Fatigue commonly caused by iron deficiency without anemia

Fatigue, often accompanied by depression and anxiety, frequently has iron deficiency shown by suboptimal levels of serum ferritin but occurring without anemia. This often goes unrecognized in clinical practice. An earlier study published in BMJ (British Medical Journal) reports on the effect of iron on unexplained fatigue:

"Fatigue is common in the general population. Prevalence rates of 14% to 27% have been reported in primary care, and in 1-2% of patients fatigue is the main reason for consultation. Women were three times more likely than men to mention fatigue in a study conducted in general practice. Although the symptom of fatigue is related to iron deficiency anaemia, evidence is lacking for any association between iron deficiency and tiredness in the absence of anaemia. Iron deficiency associated with increased fatigue was, however, shown in a recent longitudinal study on women's health. In a European study, about 20% of women of childbearing age had a serum ferritin concentration less than 15 μg/l, and only 4% of these women had iron deficiency anaemia. We examined the effect of iron therapy in women with unexplained fatigue in the absence of anaemia."

The authors conducted a double blind randomized placebo controlled trial with 144 women aged 18 to 55 who were assigned to either 80 mg/day of oral ferrous sulphate or placebo for four weeks. Their results were of great significance to any practitioner who deals with fatigue:

"136 (94%) women completed the study. Most had a low serum ferritin concentration; <or= 20 microg/l in 69 (51%) women. Mean age, haemoglobin concentration, serum ferritin concentration, level of fatigue, depression, and anxiety were similar in both groups at baseline. Both groups were also similar for compliance and dropout rates. The level of fatigue after one month decreased by -1.82/6.37 points (29%) in the iron group compared with -0.85/6.46 points (13%) in the placebo group (difference 0.95 points). Subgroups analysis showed that only women with ferritin concentrations <or= 50 μg/l improved with oral supplementation."

Ferritin reference range is often too low

50 μg/l = 50 ng/L, the level that I and numerous others have found more accurate for serum ferritin than what is often the standard reference range. Regarding this the authors state:

"We found a significant response only in the patients with a baseline serum ferritin concentration ≤ 50 μg/l. This suggests that iron deficiency could be present even with a “normal” concentration of serum ferritin. Indeed, the lower limit for serum ferritin concentration is controversial: iron stores in the bone marrow may serve as a better indicator of iron deficiency. One study compared serum ferritin concentrations with iron stores in the bone marrow and found that a serum ferritin concentration of 50 μg/l was associated with a 50% chance of iron deficiency occurring in the bone marrow. The lower reference limits for serum ferritin and haemoglobin concentrations have been considered too low for women. The authors of that study advocate the adoption of the same reference values for both men and women that “would be expected to have fundamental and positive implications for women's health and welfare.” Our study indirectly supports their conclusion by showing that women can benefit from iron supplementation even if their red blood cell counts are considered normal."

Iron, ferritin and neurotransmitters

Iron deficiency without anemia impairs production of the neurotransmitters dopamine and serotonin.

"Iron deficiency even in the absence of anaemia is associated with decreased activity of iron dependent enzymes and therefore affects the metabolism of neurotransmitters. In people with iron deficiency anaemia the related symptoms will disappear more quickly than the accompanying increase in haematological indices."

How many people, especially women, have been fed SSRIs or NSRIs when what they needed was some iron? All of this has widespread significance:

A frequently unrecognized problem

"Women with fatigue often associate their symptoms with psychosocial stressors and not a possible emotional or biomedical cause. Conversely, medical investigators tend to associate fatigue with emotional causes and more rarely with biomedical causes. We found that iron deficiency may be an under-recognised cause of fatigue in women of childbearing age. Thus, identifying iron deficiency without anaemia as a potential cause of fatigue is important. It may avoid the inappropriate attribution of symptoms to putative emotional causes or life stressors and thereby reduce unnecessary use of healthcare resources. Instituting iron therapy early may also improve quality of life."

The authors conclude:

"Non-anaemic women with unexplained fatigue may benefit from iron supplementation. The effect may be restricted to women with low or borderline serum ferritin concentrations."

Pay attention to serum ferritin below 50 mg/mL

A paper published in Medical Clinics of North America also recognizes serum ferritin below 50 mg/mL as a marker for fatigue. The authors include these key points:

•   Further defining a patient’s complaint of “fatigue” as either sleepiness, dyspnea on exertion, weakness, generalized lack of energy, or feeling down or depressed can aid in evaluation and management.
•   Even in the absence of anemia, in women of child-bearing age with a ferritin less than 50 ng/mL, iron replacement is associated with improvement of subjective fatigue.

