The origin of ferritin reference intervals: a systematic review

Area of Science:

• Clinical Chemistry
• Hematology
• Laboratory Medicine

Background:

• Iron deficiency is a widespread health issue causing significant morbidity and mortality.
• Current laboratory reference intervals for serum ferritin, particularly the lower limit of normal (LLN), may not accurately reflect iron deficiency in adults.
• This potential underdiagnosis contributes to health inequities.

Purpose of the Study:

• To systematically review and summarize ferritin reference intervals in healthy adults.
• To assess the methodological quality of studies determining these reference intervals.
• To evaluate the scientific basis of current laboratory-reported lower limits of normal for serum ferritin.

Main Methods:

• A systematic review and meta-analysis of medical literature databases and grey literature was conducted.
• Studies determining ferritin reference intervals in healthy adults were identified (up to Nov 30, 2021).
• Methodological quality assessment and data extraction were performed on eligible studies.

Main Results:

• 37 studies comprising 21,882 females and 23,650 males were analyzed.
• Median ferritin LLN was 8 μg/L for females and 25 μg/L for males.
• Many studies lacked exclusion criteria for iron deficiency risk and did not adhere to reference interval establishment guidelines, indicating a high risk of bias.

Conclusions:

• Serum ferritin reference intervals in healthy adults consistently report LLNs below 30 μg/L.
• The data supporting current ferritin reference intervals are likely biased due to methodological limitations.
• Evidence-based clinical decision limits are recommended for accurate iron deficiency diagnosis.