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Critical iron deficiency anemia with record low hemoglobin: a case report

• Audrey L. Chai   ORCID: orcid.org/0000-0002-5009-0468 1 ,
• Owen Y. Huang 1 ,
• Rastko Rakočević 2 &
• Peter Chung 2  

Journal of Medical Case Reports volume  15 , Article number:  472 ( 2021 ) Cite this article

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Anemia is a serious global health problem that affects individuals of all ages but particularly women of reproductive age. Iron deficiency anemia is one of the most common causes of anemia seen in women, with menstruation being one of the leading causes. Excessive, prolonged, and irregular uterine bleeding, also known as menometrorrhagia, can lead to severe anemia. In this case report, we present a case of a premenopausal woman with menometrorrhagia leading to severe iron deficiency anemia with record low hemoglobin.

Case presentation

A 42-year-old Hispanic woman with no known past medical history presented with a chief complaint of increasing fatigue and dizziness for 2 weeks. Initial vitals revealed temperature of 36.1 °C, blood pressure 107/47 mmHg, heart rate 87 beats/minute, respiratory rate 17 breaths/minute, and oxygen saturation 100% on room air. She was fully alert and oriented without any neurological deficits. Physical examination was otherwise notable for findings typical of anemia, including: marked pallor with pale mucous membranes and conjunctiva, a systolic flow murmur, and koilonychia of her fingernails. Her initial laboratory results showed a critically low hemoglobin of 1.4 g/dL and severe iron deficiency. After further diagnostic workup, her profound anemia was likely attributed to a long history of menometrorrhagia, and her remarkably stable presentation was due to impressive, years-long compensation. Over the course of her hospital stay, she received blood transfusions and intravenous iron repletion. Her symptoms of fatigue and dizziness resolved by the end of her hospital course, and she returned to her baseline ambulatory and activity level upon discharge.

Conclusions

Critically low hemoglobin levels are typically associated with significant symptoms, physical examination findings, and hemodynamic instability. To our knowledge, this is the lowest recorded hemoglobin in a hemodynamically stable patient not requiring cardiac or supplemental oxygen support.

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Anemia and menometrorrhagia are common and co-occurring conditions in women of premenopausal age [ 1 , 2 ]. Analysis of the global anemia burden from 1990 to 2010 revealed that the prevalence of iron deficiency anemia, although declining every year, remained significantly high, affecting almost one in every five women [ 1 ]. Menstruation is considered largely responsible for the depletion of body iron stores in premenopausal women, and it has been estimated that the proportion of menstruating women in the USA who have minimal-to-absent iron reserves ranges from 20% to 65% [ 3 ]. Studies have quantified that a premenopausal woman’s iron storage levels could be approximately two to three times lower than those in a woman 10 years post-menopause [ 4 ]. Excessive and prolonged uterine bleeding that occurs at irregular and frequent intervals (menometrorrhagia) can be seen in almost a quarter of women who are 40–50 years old [ 2 ]. Women with menometrorrhagia usually bleed more than 80 mL, or 3 ounces, during a menstrual cycle and are therefore at greater risk for developing iron deficiency and iron deficiency anemia. Here, we report an unusual case of a 42-year-old woman with a long history of menometrorrhagia who presented with severe anemia and was found to have a record low hemoglobin level.

A 42-year-old Hispanic woman with no known past medical history presented to our emergency department with the chief complaint of increasing fatigue and dizziness for 2 weeks and mechanical fall at home on day of presentation.

On physical examination, she was afebrile (36.1 °C), blood pressure was 107/47 mmHg with a mean arterial pressure of 69 mmHg, heart rate was 87 beats per minute (bpm), respiratory rate was 17 breaths per minute, and oxygen saturation was 100% on room air. Her height was 143 cm and weight was 45 kg (body mass index 22). She was fully alert and oriented to person, place, time, and situation without any neurological deficits and was speaking in clear, full sentences. She had marked pallor with pale mucous membranes and conjunctiva. She had no palpable lymphadenopathy. She was breathing comfortably on room air and displayed no signs of shortness of breath. Her cardiac examination was notable for a grade 2 systolic flow murmur. Her abdominal examination was unremarkable without palpable masses. On musculoskeletal examination, her extremities were thin, and her fingernails demonstrated koilonychia (Fig. 1 ). She had full strength in lower and upper extremities bilaterally, even though she required assistance with ambulation secondary to weakness and used a wheelchair for mobility for 2 weeks prior to admission. She declined a pelvic examination. No bleeding was noted in any part of her physical examination.

Koilonychia, as seen in our patient above, is a nail disease commonly seen in hypochromic anemia, especially iron deficiency anemia, and refers to abnormally thin nails that have lost their convexity, becoming flat and sometimes concave in shape

She was admitted directly to the intensive care unit after her hemoglobin was found to be critically low at 1.4 g/dL on two consecutive measurements with an unclear etiology of blood loss at the time of presentation. Note that no intravenous fluids were administered prior to obtaining the hemoglobin levels. Upon collecting further history from the patient, she revealed that she has had a lifetime history of extremely heavy menstrual periods: Since menarche at the age of 10 years when her periods started, she has been having irregular menstruation, with periods occurring every 2–3 weeks, sometimes more often. She bled heavily for the entire 5–7 day duration of her periods; she quantified soaking at least seven heavy flow pads each day with bright red blood as well as large-sized blood clots. Since the age of 30 years, her periods had also become increasingly heavier, with intermittent bleeding in between cycles, stating that lately she bled for “half of the month.” She denied any other sources of bleeding.

Initial laboratory data are summarized in Table 1 . Her hemoglobin (Hgb) level was critically low at 1.4 g/dL on arrival, with a low mean corpuscular volume (MCV) of < 50.0 fL. Hematocrit was also critically low at 5.8%. Red blood cell distribution width (RDW) was elevated to 34.5%, and absolute reticulocyte count was elevated to 31 × 10 9 /L. Iron panel results were consistent with iron deficiency anemia, showing a low serum iron level of 9 μg/dL, elevated total iron-binding capacity (TIBC) of 441 μg/dL, low Fe Sat of 2%, and low ferritin of 4 ng/mL. Vitamin B12, folate, hemolysis labs [lactate dehydrogenase (LDH), haptoglobin, bilirubin], and disseminated intravascular coagulation (DIC) labs [prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, d -dimer] were all unremarkable. Platelet count was 232,000/mm 3 . Peripheral smear showed erythrocytes with marked microcytosis, anisocytosis, and hypochromia (Fig. 2 ). Of note, the patient did have a positive indirect antiglobulin test (IAT); however, she denied any history of pregnancy, prior transfusions, intravenous drug use, or intravenous immunoglobulin (IVIG). Her direct antiglobulin test (DAT) was negative.

A peripheral smear from the patient after receiving one packed red blood cell transfusion is shown. Small microcytic red blood cells are seen, many of which are hypochromic and have a large zone of pallor with a thin pink peripheral rim. A few characteristic poikilocytes (small elongated red cells also known as pencil cells) are also seen in addition to normal red blood cells (RBCs) likely from transfusion

A transvaginal ultrasound and endometrial biopsy were offered, but the patient declined. Instead, a computed tomography (CT) abdomen and pelvis with contrast was performed, which showed a 3.5-cm mass protruding into the endometrium, favored to represent an intracavitary submucosal leiomyoma (Fig. 3 ). Aside from her abnormal uterine bleeding (AUB), the patient was without any other significant personal history, family history, or lab abnormalities to explain her severe anemia.

