From the Guidelines
When investigating iron deficiency anemia (IDA) of unknown etiology, a systematic approach is essential, starting with a thorough history and physical examination, followed by laboratory testing, including complete blood count, iron studies, and fecal occult blood testing, and endoscopic evaluation with bidirectional endoscopy recommended for men and postmenopausal women, as suggested by the American Gastroenterological Association (AGA) 1. The initial steps in investigating IDA of unknown etiology should focus on:
- A thorough history and physical examination to identify potential sources of blood loss, particularly from the gastrointestinal tract
- Laboratory testing, including:
- Complete blood count
- Iron studies (serum iron, ferritin, total iron binding capacity)
- Fecal occult blood testing
- Endoscopic evaluation, with the AGA recommending bidirectional endoscopy for asymptomatic postmenopausal women and men with IDA, using a cut-off of 45 ng/mL for ferritin to diagnose iron deficiency 1 For premenopausal women, upper endoscopy should be performed first, with colonoscopy considered if no cause is found, as the AGA suggests bidirectional endoscopy over iron replacement therapy only in this population 1. Additional testing may include:
- Celiac disease screening with tissue transglutaminase antibodies
- Helicobacter pylori testing
- Urinalysis to check for hematuria In certain cases, capsule endoscopy or CT enterography may be needed to evaluate the small bowel, and rare causes such as autoimmune gastritis, hereditary hemorrhagic telangiectasia, or malabsorption syndromes should be considered if initial investigations are unrevealing. While investigating, iron replacement therapy should be initiated with oral ferrous sulfate, as recommended by the British Society of Gastroenterology 1, and if oral therapy is not tolerated or ineffective, intravenous iron formulations like iron sucrose or ferric carboxymaltose may be necessary. This comprehensive approach helps identify the underlying cause of iron deficiency while simultaneously treating the deficiency itself, with the goal of improving morbidity, mortality, and quality of life outcomes.
From the Research
Investigations for Iron Deficiency Anemia (IDA) of Unknown Etiology
The following investigations are recommended for IDA of unknown etiology:
- Conduct serological celiac disease screening with transglutaminase antibody (IgA type) and IgA testing 2
- Perform bidirectional endoscopy (gastroscopy and colonoscopy) 2, 3
- Small intestine investigation (capsule endoscopy, CT, or MRI enterography) if there are red flags indicating malignant or inflammatory small bowel disease 2
- Full blood examination and serum ferritin level to diagnose iron deficiency anemia 3
- Reticulocyte hemoglobin content (CHr) to diagnose iron deficiency and iron deficiency anemia, and to monitor iron therapy 4
- Serum iron studies (i.e. serum iron, Total iron binding capacity (TIBC) and serum ferritin) to confirm the diagnosis of iron deficiency anemia 5
Diagnostic Strategy
The diagnostic strategy for unexplained anemia with iron deficiency includes:
- Conducting serological celiac disease screening and bidirectional endoscopy 2
- Evaluating patients for coeliac disease 3
- Searching for a source of bleeding in adults 6
- Using reticulocyte hemoglobin content (CHr) to diagnose iron deficiency and iron deficiency anemia, and to monitor iron therapy 4
Special Considerations
- Bidirectional endoscopy is not required in premenopausal women < 40 years of age 2
- Small intestine investigation is not recommended routinely after negative bidirectional endoscopy but should be conducted if there are red flags indicating malignant or inflammatory small bowel disease 2
- Oral iron therapy is considered front line therapy except for conditions such as gastric bypass, heavy uterine bleeding, inflammatory bowel disease, and hereditary hemorrhagic telangiectasia 6