Iron deficiency anemia: Higher ferritin lower limit for greater safety?

Pittsburgh. For several years, the American Society of Gastroenterologists (AGA) has recommended in its guidelines that iron deficiency should be considered the cause of anemia not only when serum ferritin is ≤ 15 µg/l (as recommended by the WHO), but already at values ≤ 45 µg/l ( Gastroenterology 2020; online August 15 ).

If medical history and clinical examinations do not provide clear explanations for iron deficiency anemia (IDA) (e.g., vegan diet, blood loss outside the GI tract), the AGA strongly recommends esophagogastroduodenoscopy (EGD) plus colonoscopy for men and postmenopausal women. For premenopausal women, bidirectional endoscopy is merely suggested; alternatively, iron supplementation can be attempted first.

According to the professional association, raising the lower ferritin limit makes it possible to reduce the number of overlooked serious causes of IDA, especially GI tumors, without excessively increasing the number of false-positive diagnoses.

Skepticism about the approach

Doubts about this approach are raised in a research letter written by Omar Al Ta'ani of the Allegheny Health Network in Pittsburgh and colleagues ( JAMA Intern Med 2025; online August 25 ). The team of doctors has roughly calculated what the implementation of these recommendations would actually mean: Using data from the cross-sectional NHANES study, they conclude that raising the lower ferritin limit in the United States would increase the number of (non-pregnant) adults with IDA from 5.9 to 9.2 million.

Of the 3.3 million additional IDA patients, 1.5 million would be men and postmenopausal women with a strong recommendation for endoscopy and 1.8 million premenopausal women with a conditional recommendation.

Since there are no validated instruments for detecting menorrhagia, the main cause of IDA in premenopausal women, the group of physicians sees a risk that many of the young women would also be examined using EGD and colonoscopy despite the expected low yield.

More endoscopies

While Al Ta'ani et al. acknowledge that their calculation likely overestimates the number of additional endoscopies that would be required if guidelines were followed, because, for example, the AGA recommendations do not apply to people with IDA and GI symptoms (e.g., hematochezia), and these symptoms are not captured in NHANES, their results nevertheless highlight that "additional research is needed to develop guidelines for IDA management stratified by the most likely cause of IDA."

The authors of an accompanying editorial also consider the AGA recommendations to be double-edged ( JAMA Intern Med 2025; online August 25 ): "Because bidirectional endoscopy is performed too infrequently, raising the threshold might improve detection [of GI cancers] in high-risk groups. However, in premenopausal women, there is a risk that even a conditional recommendation could drive low-yield endoscopies."

Commentators from the University of Michigan, led by Andrew Read, therefore propose a gender- and age-specific approach:

Older people with asymptomatic new-onset anemia: The pre-test probability of IDA is around 15 percent. A serum ferritin level of < 45 µg/L therefore has sufficient diagnostic power: A positive result increases the post-test probability to 66 percent, while a negative result reduces it to 3 percent. Although a normal ferritin level cannot rule out IDA because it is an acute-phase protein, transferrin saturation, for example, should also be considered in this case. "Nevertheless, ferritin clearly has clinical utility in the evaluation of anemia in this population, especially given the close relationship between increasing age and GI cancer," according to Read et al. A positive (low) ferritin level should therefore prompt EGD and colonoscopy, while a negative (normal) level should prompt investigation of other causes of anemia.
Younger men with anemia: According to Read, the pre-test probability of iron deficiency is similar to that in older people. "Unless there are other symptoms or test results (e.g., elevated tissue transglutaminase), a positive (low) ferritin should prompt bidirectional endoscopy, whereas a negative test makes a GI cause unlikely."
Premenopausal women with anemia: Due to the high pre-test probability of IDA of approximately 80 percent, serum ferritin is of little information, as Read et al. emphasize. While a value < 45 µg/L increases the post-test probability to 98 percent, a negative result reduces it to only 39 percent, a value too high to rule out IDA. Other iron markers may be useful in this group, but clinical assessment is even more important: It must be clarified whether menorrhagia could be a causative factor and whether GI symptoms and red flags are present.

In the German S1 guideline on iron deficiency anemia, the recommendations for determining the cause are quite general: "In the absence of evidence of a alimentary cause, appropriate methods must be used to search for malabsorption disorders (e.g., gluten-sensitive enteropathy, chronic inflammatory bowel diseases, and other malabsorption syndromes, including Helicobacter pylori colonization of the stomach), losses exceeding the capacity for compensation (open and occult chronic blood loss), chronic inflammatory diseases (with iron shift into the circulating blood vessels), or rare genetic causes."