Computed tomography (CT) of the abdomen and pelvis with contrast was obtained revealing an approximately 3.5 × 3.0 cm heterogeneously enhancing mass protruding into the endometrial canal favored to represent an intracavitary submucosal leiomyoma

The patient’s presenting symptoms of fatigue and dizziness are common and nonspecific symptoms with a wide range of etiologies. Based on her physical presentation—overall well-appearing nature with normal vital signs—as well as the duration of her symptoms, we focused our investigation on chronic subacute causes of fatigue and dizziness rather than acute medical causes. We initially considered a range of chronic medical conditions from cardiopulmonary to endocrinologic, metabolic, malignancy, rheumatologic, and neurological conditions, especially given her reported history of fall. However, once the patient’s lab work revealed a significantly abnormal complete blood count and iron panel, the direction of our workup shifted towards evaluating hematologic causes.

With such a critically low Hgb on presentation (1.4 g/dL), we evaluated for potential sources of blood loss and wanted to first rule out emergent, dangerous causes: the patient’s physical examination and reported history did not elicit any concern for traumatic hemorrhage or common gastrointestinal bleeding. She denied recent or current pregnancy. Her CT scan of abdomen and pelvis was unremarkable for any pathology other than a uterine fibroid. The microcytic nature of her anemia pointed away from nutritional deficiencies, and she lacked any other medical comorbidities such as alcohol use disorder, liver disease, or history of substance use. There was also no personal or family history of autoimmune disorders, and the patient denied any history of gastrointestinal or extraintestinal signs and/or symptoms concerning for absorptive disorders such as celiac disease. We also eliminated hemolytic causes of anemia as hemolysis labs were all normal. We considered the possibility of inherited or acquired bleeding disorders, but the patient denied any prior signs or symptoms of bleeding diatheses in her or her family. The patient’s reported history of menometrorrhagia led to the likely cause of her significant microcytic anemia as chronic blood loss from menstruation leading to iron deficiency.

Over the course of her 4-day hospital stay, she was transfused 5 units of packed red blood cells and received 2 g of intravenous iron dextran. Hematology and Gynecology were consulted, and the patient was administered a medroxyprogesterone (150 mg) intramuscular injection on hospital day 2. On hospital day 4, she was discharged home with follow-up plans. Her hemoglobin and hematocrit on discharge were 8.1 g/dL and 24.3%, respectively. Her symptoms of fatigue and dizziness had resolved, and she was back to her normal baseline ambulatory and activity level.

Discussion and conclusions

This patient presented with all the classic signs and symptoms of iron deficiency: anemia, fatigue, pallor, koilonychia, and labs revealing marked iron deficiency, microcytosis, elevated RDW, and low hemoglobin. To the best of our knowledge, this is the lowest recorded hemoglobin in an awake and alert patient breathing ambient air. There have been previous reports describing patients with critically low Hgb levels of < 2 g/dL: A case of a 21-year old woman with a history of long-lasting menorrhagia who presented with a Hgb of 1.7 g/dL was reported in 2013 [ 5 ]. This woman, although younger than our patient, was more hemodynamically unstable with a heart rate (HR) of 125 beats per minute. Her menorrhagia was also shorter lasting and presumably of larger volume, leading to this hemoglobin level. It is likely that her physiological regulatory mechanisms did not have a chance to fully compensate. A 29-year-old woman with celiac disease and bulimia nervosa was found to have a Hgb of 1.7 g/dL: she presented more dramatically with severe fatigue, abdominal pain and inability to stand or ambulate. She had a body mass index (BMI) of 15 along with other vitamin and micronutrient deficiencies, leading to a mixed picture of iron deficiency and non-iron deficiency anemia [ 6 ]. Both of these cases were of reproductive-age females; however, our patient was notably older (age difference of > 20 years) and had a longer period for physiologic adjustment and compensation.

Lower hemoglobin, though in the intraoperative setting, has also been reported in two cases—a patient undergoing cadaveric liver transplantation who suffered massive bleeding with associated hemodilution leading to a Hgb of 0.6 g/dL [ 7 ] and a patient with hemorrhagic shock and extreme hemodilution secondary to multiple stab wounds leading to a Hgb of 0.7 g/dL [ 8 ]. Both patients were hemodynamically unstable requiring inotropic and vasopressor support, had higher preoperative hemoglobin, and were resuscitated with large volumes of colloids and crystalloids leading to significant hemodilution. Both were intubated and received 100% supplemental oxygen, increasing both hemoglobin-bound and dissolved oxygen. Furthermore, it should be emphasized that the deep anesthesia and decreased body temperature in both these patients minimized oxygen consumption and increased the available oxygen in arterial blood [ 9 ].

Our case is remarkably unique with the lowest recorded hemoglobin not requiring cardiac or supplemental oxygen support. The patient was hemodynamically stable with a critically low hemoglobin likely due to chronic, decades-long iron deficiency anemia of blood loss. Confirmatory workup in the outpatient setting is ongoing. The degree of compensation our patient had undergone is impressive as she reported living a very active lifestyle prior to the onset of her symptoms (2 weeks prior to presentation), she routinely biked to work every day, and maintained a high level of daily physical activity without issue.

In addition, while the first priority during our patient’s hospital stay was treating her severe anemia, her education became an equally important component of her treatment plan. Our institution is the county hospital for the most populous county in the USA and serves as a safety-net hospital for many vulnerable populations, most of whom have low health literacy and a lack of awareness of when to seek care. This patient had been experiencing irregular menstrual periods for more than three decades and never sought care for her heavy bleeding. She, in fact, had not seen a primary care doctor for many years nor visited a gynecologist before. We emphasized the importance of close follow-up, self-monitoring of her symptoms, and risks with continued heavy bleeding. It is important to note that, despite the compensatory mechanisms, complications of chronic anemia left untreated are not minor and can negatively impact cardiovascular function, cause worsening of chronic conditions, and eventually lead to the development of multiorgan failure and even death [ 10 , 11 ].

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

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Audrey L. Chai & Owen Y. Huang

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AC, OH, RR, and PC managed the presented case. AC performed the literature search. AC, OH, and RR collected all data and images. AC and OH drafted the article. RR and PC provided critical revision of the article. All authors read and approved the final manuscript.

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Correspondence to Audrey L. Chai .

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Chai, A.L., Huang, O.Y., Rakočević, R. et al. Critical iron deficiency anemia with record low hemoglobin: a case report. J Med Case Reports 15 , 472 (2021). https://doi.org/10.1186/s13256-021-03024-9

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• Iron deficiency anaemia: pathophysiology, assessment, practical management
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• http://orcid.org/0000-0003-1026-3173 Aditi Kumar 1 ,
• Esha Sharma 2 ,
• Alexandra Marley 1 ,
• Mark A Samaan 2 ,
• http://orcid.org/0000-0002-8782-0292 Matthew James Brookes 1 , 3
• 1 Department of Gastroenterology , The Royal Wolverhampton NHS Trust , Wolverhampton , UK
• 2 Inflammatory Bowel Disease Unit , Guys and St Thomas' NHS Foundation Trust , London , UK
• 3 Research Institue , Faculty of Science and Engineering, University of Wolverhampton , Wolverhampton , UK
• Correspondence to Dr Aditi Kumar; aditikumar{at}nhs.net

The WHO has recognised iron deficiency anaemia (IDA) as the most common nutritional deficiency in the world, with 30% of the population being affected with this condition. Although the most common causes of IDA are gastrointestinal bleeding and menstruation in women, decreased dietary iron and decreased iron absorption are also culpable causes. Patients with IDA should be treated with the aim of replenishing iron stores and returning the haemoglobin to a normal level. This has shown to improve quality of life, morbidity, prognosis in chronic disease and outcomes in pregnancy. Iron deficiency occurs in many chronic inflammatory conditions, including congestive cardiac failure, chronic kidney disease and inflammatory bowel disease. This article will provide an updated overview on diagnosis and management of IDA in patients with chronic conditions, preoperative and in pregnancy. We will discuss the benefits and limitations of oral versus intravenous iron replacement in each cohort, with an overview on cost analysis between the different iron formulations currently on the market.