 Low ferritin in non-anemic menstruating women

Research reported in CMAJ (Canadian Medical Association Journal) offered similar data from a double-blind, placebo-controlled trial:

"The true benefit of iron supplementation for nonanemic menstruating women with fatigue is unknown. We studied the effect of oral iron therapy on fatigue and quality of life, as well as on hemoglobin, ferritin and soluble transferrin receptor levels, in nonanemic iron-deficient women with unexplained fatigue."

The authors  randomly assigned 198 women aged 18–53 years who complained of fatigue and who had a ferritin level of less than 50 ug/L and hemoglobin greater than 12.0 g/dL to receive either oral ferrous sulfate (80 mg of elemental iron daily) or placebo for 12 weeks and measured fatigue as measured on the Current and Past Psychological Scale along with the biological markers at 6 and 12 weeks:

"The mean score on the Current and Past Psychological Scale for fatigue decreased by 47.7% in the iron group and by 28.8% in the placebo group (difference –18.9%)... Compared with placebo, iron supplementation increased hemoglobin (0.32 g/dL) and ferritin (11.4 μg/L) and decreased soluble transferrin receptor (−0.54 mg/L) at 12 weeks."

Commenting on these results, the authors state:

"We found that iron supplementation for 12 weeks decreased fatigue by almost 50% from baseline, a significant difference of 19% compared with placebo, in menstruating iron-deficient nonanemic women with unexplained fatigue and ferritin levels below 50 μg/L. Iron supplementation did not have a significant effect on measured indicators of quality of life apart from those directly related to fatigue. However, our results suggest that iron supplementation improves hemoglobin, ferritin, hematocrit, mean corpuscular volume and soluble transferrin as early as six weeks after starting treatment."

Ferritin, iron and the brain

"The effects of iron deficiency on fatigue can be explained by decreased activity of iron-dependent enzymes; for example, those affecting the metabolism of neurotransmitters that enhance neurophysiologic changes. However, we presume that such physiologic changes could be confused with depression or anxiety; thus, the effect of iron supplementation on mood disorders remains unknown...Furthermore, blood markers do not necessarily reflect iron stores in other compartments. A recent study suggests that following blood donation, iron supplementation can improve erythropoiesis without affecting fatigue or muscular function. Therefore, fatigue might only occur once iron deficiency becomes present in brain tissue."

Ferritin, iron and hemoglobin

"Our results suggest that an increase in erythropoiesis could be limited to women with a hemoglobin concentration below 13.0 g/dL. The appropriateness of the official definition of the lower limit for normal hemoglobin concentrations in women has been debated. The biological definition of iron-deficiency anemia is based on the reduction of erythropoiesis due to a lack of available iron. Hemoglobin cutoff values serve as a surrogate and do not truly reflect all individuals’ erythropoietic function correctly. Our results confirm that some women with 12.0 g/dL or higher hemoglobin concentrations have increased erythropoiesis following iron supplementation, suggesting that they were iron deficient."

Clinicians should diligently attend to the authors' concluding recommendations:

"For women with unexplained prolonged fatigue, iron deficiency should be considered when ferritin values are below 50 μg/L, even when hemoglobin values are above 12.0 g/dL. Biological markers can be tested at six weeks to confirm iron deficiency."

A variety of possible symptoms

A program to supplement female blood donors without anemia with iron reported in a paper published in the journal Vox Sanguinis highlights some of the symptoms that can attend low ferritin:

"The determination of serum ferritin levels revealed iron deficiency in many non-anaemic premenopausal female blood donors at our Institution...Substitution lasted 16 weeks and the donation interval was extended... Significant results were serum ferritin increase (from a mean value of 7·12 to 25·2 ng/ml), resolution of prostration, fatigue, sleep disturbances, tension in the neck, hair loss and nail breakage. No case of anaemia occurred...."

 Frequently undiagnosed

The problem of iron deficiency without anemia remaining undiagnosed persists since it was recognized in a paper published in the Swiss medical journal Praxis as long as twenty years ago:

"Iron deficiency (ID) without anaemia frequently remains undiagnosed when symptoms are attributed to ID with anaemia. Serum ferritin is the primary diagnostic parameter, whereas <10 microg/l represent depleted iron stores, 10-30 microg/l can confirm ID without anaemia and 30-50 microg/l might indicate functional ID."

