Mei
Z
,
Addo
OY
,
Jefferds
ME
, et al
.
Physiologically based serum ferritin thresholds for iron deficiency in children and non-pregnant women: a US National Health and Nutrition Examination Surveys (NHANES) serial cross-sectional study
.
Lancet Haematol
.
2021
;
8
(
8
):
e572
e582
. .

The recognition and diagnosis of iron deficiency remains inconsistent amongst health care providers, despite being such a common condition worldwide. The World Health Organization (WHO) recently recommended ferritin thresholds of less than 15 μg/L (adults) and less than 12 μg/L (children) for the diagnosis of iron deficiency, but these thresholds were based largely on expert opinion along with historical studies correlated with absence of bone marrow iron stores.1,2 

Several experts have questioned the appropriateness of these WHO thresholds.3,4  In this study, Dr. Zuguo Mei and colleagues propose that changes in markers of iron-deficient erythropoiesis may be used to ascertain more suitable ferritin thresholds for iron deficiency, particularly as iron deficiency may begin and be associated with adverse effects before overt anemia or absence of marrow iron stores occurs.5 

Iron-deficient erythropoiesis refers to the production of red cells despite inadequate iron supply, leading to the production of microcytic and hypochromic cells followed by anemia. When iron-deficient erythropoiesis occurs, the body also induces the production of the surface transferrin receptor, and some of this molecule circulates in the blood as soluble transferrin receptor (sTfR) which serves as a biomarker of iron deficiency.6,7 

In this physiological, serial, cross-section study, the authors examined the relationship between these two biomarkers of iron deficient erythropoiesis (hemoglobin and sTfR) and ferritin levels, at the population level. They analyzed biomarker data from the National Health and Nutrition Examination Surveys (NHANES) during three time periods (2003-2006, 2007-2010, and 2015-2018) in children (n = 2,569) and nonpregnant women (n = 7,498) for this analysis. The new ferritin thresholds were determined by using restricted cubic spline regression models to ascertain the relationship between changes in these biomarkers and ferritin levels. They included premenopausal, nonpregnant women (age, 15-49 years) and children (age, 12-59 months) in this analysis. They excluded individuals who would be suspected of having spurious ferritin levels for comorbid illnesses (e.g., white blood cells > 10 × 109/L as surrogate for infection, C-reactive protein > 5.0 mg/L for chronic inflammation, alanine transaminase or aspartate aminotransferase > 70 IU/L for liver disease).

In adults, the authors found that the ferritin threshold at which hemoglobin concentration plateaued and the sTfR value reached its minimal point was approximately 25 μg/L, whereas for children the threshold value was approximately 20 μg/L. These thresholds were relatively consistent across the three time periods observed, though in adults the ferritin overall was lower between 2015 and 2018. These thresholds overall were higher than those recommended by the WHO guideline.1 

There were some limitations with this study. Ferritin is an acute phase reactant, and though the authors attempted to screen and exclude for patients with infection, liver, dysfunction, and inflammatory disease, the methods for doing this were imperfect. The study also could not adjust for variations in ferritin assays used.

In Brief

However, these data call into question whether the WHO ferritin threshold should be re-examined. While absence of bone marrow stores is a longstanding definition of established iron deficiency, evidence of iron-deficient erythropoiesis may be a more appropriate physiological representation of the onset of iron deficiency. By the time iron deficiency has progressed to the advanced stage of marrow iron depletion, the physiological impacts of iron deficiency on cellular function and metabolism may have already occurred. A higher ferritin threshold would have substantial implications for public health policy and greatly increase the proportion of individuals in both developed and developing countries diagnosed with this condition, but would also be an impetus for early screening, diagnosis, and therapy.

In my own adult hematology practice, a ferritin level of 25 μg/L even in the absence of microcytosis, hypochromia, or anemia would be a compelling reason to initiate iron supplementation, to hopefully pre-empt and avoid the overt manifestations and morbidity associated with overt iron deficiency anemia. Whether guidelines will ultimately be updated to reflect this will depend on further validation and research, which I eagerly look forward to seeing.

Competing Interests

Dr. Tseng indicated no relevant conflicts of interest.

References

1.
World Health Organization
.
2020
.
WHO guideline on use of ferritin concentrations to assess iron status in individuals and populations
.
World Health Organization
.
2.
Guyatt
GH
,
Petterson
C
,
Ali
M
, et al
.
Diagnosis of iron-deficiency anemia in the elderly
.
Am J Med
.
1990
;
88
(
3
):
205
209
.
3.
Braat
S
,
Pasricha
SR
.
Finding ferritin in the plateaus and valleys of iron deficiency
.
Lancet Haematol
.
2021
;
8
(
8
):
e539
-
e540
.
4.
Foy
BH
,
Li
A
,
McClung
JP
, et al
.
Data-driven physiologic thresholds for iron deficiency associated with hematologic decline
.
Am J Hematol
.
2020
;
95
(
3
):
302
309
.
5.
Muñoz
M
,
Gómez-Ramírez
S
,
Besser
M
, et al
.
Current misconceptions in diagnosis and management of iron deficiency
.
Blood Transfus
.
2017
;
15
(
5
):
422
437
.
6.
Lopez
A
,
Cacoub
P
,
Macdougall
IC
, et al
.
Iron deficiency anaemia
.
Lancet
.
2016
;
387
(
10021
):
907
916
.
7.
Suominen
P
,
Punnonen
K
,
Rajamäki
A
, et al
.
Serum transferrin receptor and transferrin receptor-ferritin index identify healthy subjects with subclinical iron deficits
.
Blood
.
1998
;
92
(
8
):
2934
2939
.