• iron deficiency
• inflammatory bowel disease
• iron absorption
• iron metabolism

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https://doi.org/10.1136/bmjgast-2021-000759

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Introduction

The WHO has recognised iron deficiency anaemia (IDA) as the most common nutritional deficiency in the world, with 30% of the population being affected with this condition. 1 While IDA is more prevalent in children and women, adult men are also susceptible depending on their socioeconomic status and health conditions. 2 Although the most common causes of IDA are gastrointestinal (GI) bleeding and menstruation in women, decreased dietary iron intake and absorption are also culpable causes. 3

Iron is required for various cellular functions, including but not limited to enzymatic processes, DNA synthesis, oxygen transport and mitochondrial energy generation. 4 5 As such, the symptoms of IDA can vary over a wide range. Shortness of breath, fatigue, palpitations, tachycardia and angina can result from reduced blood oxygen levels. This resultant hypoxemia can subsequently cause a compensatory decrease in intestinal blood flow, leading to motility disorder, malabsorption, nausea, weight loss and abdominal pain. Central hypoxia can cause headaches, vertigo and lethargy as well as cognitive impairment with several studies showing an improvement in cognitive functions once anaemia has normalised. 6–9 It is well known that IDA significantly affects quality of life (QoL) 9 with recent evidence demonstrating that treating IDA improves QoL, regardless of the underlying cause for anaemia. 8 10

In this review, we will discuss the pathophysiology, diagnosis, treatment and complications in the management of IDA. The investigative criteria for IDA are beyond the scope of this article and have been comprehensively outlined in the recent British Society of Gastroenterology guidelines. 11

Pathophysiology

Iron is an essential element and is controlled primarily by dietary intake, intestinal absorption and iron recycling. 12 Dietary iron can be found in two forms: haem and non-haem iron. Haem iron is easily absorbable and arises from haemoglobin (Hb) and myoglobin in the form of animal meat, poultry and fish. Non-haem iron is mostly found in plant food but is not as easily absorbable. Compounds such as phytate, oxalate, polyphenols and tannin, which are found in plants, diminish the uptake of non-haem iron, as do some drugs, such as proton pump inhibitors. 13 14 Ascorbic acid, citrate and gastric acid, conversely, facilitate iron absorption. 15 In a healthy diet, approximately 5–15 mg of elemental iron and 1–5 mg of haem iron are ingested daily although only 1–2 mg is ultimately absorbed into the intestine, predominantly in the duodenum and proximal jejunum. 16 Please see figure 1 for details on the iron absorption pathways.

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The two different iron absorption pathways. Non-haem absorption pathway (left): insoluble ferric iron (Fe 3+ ) is reduced to absorbable ferrous iron (Fe 2+ ), which is carried out by the enzyme duodenal cytochrome B (DcytB). The divalent metal transporter 1 (DMT1) imports Fe 2+ across the apical surface and into the cell, which can then be either stored as ferritin or exported into circulation through ferroportin. Prior to exiting the enterocyte, Fe 2+ must be oxidised back to Fe 3+ by hephaestin or ceruloplasmin. Haem absorption pathway (right): the haem carrier protein (HCP1) transports haem iron directly into the enterocyte. Once inside the enterocyte, haem iron can either be released into plasma via the haem exporter FLVCR1 or be converted back into Fe 2+ via the haem oxidase (HO) enzyme. The ferroportin receptor then releases Fe 2+ into the plasma. Hepcidin, a hepatic peptide hormone, controls ferroportin, the sole iron exporter, by promoting its endocytosis. Hepcidin production and circulation are regulated by plasma iron concentration and iron stores. Hepcidin is increased in the presence of inflammation, which then promotes the degradation of ferroportin and subsequently impairs the exportation of cellular iron into plasma. Figure taken with permission from Kumar and Brookes. 84

Assessment and diagnosis

The WHO defines anaemia as blood Hb level below 130 g/L in men and 120 g/L in women. 1 In isolated iron deficiency, serum ferritin (the storage molecule for iron) should be less than 30 ug/L. 17 However, ferritin is an acute phase protein and can be increased in the presence of inflammation. 18 Thus, if there is evidence of concomitant inflammation, such as elevated C reactive protein, ferritin less than 100 ug/L is indicative of IDA. 19 Transferrin, the iron transporter, is generally elevated; however, it is a negative acute phase protein and, therefore, can be normal or reduced in chronic inflammatory states. 20 Serum iron and transferrin saturations (TSAT) will be reduced with TSAT less than 20% required for the diagnosis of IDA. 17 See table 1 for the breakdown of diagnostic criteria for IDA. It is crucial to note that iron deficiency should not be excluded in the presence of a normal Hb as a significant amount of iron must be lost before the Hb levels begin to decline. Thus, a low mean corpuscular Hb with a normal Hb or an increase in red cell distribution width signifies mild iron deficiency without anaemia. 21

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Diagnostic criteria for iron deficiency anaemia

Patients with IDA should be treated with the aim of replenishing iron stores and returning the Hb to a normal level. This has been shown to improve QoL, morbidity, prognosis in chronic disease and outcomes in pregnancy. 22 Iron replenishment can occur via three routes: oral iron, parenteral oral and transfusion of packed red cells. Each route has its benefits and limitations, which will be discussed below in greater detail.

Conventional oral iron formulations

The British Society of Gastroenterology recommends ferrous preparations, specifically ferrous sulphate, as first-line therapy for iron replenishment as they are cheap, have good bioavailability, available in multiple preparations and have been shown to replenish iron stores and correct anaemia effectively. 11 However, there are also many limitations to their use, with the most common being the frequency and severity of side effects. A systematic review demonstrated that GI side effects were the most problematic with constipation being the most frequent complaint, followed by nausea and diarrhoea. 23 This will have a resultant effect on patient adherence, likely leading to cessation and, thus, inadequate treatment. 24

The appropriate dosing of ferrous iron preparations is also a contentious issue between clinicians. To adequately replenish iron stores, therapeutic treatment of IDA was initially felt to require 200 mg of iron sulphate 2–3 times per day in order to raise Hb by 20 g/L over a 4-week period, with treatment continuing for 3 months. 25 However, the daily doses of elemental iron should not be greater than 100 mg/day 26 as the body can only absorb 10–20 mg of iron per day. 26 It should be noted that 200 mg of ferrous sulphate is equivalent to 65 mg of elemental iron. 27

A recent study compared oral iron dosing regimens in women with mild anaemia with divided daily, once daily and alternate-day dosing. The results demonstrated superiority with alternate-day dosing, with 33% greater fractional iron absorption over 14 doses. 28 In addition, a randomised trial of elderly patients with IDA received 15 mg, 50 mg or 150 mg of elemental iron per day. After 2 months, the mean increase in Hb was the same in all groups (1.4 g/dL); however, adverse effects were significantly greater with higher doses. 29 It is, therefore, an evolving view that a single daily dose (40–60 mg) or a slightly higher alternate-day dose (80–100 mg) is the preferred dosing regimen in order to reduce the side effects and optimise the proportion of elemental iron absorbed. 28–30

Sodium feredetate is a water-soluble EDTA compound with higher bioavailability than the ferrous iron salt preparations. In the UK, it is available as a liquid preparation (Sytron); however, it is also available in tablet form (Ecofer, not currently licensed in the UK) often in combination with B12 and folate. 31 In a study looking at treatment of IDA in pregnant women, sodium feredetate increased Hb by 1.28 g/dL after 1 month of treatment and 2.11 g/dL after 2 months of treatment. This was in comparison to the group of women who received ferrous sulphate, where the mean Hb rose by 1 g/dL after 1 month and 1.58 g/dL after 2 months. As well as a significantly greater increase in Hb, there were significantly fewer side effects seen with sodium feredetate than ferrous sulphate. 32 This study also highlighted the improved bioavailability of sodium feredetate as this cohort was given one 231 mg tablet once per day for 2 months (equivalent to 33 mg of elemental iron) compared with the ferrous sulphate cohort who were given 200 mg tablets two times per day for 2 months (equivalent to 60 mg of elemental iron).