Ferritin indicates inflammation when elevated

It's very important for clinicians to remember that ferritin is an acute phase reactant (like CRP) that indicates inflammation when elevated (in the absence of hemochromatosis):

"In case of increased CRP or ALT, normal/elevated ferritin should be interpreted with caution."

Iron dosage

"Intravenous iron is indicated if oral iron is not effective or tolerated. At ferritin <10 microg/l, a cumulative dose of 1000 mg iron and at ferritin 10-30 microg/l, a cumulative dose of 500 mg is advised. At ferritin 30-50 microg/l a first dose of 200 mg might be considered. Ferritin shall be reassessed not sooner than 2 weeks after the last oral or 8-12 weeks after the last iv iron administration."

Health care professionals also have undiagnosed iron deficiency

A study published in the International Journal of Biomedical Science showed that substantial percentage of educated hospital employees in Switzerland were suffering unknowingly of iron deficiency without anemia:

"Iron deficiency (ID) has been associated with depression, chronic fatigue, impaired endurance performance and restless leg syndrome, all of which lead to sleep disturbances...We sought to examine the iron status of reportedly healthy individuals by a framed study design in 58 highly educated Swiss hospital employees and to compare the use of non invasive tests for assessing iron deficiency (ID)... All subjects felt well and were working at their maximum capacity. The male subjects were neither anaemic nor had decreased iron parameters however 50% (23/46) of the women had a serum ferritin of below 22 μg/L, still 33% (15/46) of the women had a ferritin value below the more stringent cut off value of 15 μg/L. In 15% (7/46) of the women we diagnosed iron deficient anaemia. Red meat consumption correlated with ferritin values as did the menstrual blood loss which was estimated by asking the amount of tampons used. Of the additionally analysed iron parameters only the percentage of hypochromic erythrocytes, soluble transferrin receptor and transferrin values were significantly correlated with ferritin and reached an AUCROC of ≥0.7 indicating good predictive tests. Nevertheless neither soluble transferrin receptor nor transferrin showed diagnostic advantages for the diagnosis of ID compared to ferritin alone or together with erythrocyte parameters. Working in a hospital environment and having access to health education does not seem to correlate with prevention of ID or ID anaemia in female hospital employees."

Clinicians should note that other commonly used tests did not cut the mustard:

"As alternative tests we evaluated serum iron, transferrin and transferrin saturation, since these tests are commonly used to assess ID. We found these alternatives to be of little use. For example serum iron exhibits diurnal variations and may reach reference values after ingestion of red meat by iron depleted subjects. In our study serum iron had a poor diagnostic impact (AUC_ROC of 0.56), which is even lower than the reported (AUC_ROC of 0.7) (32). Transferrin saturation had a similarly poor AUC_ROC of 0.67. Transferrin had some diagnostic value as the AUCROC was found to be 0.8, a finding consistent with earlier studies in patients with ID anaemia. Nevertheless none of the above assays offers any advantage over determination of ferritin alone and should no longer be used for diagnosis."

Anger, tension and fatigue in iron deficiency without anemia

How often might biological symptoms be mistaken for neurotic conditions? A study recently published in Biological Trace Element Research demonstrates a correlation between anger and tension along with fatigue in iron deficiency without anemia:

"Iron deficiency without anemia (IDNA), the most prevalent nutritional deficiency worldwide, affects young women of reproductive age. This study aimed to elucidate the relationship between IDNA and mental and somatic symptoms including anger and fatigue using the Japanese version of the Cornell Medical Index Health Questionnaire (CMI-J)...The subjects were classified as having IDNA (hemoglobin (Hb)≥12 g/dL and serum ferritin<20 ng/mL; n=29), having iron deficiency anemia (IDA) (Hb<12 g/dL and serum ferritin<20 ng/mL; n=10), or having a normal iron status (Hb≥12 g/dL and serum ferritin≥20 ng/mL; n=36)."

Psychological complaints were clearly higher in iron deficiency without anemia:

"Sections M-R (mental complaints) were significantly higher in the IDNA subjects than in the normal subjects. No significant difference in CMI scores was found between the normal and IDA subjects. Sections I (fatigability), Q (anger), and R (tension) were significantly higher in the IDNA subjects than in the normal subjects, regardless of no significant differences between the normal and IDA subjects in those sections. Young women with IDNA demonstrated a significantly higher proportion of neurotic tendencies (grades II-IV)....The findings suggest that IDNA may be a risk factor for anger, fatigue, and tension in women of childbearing age."

