficiency is challenging in the elderly. 39 Serum ferritin below 50 ug/L should be investigated for iron deficiency in the elderly 2 though cut-offs between 30 and 100 mg/L have been proposed. 39 Serum ferritin levels may also be increased by comorbidity.
Investigation of anemia in the elderly is recommended if the life expectancy is more than a year. 40 An individualised approach is recommended, recognizing the risks of invasive investigations and surgeries to elderly patients with increasing frailty and multimorbidity. 41 Replacement options for elderly patients are similar to the options for younger patients. If standard dosing is not tolerated, low dose iron therapy (15 mg elemental iron per day, or 30 mg every other day) is an effective treatment in octogenarians, with significantly reduced adverse effects (refer to Appendix A: Oral Iron Formulations and Adult Doses).  Note: iron stores take longer to replete with lower iron doses. Refer to Treatment with Oral Iron on page 6 for strategies to improve tolerance and compliance. IV iron may also be considered in appropriate clinical situations as reviewed above (refer to Appendix B: Intravenous Iron Formulations and Adult Doses).

# Vegetarian and Vegan Diets
Well-balanced vegetarian and vegan diets can provide sufficient iron intake for children, adolescents 45 and adults. Vegetarians require 1.8 times higher iron intake than non-vegetarians because non-heme iron is not absorbed as well as heme iron. 46 If uncertain, consider referral to a registered dietitian.
Refer to Resources section for information on getting enough dietary iron and choosing iron-rich foods, including patient handouts. Patients in BC can also phone a dietitian at 8-1-1. 

# Indications for specialist referral