Novel oral iron formulations

Ferric maltol, a novel preparation, is a non-salt oral iron formulation composed of stable ferric iron complexed with a sugar derivative, tri-maltol. It is licenced in the European Union and the USA and sold under the brand names Feraccru and Accrufer, respectively. When absorbed, the maltol ligand remains complexed to iron, which reduces the formation of free iron and facilitates iron transport across the enterocyte. 33 This subsequently increases the bioavailability of iron such that lower doses of elemental iron are required to treat IDA compared with the ferrous iron preparations. 34 Furthermore, ferric maltol has been shown to have less of an effect on the gut microbiome. 35 Studies on the use of ferric maltol has been limited to patients with inflammatory bowel disease (IBD), with results demonstrating improvement in Hb levels beyond 12 weeks with sustained normal Hb levels up to 64 weeks when compared with placebo. 36 37 When compared with intravenous ferric carboxymaltose, however, ferric maltol was shown to be inferior and did not meet the primary endpoint of increasing Hb by 2 g/L or Hb normalisation by 12 weeks (85% vs 68%, respectively). 38

Finally, sucrosomial iron is an innovative oral iron-containing carrier, in which ferric pyrophosphate is within a phospholipid bilayer membrane forming the ‘sucrosome’, creating a gastroresistant complex, which can be transported to the intestinal mucosa where it is absorbed without free iron interacting with the gut wall. 39 40 This unique structure protects iron from the acidic environment in the stomach, increases intestinal epithelial absorption and ensures high bioavailability while reducing the risk for potential adverse GI effects. 39 Despite lower doses of elemental iron, this newer oral iron preparation (30–60 mg/day) has also shown greater efficacy in increasing Hb and ferritin concentrations compared with ferrous sulphate (105–210 mg/day), with a mean Hb increase in 2.7 g/dL and 1.4 g/dL, respectively, over a 12-week course of treatment. 39

Recent studies have demonstrated sucrosomial iron to be non-inferior to parenteral iron in patients with anaemia secondary to coeliac disease, cancer, bariatric surgery and chronic kidney disease (CKD). 41–43 In a study looking at patients with IDA as a result of benign GI or gynaecological bleeding who had previously not responded to or not tolerated ferrous sulphate were randomised to receive a high dose of either sucrosomial iron or intravenous ferrous gluconate. Results demonstrated that patients were comparable at baseline and rise in Hb was not significantly different between the two groups, with the number of weeks required to achieve an Hb target value of 12 g/dL was four in the sucrosomial iron group and 3.5 in the ferrous gluconate group. 44

Intravenous iron

An alternative to oral iron supplementation is parenteral administration. Intravenous iron is the preferred route of administration in some patients and is increasingly favoured due to its rapid correction of Hb, fewer side effects and improved safety profile. The primary advantage of intravenous iron is that it bypasses the GI tract absorption, thereby avoiding further mucosal aggravation and inflammation and producing less side effects. 45 Clinicians also do not have to worry about patient’s adherence to medication.

There are a variety of intravenous iron preparations with selection of the agent dependent on multiple factors including cost considerations, patient and physician preference and product availability. It is important to note that clinical studies of the various formulations follow different protocols, and as of yet, there are no large head-to-head trials between these formulations comparing efficacy and safety profile.

Older intravenous iron preparations such as high-molecular weight dextran iron (Dexferrum) have been discontinued due to their unfavourable safety profiles with relatively high incidence of anaphylaxis. 46 The lower molecular weight dextran compounds such as Cosmofer are, however, still in use and have been shown to be effective with a much lower incidence of anaphylactoid reactions. 47 While there has not been a study comparing the different preparations, a meta-analysis looking at the overall rate of anaphylaxis with intravenous dextran was 0.61%, 48 which is significantly greater than with the newer non-dextran intravenous preparations. 49

Ferric derisomaltose (Monofer) is an alternative intravenous iron preparation, which is often preferred to Cosmofer due to its shorter infusion time, thereby optimising the use of medical infusion units and nursing time as these drugs are often given as day-case procedures. Monofer is also preferred by some as it can be given as one infusion rather than two infusions. Ferric carboxymaltol (Ferinject) is a preparation widely used in the UK. It can be safely administered at a single dose of 1000 mg within 15 min; however, two infusions may be required in some patients, depending on their weight and Hb levels. Finally, iron sucrose (Venofer) is given by a slow injection of 100–200 mg 2–3 times a week. 50 It has been shown to be effective, although a comparison study showed Ferinject to be superior. In this study, Ferinject was associated with a higher rate of achieving a 2 g/dL increase in Hb concentration in comparison to iron sucrose by a relative risk of 1.65. 51 While Venofer has been extensively studied, the major drawback in its use is the need for multiple infusions, which can not only be less acceptable to patients but also made difficult for overstretched healthcare services.

Red blood cell transfusion

It is advised that transfusions should be reserved for patients with severe anaemia, haemodynamically unstable and/or have associated comorbid conditions. 26 However, while severe anaemia is defined as Hb <70 g/dL, many of these patients may be haemodynamically stable and rather have chronic anaemia, remaining asymptomatic. Although a unit of blood contains approximately 200 mg of iron, 22 these patients are very likely to require further iron supplementation to adequately replenish their iron stores, particularly if the cause for their anaemia is chronic and not easily treatable, for example, advanced malignancy or haematological disease.

Clinicians are rightly reluctant to transfuse patients unnecessarily as it is associated with not insignificant risks. These include an increased mortality with liberal blood transfusion in the setting of upper GI bleeding. 52 There is also increased incidence of transfusion-related reactions. This includes the risk of Transfusion Related Acute Lung Injury, which is one of the most serious reactions, the incidence of which is approximately 1 in 5000 transfusions. 53 Furthermore, there remains a small risk for transmitting infections, both viral and bacterial. 54–56

Considerations in management

Comorbidities.