Mental quality of life and cognitive function

A study recently published in PLOS One (Public Library of Science) demonstrated improvements in general mental well-being in addition to fatigue from a single dose of IV iron in the form of ferric carboxymaltose:

"Unexplained fatigue is often left untreated or treated with antidepressants. This randomized, placebo-controlled, single-blinded study evaluated the efficacy and tolerability of single-dose intravenous ferric carboxymaltose (FCM) in iron-deficient, premenopausal women with symptomatic, unexplained fatigue."

The authors also note:

"Since iron is not only a component of hemoglobin (Hb) but also a key element of various essential enzymes in all metabolic pathways (e.g. oxidative phosphorylation), ID can have an Hb-independent effect on physical performance and fatigue...A slow onset of ID-associated symptoms may lead patients to adapt to fatigue and consequently, they may not request medical help. Therefore, ID may be broadly unrecognized despite being one of the most prevalent nutrient deficiencies affecting human health."

In their study that included 290 women, 144 of whom were given the IV FCM and the rest placebo...

"Fatigue was reduced in 65.3% (FCM) and 52.7% (placebo) of patients (OR 1.68). A 50% reduction of PFS score was achieved in 33.3% FCM- vs. 16.4% placebo-treated patients At Day 56, all FCM-treated patients had hemoglobin levels ≥120 g/L (vs. 87% at baseline); with placebo, the proportion decreased from 86% to 81%. Mental quality-of-life (SF-12) and the cognitive function scores improved better with FCM."

The authors concluded:

"A single infusion of FCM improved fatigue, mental quality-of-life, cognitive function and erythropoiesis in iron-deficient women with normal or borderline hemoglobin. Although more side effects were reported compared to placebo, FCM can be an effective alternative in patients who cannot tolerate or use oral iron, the common treatment of iron deficiency. Overall, the results support the hypothesis that iron deficiency can affect women’s health, and a normal iron status should be maintained independent of hemoglobin levels."

Fatigue, lack of concentration, headache and sleep disorders

Effectiveness of a single IV dose of FCM was also demonstrated in a study published this year in Geburtshilfe und Frauenheilkunde (Obstetrics and Gynecology):

"In total, data from 273 patients was evaluated. 193 of these patients displayed iron deficiency anaemia (IDA), and 68 had iron deficiency without anaemia (ID). The reasons for the ID/IDA were hypermenorrhoea (HyM) (n = 170), post-partum condition (PP) (n = 53) or another indication (n = 53)...The primary, serious accompanying symptoms of anaemia were fatigue (72 %), lack of concentration (42 %), pale mucous membranes (42 %), headache (26 %) and sleep disorders (21 %)...FCM was most frequently administered via infusion (92 %; average infusion duration 21 minutes)...In all subgroups, 92 % of women displayed a marked improvement in all of their symptoms."

Low ferritin can be obscured by inflammation

Ferritin is, of course, a acute-phase reactant that can increased by inflammation. A recent paper published in The New England Journal of Medicine on microcytic anemia describes how ferritin levels that would otherwise appear low are elevated due to inflammation:

"Although the transcription of ferritin mRNA is up-regulated by inflammation, the synthesis of ferritin is regulated by cellular iron content, with ferritin mRNA being translated to protein only when the cell is iron-replete. Thus, a patient with adequate iron may have a very high ferritin level with inflammation, whereas it is rare for a patient with iron deficiency to have a ferritin level of more than 100 ng per milliliter. The lower limit of the normal range depends on the clinical situation. A ferritin level of 15 ng per milliliter is very specific for iron deficiency, but in older patients or those with inflammatory states, one cannot rule out iron deficiency until the ferritin level is more than 100 ng per milliliter. Guyatt et al. found that the likelihood ratio for iron deficiency is positive up to a ferritin level of 40 ng per milliliter in the absence of inflammation and up to 70 ng per milliliter in the presence of inflammation. Although not perfect, the serum ferritin assay is the test most likely to provide information about a patient’s iron status, but the patient’s age and clinical condition need to be considered in the interpretation of results."

Clinical Bottom Line

In cases of fatigue unexplained by other causes, depression, sleep disorders, poor concentration, hair loss, and restless legs syndrome (since iron is necessary for the production of dopamine), iron should be considered when serum ferritin is below 50 ng/L even in the absence of anemia and below 70 ng/L in the presence of inflammation.