What is the cause of anemia in a patient with Crohn's (Crohn's disease) disease and normal C-Reactive Protein (CRP) and fecal calprotectin levels?

Anemia in Crohn's Disease with Normal Inflammatory Markers

In a Crohn's disease patient with normal CRP and fecal calprotectin, the anemia is most likely due to non-inflammatory causes: iron deficiency from chronic occult blood loss, vitamin B12 or folate malabsorption from ileal disease, or medication-related bone marrow suppression—not active intestinal inflammation. 1

Understanding the Clinical Context

Normal biomarkers reliably exclude active inflammation in this scenario:

• Fecal calprotectin <150 μg/g combined with normal CRP (<5 mg/L) effectively rules out endoscopically active inflammation in Crohn's disease patients, with a false-negative rate of only 3.8% in asymptomatic patients. 1

• The 2023 AGA guidelines specifically state that this biomarker combination allows clinicians to avoid endoscopic evaluation for disease activity assessment, as the likelihood of significant mucosal inflammation is very low. 1

• Fecal calprotectin correlates more closely with endoscopic disease activity (correlation coefficient r=0.75) than CRP (r=0.53), making the combination of both being normal highly reassuring. 2

Primary Causes of Anemia to Investigate

Iron Deficiency Anemia

• Chronic occult blood loss from previous disease activity or residual mucosal abnormalities remains the most common cause of anemia in Crohn's disease, even during periods of biochemical remission. 3

• Check complete iron studies (serum iron, ferritin, transferrin saturation, total iron-binding capacity) to confirm iron deficiency. 3

Vitamin B12 Deficiency

• Ileal disease or prior ileal resection causes malabsorption of vitamin B12, leading to megaloblastic anemia independent of current inflammatory activity. 4, 3

• Crohn's disease affecting the terminal ileum disrupts intrinsic factor-B12 complex absorption, even when the mucosa appears quiescent. 4

• Measure serum B12 and methylmalonic acid levels to diagnose B12 deficiency. 3

Folate Deficiency

• Proximal small bowel involvement can impair folate absorption, and sulfasalazine therapy interferes with folate metabolism. 3

• Check serum and red blood cell folate levels, particularly in patients on sulfasalazine or methotrexate. 3

Medication-Related Causes

• Immunomodulators (azathioprine, 6-mercaptopurine, methotrexate) can cause bone marrow suppression leading to anemia, leukopenia, or thrombocytopenia. 3

• Review complete blood count with differential and consider checking thiopurine methyltransferase (TPMT) activity if on thiopurines. 3

Diagnostic Algorithm

Step 1: Obtain complete anemia workup

• Complete blood count with indices (MCV, MCH, MCHC) to classify anemia type
• Reticulocyte count to assess bone marrow response
• Iron studies (ferritin, serum iron, TIBC, transferrin saturation)
• Vitamin B12 and folate levels
• Peripheral blood smear if macrocytic anemia present 3

Step 2: Consider disease-specific factors

• Review prior surgical history (ileal resections increase B12 deficiency risk)
• Assess disease location (ileal disease → B12 deficiency; proximal small bowel → folate deficiency)
• Review current medications for myelosuppressive agents 3

Step 3: Endoscopy is NOT routinely indicated

• The combination of normal fecal calprotectin and CRP makes endoscopically active disease highly unlikely (negative predictive value >95%). 1

• Only proceed to endoscopy if there is clinical discordance (new symptoms, unexplained findings) or if anemia workup suggests ongoing blood loss despite normal biomarkers. 1

Common Pitfalls to Avoid

• Do not assume normal biomarkers mean the patient has no Crohn's-related complications—nutritional deficiencies and malabsorption can persist even during disease remission. 3

• Do not overlook medication side effects—immunomodulators are a frequent cause of anemia in Crohn's patients with quiescent disease. 3

• Do not rush to endoscopy—the 2023 AGA guidelines explicitly recommend against routine endoscopic assessment when both fecal calprotectin <150 μg/g and CRP are normal in asymptomatic or mildly symptomatic patients. 1

• Remember that approximately 8.5% of patients with fecal calprotectin <150 μg/g may still have endoscopic activity, but this false-negative rate is acceptable for clinical decision-making and does not warrant routine endoscopy in the absence of other concerning features. 1