IDA occurs in many chronic inflammatory conditions, including congestive cardiac failure (CCF), CKD and IBD ( table 2 ). To complicate matters, symptoms such as fatigue are commonly seen in these conditions, which can mimic and be confused with symptoms of IDA. Consequently, the management of IDA can often be overlooked. Untreated IDA can have greater consequences in these conditions causing an exacerbation of the underlying disease. 6

A list of common conditions and patient groups who have an increased risk of developing iron deficiency anaemia

Congestive cardiac failure

In CCF, IDA is one of the most prevalent comorbid conditions 57 and can be a result of multiple factors including reduced appetite, increased GI blood losses as a result of antiplatelet or anticoagulant medication and decreased GI absorption due to oedema. 58

The median dose of iron needed to replete iron sufficiently in patients with CCF with IDA is 1000 mg. 59 If patients were given ferrous sulphate, the first-line oral preparation, the bioavailability is only 10% at best, 60 and, thus, patients would need a minimum of 50 days at a dose of 200 mg/day to correct the iron deficit. Realistically, considering missed doses or non-adherence, it can take up to 6 months to adequately replenish iron stores. 58 Thus, intravenous iron should be considered first line for the treatment of iron deficiency in CCF. 6 The Ferinject Assessment in Patients with Iron Deficiency and Heart Failure (FAIR-HF) and Ferric Carboxymaltose Evaluation on Performance in Patients with Iron Deficiency in Combination with Chronic Heart Failure (CONFIRM-HF) trials demonstrated the benefit of ferric carboxymaltose compared with placebo in correcting IDA by improving exercise capacity, cardiac function, symptom severity and QoL. 61

Chronic kidney disease

The causes of IDA in CKD are similar to those in CCF, namely, reduced GI iron absorption, poor nutrition and blood loss caused by dialysis and frequent blood sampling. A recent meta-analysis and systematic review demonstrated intravenous iron to be more effective than oral iron in treating IDA in CKD, regardless of requirement for dialysis. 6 62 The Kidney Disease: Improving Global Outcomes clinical practice guidelines also recommend intravenous iron as first-line treatment for patients with stage 5 CKD. 63 However, ferric citrate might be an alternative oral preparation with a recent trial of 203 patients given 1 g three times per day showing fewer hospitalisation rates and lower incidence of death, dialysis or transplantation. 64 Despite the evidence provided for intravenous preparations, oral iron remains first-line therapy for many clinicians and patients as it is readily available, inexpensive and avoids the need for intravenous access, which can cause injury to blood vessels that may be needed in the future for critical vascular access. 65 Furthermore, there are concerns regarding potential side effects with intravenous iron including anaphylaxis, hypersensitivity, susceptibility to infections and cardiovascular events, hypophosphataemia and iron overload. 66 While human erythropoietin (EPO) and EPO-stimulating agents (ESA) have been in use for decades, they are associated with worsening hypertension, seizures and dialysis access clotting. 67 68 Moreover, ESA has not shown to reduce adverse outcomes associated with anaemia, including mortality rate, hospitalisations and progression of kidney disease. 69

Inflammatory bowel disease

IDA has been acknowledged as one of the most common extra intestinal manifestations of IBD. 20 Impaired GI iron absorption is caused by chronically inflamed bowel, chronic blood losses, bowel resection and malnutrition. 6 Improvement in iron status through treatment with intravenous iron has led to significant improvement in QoL in patients with IBD. 10 Adverse effects from oral iron are well recognised but have greater consequences in patients with IBD. Absorption from the GI tract is limited (on average 10%–20% of ingested amount) and unabsorbed iron is exposed to the ulcerated intestinal surface, which can cause further mucosal damage as well as changes to gut microbiota, 70 although it is not yet established whether oral iron exacerbates IBD inflammation beyond animal models. The European Crohn’s and Colitis Organisation (ECCO) guidelines advise the use of intravenous iron as first-line therapy in patients with active disease, severe anaemia (Hb <100 g/L), if previously intolerant to oral iron and for patients in need of concomitant treatment with EPO. 26 However, there is a place for both oral and intravenous iron in patients with IBD, which is further outlined in figure 2 .

Iron deficiency treatment pathway in patients with IBD patients as followed by the South East London Clinical Commissioning Group. 85 Hb, haemoglobin; IBD, inflammatory bowel disease.

IDA is associated with multiple types of cancer, including GI (colorectal, pancreatic, oesophageal, gastric), lung, genitourinary (cervical, prostate, testicular), breast and haemotological (lymphoma, leukaemia, myeloma). 71 In cancer patients, iron deficiency is associated with fatigue and weakness irrespective of the presence of anaemia. 66 Iron deficiency can occur frequently by means of chemotherapy-induced anaemia and anaemia of chronic disease. 66 Blood transfusions, ESA therapy and intravenous iron are the potential treatment options for IDA in patients with cancer. The aim is to improve QoL and reduce reliance on blood transfusions that are often associated with further multiorgan complications. Beneficial effects of ESAs are limited and both the European medicines agency and Food and Drug Administration have recommended restricting their use to patients with symptomatic anaemia and those undergoing specific chemotherapy. 72 A consensus of cancer experts suggest intravenous iron should be used over oral iron supplementation due to reduced efficacy and poor tolerance and adherence in the latter. 72 This is corroborated by a meta-analysis of 11 randomised studies, where intravenous iron had an improved haematopoietic response in chemotherapy-induced anaemia with no safety concerns and an overall reduction in blood transfusion requirement, compared with oral iron. 73

Elderly population

Another high-risk population are the elderly where prevalence of iron deficiency increases rapidly with age due to reduce oral intake, poor absorption and excess loss. 74 A meta-analysis of trial data shows treatment of iron deficiency with both oral and intravenous iron reduces blood transfusion requirements and increases Hb levels but does not significantly impact mortality 68 Oral supplementation is recommended for treatment of IDA in this population, and lower doses of oral iron may be effective and better tolerated among elderly patients. For those whose oral treatment has been unsuccessful, intravenous treatment should be considered to avoid adverse effects and effectively treat anaemia. However, potential adaptations of oral therapy should also be considered such as liquid formulations or reducing dose frequency. 74

IDA in surgery

There is a growing field of evidence to focus on the impact of iron deficiency on morbidity and mortality in the perioperative period. Recently published national guidance recommends that IDA should be identified and treated pre and postoperatively, 75 whether that be via oral or intravenous iron supplementation. Intravenous iron is recommended for those who are unable to tolerate oral iron, those with functional iron deficiency and those with surgical procedures close to the time the IDA was diagnosed. 75 Further research is necessary to assess the impact of the timing of iron replacement prior to surgery.

Anaemia in pregnancy is defined as Hb <110 g/L with ferritin levels <100 μg/L. 11 The total iron loss in pregnancy approximately 1000 mg, and, thus, the recommended daily dietary allowance for iron in pregnancy is 27 mg compared with 8 mg in the adult non-pregnant population. 76 The usual recommended dose of elemental iron is 80 mg, which is equivalent to 250 mg of oral iron sulphate tablets. 76 Intermittent oral iron has been reported to be effective as daily iron dosing in raising Hb levels and is associated with a lower incidence of adverse effects. 77 However, a meta-analysis has demonstrated intravenous iron sucrose improved Hb (mean difference 7.17 g/L) and serum ferritin levels (mean difference 49.66 ug/L) while ferric carboxymaltose improved Hb levels (mean difference 8.52 g/L), compared with oral ferrous sulphate. 78 Furthermore, side effects were less common with the parenteral formulations, but included local pain, skin irritation and rarely allergic reactions.

Adverse effects

As previously discussed, the common adverse effects of oral iron are well known among healthcare professionals and patients. The potential adverse effects of intravenous iron have more recently been publicised as they become further researched and understood. The rare adverse effect of hypersensitivity reactions has been known for some time and have dictated specialised protocols and training for healthcare professionals routinely administering intravenous iron.

Hypophosphataemia is an increasingly recognised adverse effect of intravenous iron. The risk of persistent hypophosphataemia and osteomalacia is possibly higher with ferric carboxymaltose than with the other intravenous iron preparations. A key mechanism is the carbohydrate moieties in ferric carboxymaltose inhibit degradation of fibroblast growth factor 23, resulting in greater renal loss of phosphate. 79 Phosphate replacement is an ineffective management strategy due to this mechanism as any phosphate replaced is lost through greater renal wasting. 80 Although the clinical significance is not yet fully understood, it is expected to have more of an effect on those patients requiring higher doses, repeat courses and are at a higher risk of electrolyte imbalances due to malnutrition. 79

A less commonly recognised adverse effect is that of extravasation of intravenous iron that can cause long-lasting tattoo-like skin discolouration preceded by skin irritation and pain at the injection site. Though this adverse effect is considered to be rare (occurring at a rate of approximately 1.6%), the skin staining can last for several months after the initial infusion despite pharmacological interventions to resolve the reaction. 81 82 Though the extravasation of intravenous iron is not expected to cause harm, the long-lasting effects of the skin stain can have negative psychological and social impact on patients, so awareness of this phenomenon among healthcare professionals is imperative. Patients should be informed of this potential adverse effect prior to administration of intravenous iron.

Cost implications

It is important to consider both the cost of the impact of iron deficiency to the healthcare system and the cost of the individual treatments when assessing the overall cost of IDA management ( table 3 ). Oral treatment with standard ferric salts is by far the lowest cost option with convenient administration and low drug cost (a 12-week course is approximately £2). Conversely, intravenous iron preparations can cost approximately £1400 per patient infusion when based on the highest iron requirement and including costs to the healthcare system for patient day-case admission. However, the most significant cost to the healthcare system is that of untreated IDA, which can result in emergency hospitalisation and multiple blood transfusions, approximately £1700 per admission on average. Brookes et al reviewed management of IDA in England between 2012 and 2018 and identified that £42.4 million was spent on emergency hospital admissions. In comparison, £46 million was spent on day case admissions, although four times as many patients were treated in the outpatient setting. 83 Though intravenous iron administration can seem more expensive than oral treatment, these findings strongly suggest that there is a need for a national strategy for standardising and streamlining elective intravenous iron administration to prevent more costly emergency admissions. For those who have not tolerated standard oral supplementation, ferric maltol may offer a more suitable alternative than intravenous iron. The cost of ferric maltol is significantly more than the standard oral iron (approximately £170 for a 12-week course) but much less than intravenous iron. If oral intolerance is the drive for choosing intravenous treatment, then ferric maltol may offer an alternative choice with less potential adverse effects, although direct comparisons of this drug with other iron formulations still need to be studied.

Cost analysis per drug

Looking to the future: service development and redesign

IDA is the most common nutritional disorder globally and is associated with multiple comorbid states with severe implications in QoL. Despite national guidance on managing IDA, there is still wide variability in current practices, not just between National Health Service trusts but also between clinicians and departments. Choosing between intravenous and oral iron therapies is dependent on many factors, including the therapy goal, response to prior therapy, patient preference, cost and ease of access to an infusion centre. A standardised pathway steered by evidence-based medicine can reduce this variance in care, while simultaneously supporting cost-effective anaemia management across and between the new integrated care systems.

Ethics statements

Patient consent for publication.

Not applicable.

Ethics approval

This study does not involve human participants.

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Contributors AK, AM and ES wrote the manuscript. MAS and MJB provided critical revisions of the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests ES served as a speaker and/or an advisory board member for Takeda, Janssen and Pharmacosmos. MAS served as a speaker, a consultant and/or an advisory board member for Abbvie, Bristol Myers Squibb, Sandoz, Janssen, Takeda, MSD, Falk and Samsung Bioepis. MJB has received funding from Vifor International and Tillotts Pharma in the form of grants for research work and travel expenses, outside of the submitted work.

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Case 2: Recurrent Anemia in a 10-year-old Girl

AUTHOR DISCLOSURE

Drs Rani, Imdad, and Beg have disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.

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Uzma Rani , Aamer Imdad , Mirza Beg; Case 2: Recurrent Anemia in a 10-year-old Girl. Pediatr Rev December 2015; 36 (12): 548–550. https://doi.org/10.1542/pir.36-12-548

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A 10-year-old premenarchal girl presents to the emergency department with an episode of syncope. She has been feeling progressively more tired for the last week, and her mother noticed that she was pale. The girl has had intermittent headaches but no complaints of palpitations, weight loss, abdominal pain, or rectal bleeding. Her diet consists of vegetables and meat. She is taking oral iron supplements because she presented with similar symptoms 4 months ago and was found to have severe anemia (hemoglobin of 4.9 g/dL [49.0 g/L]). The cause of the anemia at that time was determined to be iron deficiency, based on peripheral blood smear, iron studies, and bone marrow examination. A stool guaiac test was negative and hemoglobin electrophoresis yielded normal results. After packed red blood cell transfusion, she was started on ferrous sulfate supplements. Her anemia responded to iron supplements; her hemoglobin 3 months later measured 11 g/dL...

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• Volume 106, Issue Suppl 2
• 66 Iron Deficiency Anemia in Adolescent – An unexpected diagnosis: Case Report
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• Alexandra M Rodrigues ,
• Rita Andrade ,
• Joana Filipe Ribeiro ,
• Catarina Francisco ,
• Leonor Salicio ,
• António Manso ,
• Sónia Santos
• Hospital de Sousa Martins – Unidade Local Saúde da Guarda, Guarda, Portugal

Background Iron deficiency anemia (IDA) in adolescents is very common. The major causes at this age are an inadequate diet. Obesity or malnutrition are also causes of IDA. Besides that, many adolescents have genital losses (girls) or gastrointestinal tract disorders like inflammatory bowel disease, coeliac disease, hemorrhoids or diverticulitis. Moreover, less common chronic or acute diseases can cause this anemia.

Case Report A 17 year old female was oriented from primary care to pediatric evaluation because of iron deficiency anemia with failure of oral iron treatment after six months. In pediatric evaluation, the adolescent presented inadequate diet and no other problems. There were doubts about compliance with the iron treatment previously prescribed. She was previously healthy, had no symptoms or history of hereditary diseases or other family relevant pathology and had regular menstruation. As such, in the first evaluation, an extensive analytical study was requested, a more assertive oral iron treatment was initiated and diet correction was explained. One month later, the adolescent maintained IDA. As such, the iron treatment was doubled. Besides that, a slight increase in fecal calprotectin and thrombocytosis was detected. The rest of the analytical study did not have any changes. Thus, gastroenterology evaluation was requested for suspicion of inflammatory bowel disease. After three months, the adolescent returned and referred feeling right hypochondrial pain over the last two months which was controlled with paracetamol. Ultrasound evaluation of the abdomen was performed and revealed circumferential thickening of the ascendant colon and many mesenteric adenophaties. A CT scan was done which showed an eight centimeter long tumoral mass in the ascendant colon, as well as an inferior vena cava involvement and bulky adenopathies in venous drainage.

The adolescent was transferred to a central hospital and evaluated by pediatric oncology and surgery. A percutaneous biopsy revealed mucinous adenocarcinoma with colorectal phenotype. This diagnosis led to a surgery in which laparoscopic right hemicolectomy, epiplon excision and peritonectomy were done. After surgery, T4aN1bM1 – stage IV was established. Neoplastic markers were all negative and a KRAS gene mutation was detected.

Currently, she has a fully implanted central venous catheter and is doing adjuvant chemotherapy.

Conclusion Iron deficiency anemia is very common in adolescents but sometimes worst diseases emerge. Adenocarcinoma in adolescents is very rare and is commonly diagnosed in advanced stage presentation. Diagnostic is facilitated when abdominal symptoms begin or when there are familiar predisposing syndromes.

https://doi.org/10.1136/archdischild-2021-europaediatrics.66

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Is There Any Correlation between Migraine Attacks and Iron Deficiency Anemia? A Case-Control Study

Ali tayyebi.

1 Medical Student, Shiraz University of Medical Sciences, Shiraz, Iran

Maryam Poursadeghfard

2 Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

Masoumeh Nazeri

Tahereh pousadeghfard.

3 Department of Mathematics and Statistics, Firoozabad Branch, Islamic Azad University, Firoozabad, Iran

Background: Migraine headache is an episodic abnormality which usually presents with a severe headache, accompanied by nausea, photo and sound sensitivity, and autonomic symptoms. Iron accumulation in brain, especially peri-aqueductal grey is associated with duration of the disease, and apparently there is an association between body iron storage status and the incidence of migraine; hence, the present study was conducted to investigate the plausible association between iron-deficiency anemia and migraine in a case-control design.

Materials and Methods: After signing the written informed consent, the blood samples were collected by a well-trained technician from the patients proved to have migraine, those having migraine clinical criteria and those having migraine attack frequency as high as that prophylaxis was required, and non-migraine healthy individuals, those having not migraine and anemia except iron-deficiency anemia. Based on the sample size, each group composed of samples with at least 100 individuals.

Results: There were statistically significant differences between female cases and controls regarding hemoglobin, serum ferritin levels and iron-deficiency anemia (P: .0004; .006; .001), but no differences were observed among males (P: .606; .38; .303). Furthermore, the case-control comparisons revealed a significant difference in iron-deficiency anemia (P: .032), but no significant difference was seen in hemoglobin and serum ferritin levels (P: .161; .178).

Conclusion: The present study suggests an association between iron-deficiency anemia, hemoglobin and serum ferritin levels and the incidence of migraine in females. As a result, there might be an association between body iron storage status and the incidence of migraine, especially among females, reflecting the fact that iron supplements might be an effective treatment or prophylaxis in patients with migraine associated with iron-deficiency anemia. However, further studies are required to provide a conclusive answer to the issues remained controversial.

Introduction

Migraine headache is a periodic disorder, the most important of which is usually a severe headache associated with nausea or a sensitivity to sound and light, and is often accompanied by symptoms in the autonomic nervous system. This disease is one of the most common causes of referral to neurology clinics 1 . Iron is the most commonly received nutrient in human diet. Iron deficiency affects many of the cellular functions and processes such as oxygen transmission, neuronal malignancies, electron storage and transport, oxidative phosphorylation, neurotransmitter metabolism, immune function, and DNA synthesis 2 .

Studies have indicated that iron plays a major role in the synthesis of serotonin, dopamine and norepinephrine. Meanwhile, the serotonin level of the brain as a mediator decreases in migraine headaches    3  . Serotonin is a key neurotransmitter in migraine neurobiology and its relationship with migraine has been shown. These studies have indicated that the serotonin level in migraine attacks decreases in the central nervous system and increases in the peripheral nervous system    4  . Iron Deficiency Anemia (IDA) may in some way lead to a reduction in serotonin    5  . Many data declared that metabolic abnormalities in the brain following iron deficiency anemia lead to a reduction in neuronal activities. Also,according to some surveys, the level of monoamine oxidase enzyme activity reduces in both migraine and in IDA    6  .

In addition, both migraine and iron-deficiency anemia are more common in young women, although there are very few studies exist about the relationship between these two diseases         2  .

So, if the relationship between iron-deficiency anemia and migraine attacksis confirmed with more evidence, the treatment of iron IDA can greatly influence the rate of migraine attacks and the life quality of migraine patients. Therefore, due to the importance of the above-mentioned and unknown mechanism of migraine, and also due toless studies on the relationship between IDA and migraine, the present study was conducted to determine the relationship between these two diseases.

MATERIALS AND METHODS

The study was a cross-sectional case-control study that was conducted at Imam Reza clinic, Shiraz University of Medical Sciences from February 2017 to June 2017.

After obtaining the written consent form, the subjects were selected through available sampling. patients having International Headache Society (IHS)-based migraine criteria    7  and the prevalence of their migraine attacks was as high or severe as requiring prophylaxis met the inclusion criteria of the study. All patients were examined and selected by a neurologist. The patients were excluded from the study due to the following conditions:

• Having had iron supplementation in the last six months.
• Having a confirmed anemia, with the exception of iron-deficiency anemia such as thalassemia.
• Havingchronic illnesssuch as the asthma and chronic renal failure.

The control group consisted of healthy subjects without migraine who had referred to the laboratory for a periodic laboratory review only. The following people were also excluded from the control group:

• People with a history of confirmed migraine and anemia, with the exception of iron- deficiency anemia.
• Patients in the acute phase of inflammatory or infectious disease.

Iron-deficiencyanemia is defined asa decrease inthe amount of hemoglobin (<12 mg/dl for women and <16 mg/dl for men) and ferritin level (<50 ng/dl) for each sex.

This research wasapproved by the Ethics Committee of Shiraz University of Medical Sciences(Registration No: 93-01-01-8823).

Statistical analysis

To describe the data, mean, standard deviation and relative prevalence were used. The comparison between the two groups was performed using Chi-square and independent T-test. Data analysis was performed using SPSS 18. A value of P< 0.05 was considered statistically significant.

In this study, the case group consisted of 100 patients with an average age of 37.63 ± 9.93years, which included 76 women with an average age of 37.79 ± 10.28 years and 24 men with an average age of 37.13 ± 8.93 years. The control group included 100 normal subjects with an average age of 34.93 ± 12.25 years, which included 76 women with an average age of 36 ± 11.9 years and 24 males with an average age of 31.54 ± 12.97 years. There was no significant difference between the age of the case and control groups in the male group, the female group and the total population (P: 0.09, 0.323, 0.089) ( Table 1 ).

comparing age and iron markers in patients with migraine and controls

Abbreviations: IDA: Iron Deficiency Anemia; (a) t -statistic; (b) χ 2 -statistic (df); (c) P ≤ .05 was considered as statistically significantly different

Comparison of total hemoglobin in case and control groups

As indicated in Figure 1 , there was no statistically significant difference in hemoglobin level between the subjects suffering from migraine and the subjects in the control group (P: 0.161); however, hemoglobin levels were found to be less distributed in the control group.

Dispersion and density of hemoglobin in case and control groups without gender segregation (Independent students’ T-test).

[ Control mean ± SD: 13.97 ± 1.39, case mean ± SD: 13.59 ± 1.9 P: .161 t-statistic: 1.41]

Comparison of the ferritin level in case and control groups

Based on Figure 2 , there was no statistically significant difference in the level of ferritin between subjects with migraine and the subjects in the control group (P: 0.178), and the two similar diagrams to each group have a similar pattern.

Dispersion and density of ferritin in case and control groups without gender segregation (Independent students’ T-test).

[ Control mean ± SD: 80.69 ± 89.44, case mean ± SD: 65.25 ± 57.23, P: .178, t-statistic: 1.35]

Comparison of the prevalence of IDA in the study population in case and control groups

As indicated in Figure 3 , the relative prevalence of IDA in the migraine group (21%) was higher than the control group (10%), and no statistically significant difference was observed between the subjects suffering from migraine and the subjects in the control group ( P: 0.032).

prevalence of IDA in the case and control groups without gender segregation (Chi-square test for independence).

[P: .032, χ 2 -statistic (df): 4.619 (1)]

Comparison of hemoglobin level in male subjects in case and control groups

Figure 4 shows the distribution and density of hemoglobin in male subjects. As seen, there was no significant difference in the level of hemoglobin between the subjects suffering from migraine and the subjects in the control group (P: 0.606); however, it can be observed that hemoglobin levels are less frequent in the migraine group.

Dispersion and density of hemoglobin in the male case and control groups (Independent students’ T-test).

[ Control mean ± SD: 14.51 ± 2.03 case mean ± SD: 14.82 ± 2.03, P: .606, t-statistic: -.519]

Comparison of ferritin level in male subjects in case and control groups

Descriptive drawing 5 reveals the dispersion and density of ferritin among male subjects in case and control groups. As seen, there was no significant difference in the level of ferritin between the subjects suffering from migraine and the subjects in the control group (P: 0.38).

Dispersion and density of ferritin in the male case and control groups (Independent students’ T-test).

[ Control mean ± SD: 134.52 ± 159.62, case mean ± SD: 103.13 ± 65.95 P: .38, t-statistic: .891]

Prevalence of male subjects' IDA in case-control in male subjects

Descriptive drawing 6 points to the prevalence of IDA in men. As can be seen, although the relative prevalence of IDA in the control group (29.2%) was higher than the migraine group (16.7%), there was no statistically significant difference between the subjects with migraine and the subjects in the control group (P: 0.303).

prevalence of IDA in the male case and control groups (Chi-square test for independence).

[P: .303, χ2-statistic (df): 1.061 (1)]

Comparison of hemoglobin level in females in case and control groups

Descriptive drawing 7 indicates the dispersion and density of hemoglobin among female subjects in case and control groups. As shown, there was a statistically significant difference in the level of hemoglobin between the subjects suffering from migraine and the subjects in the control group (P- value: 0.0004). Migraine sufferers showed higher level of hemoglobin compared to the control group.

Dispersion and density of hemoglobin in the female case and control groups (Independent students’ T-test).

[Control mean ± SD: 13.8 ± 1.08, case mean ± SD: 12.87 ± 1.4, P: .0004, t-statistic: 3.721]

Comparison of ferritin level in female subjects in case and control groups

Descriptive drawing 8 shows the dispersion and density of ferritin among female subjects in case and control groups. As shown, there was a statistically significant difference in the level of ferritin between the subjects suffering from migraine and the subjects in the control group (P: 0.006).

Dispersion and density of ferritin in the female case and control groups (Independent students’ T-test).

[ Control mean ± SD: 63.69 ± 39.06, case mean ± SD: 43.09 ± 37.08 P: .006, t-statistic: 2.814]

Prevalence of IDA in females in case and control groups

Descriptive drawing 9 demonstrates the prevalence of iron-deficiency anemia among female subjects in case and control groups. As shown, the relative prevalence of iron-deficiency anemia in the migraine group (22%) was higher than the control group (3.9%), and a statistically significant difference was observed between the subjects suffering from migraine and the subjects in the control group (P: 0.001).

prevalence of IDA in thefe male case and control groups (Chi-square test for independence).

[P: .001, χ 2 -statistic (df): 11.285 (1)]

For decades, migraine was considered as an episodic disease without long-term effects on the brain, but studies that have been conducted over the past three decades offer a different perspective. Accordingly, migraine can lead to subclinical brain lesions, posterior circulatory infarcts, inferotentorial hypertension lesions, and so on 8 .

For the first time in 2001, based on magnetic resonance imaging (MRI), Welch et al. indicated that iron accumulation in the brain, especially in the periaqueductal gray (PAG) area, is associated with the duration of migrainous patients 9 . Eight years later, Kruit et al., consistent with previous findings, reported red nucleus (RN), globus pallidus (GP), and putamen iron accumulation in migraine patients 8 . It is noteworthy that Palm-Minders et al., in 2017, did not observe a difference between the migraine and the control group after conducting a follow-up study of the participants by Kruit et al. after 9 years, but noted that this result would probably be due to the increase in iron content in the brain tissue because of aging; therefore, age can be considered as one of the factors causing conflict    10  .

In a possible explanation of the relationship between iron-deficiency anemia (IDA) and migraine, paying attention to the physiology of PAG and basal ganglia is essential. The amount of non-hem iron in areas such as GP, substantia nigra (SN), RN, and cell - surface transferrin receptor in PAG is in the highest level in comparison with other regions of the brain  9 , 11  , indicating the high metabolic activity of these areas (producing high values ​​of neurotransmitters). A possible explanation for the relationship between IDA and migraine is that by decreasing iron level of serum (decreasing hemoglobin and ferritin levels), on the surface of the transferrin receptors, upregulation occurs in the above-mentioned areas, and when the iron level is increased for any reason (e.g., receiving high doses of iron in girls and women), accumulation occurs.

Another explanation is that considering the abundance of transferrin receptors, the activity of these areas due to migraine and iron absorption is high    9 , 12 .

Another possible mechanism is the altered dopaminergic function caused by IDA, since this change in dopaminergic function is considered as one of the triggers for migraine    13  . Accordingly, recent findings indicate changes in the expression of three genes involved in nigrostriatal dopamine malfunction due to IDA         14  . Therefore, the acceptable treatment of migraine obtained by D2 receptor agonists of Dopamine is justified    15  . On the other hand, further studies are needed to prove or disprove this claim.

The decrease in estrogen levels before menstrual bleeding in a group of females suffering from iron deficiency may lead to migraine attacks  16 - 19  . This estrogen reduction causes hepcidine, a protein involved in iron metabolism synthesized in the liver 20 , and causes deficiency due to estrogen regulation in the expression of ferroportin         21  . However, more studies are needed to investigate the interaction between IDA, estrogen, and migraine.

In a study conducted by Gur-Ozmen, the relationship between IDA and migraine was observed. This relationship was more significant among girls and women, as the relative prevalence of IDA in girls suffering from migraine was higher than that of men and boys. In addition, there was a significant relationship between migraine and hemoglobin level    22  . All these results are consistent with the present study. However, unlike the current study, there was no significant relationship between migraine and ferritin levels in the study conducted by Gur-Ozmen. Also, in the current study, there was no significant difference among men in the case-control groups between IDA and migraine, which may reflect the fact that IDA is not common among men. Another explanation for this finding is the small sample size of the male population in our study. Future studies can provide a satisfactory response to these issues.

In addition to the above, several studies have suggested the relationship between IDA and migraine, or the least footprint of this possible relationship, including a number of case-controls and some cross-sectional studies. Pamuk et al. stated that IDA patients had high migraines, depression, and high stress, which can be indicative of an underlying relationship between IDA and diseases and central nervous system problems 2 . A similar study conducted by Keyvani et al. in Iran states that there is a significant relationship between IDA and migraine headache    23  .

Additionally, the relationship between hemoglobin level and cognitive function in IDA patients 24 , improvement of linguistic and memory learning by iron supplementation in girls without iron- deficiency anemia 25 and an increased frequency of the restless legs syndrome in IDA patients 26 would be some evidence of central roles of iron.

Iron is necessary for monoamine oxidase enzyme (MAO) synthesis and decreasing MAO simultaneously in IDA and migraine and its increase after iron supplementation  6 , 30 , 31   suggests the effect of iron regimen on the severity and prevalence of migraine attacks in both IDA and non-IDA groups. This issue was supposed to be a link between IDA and migraine

The present study indicates the relationship between hemoglobin, ferritin, as well as IDA and migraine, especially in women and girls. Therefore, according to the results, treatment for iron- deficiency anemia or iron supplementation may be suggested as a suitable treatment or prevention method for patients suffering from both migraine and IDA at the same time. Further studies are still needed to provide a comprehensive response to the issues discussed.

The present article was extracted from the thesis written by Ali Tayyebi, and was financially supported by Shiraz University of Medical Sciences(Grants No: 93-01-01-8823).