Ghazzay et al (2020): Low with normal Feb 2021 Vol. 24 Issue 2

Low ferritin with normal hemoglobin, a common neglected and hidden hematological disorder

Hazim Ghazzay1* ,Mahir Ali Jasim2 ,Ahmed Shakir Shukur3 , MahasinAltaha4 ,Salih Q Ibrahim5

Department of Medicine, College of Medicine, University of Anbar, Iraq 2 Department of Medicine, College of Medicine, University of Anbar, Iraq 3 Department of Medicine, Azadi Teaching Hospital, Kirkuk, Iraq 4Community medicine, Anbar Medical College/ University of Anbar,Iraq 5 Department of Biochemistry, College of Medicine, Kirkuk University, Iraq *Corresponding author: Hazim Ghazzay [email protected] Mobile :009648731044087

Abstract; To highlight the clinical significance of low ferritin with normal hemoglobin in young adult women and to raise awareness aboutthis disorder among physiciansand general practitioners.This pathology is easy to be missed since normal CBC or hemoglobin will give false feeling of assurance about store in patients with long- standing generalized weakness of unknown etiology.A descriptive study of120 femalepatients who were consulting the outpatientInternal medicine clinics at Al-Ramadi Teaching Hospital, peripheral blood samples were obtained for analysis of and status.Fifty (41.7%) of all patients had ferritin less than 10 ng/mL indicating severe .Of the 120 patients with iron deficiency Fatigue is the commonest symptom that present in ninety-five patients (79.2%), followed by hair loss 88(73.3%)and dizziness 84(70.0%), headache 79 (65.8% ), poor concentration 74 (61.7% ), palpitation 72(60.0% ) , chest pain 67 (55.8% ) and legs pain (47.5%).Heavy menstrual bleeding is significantly associated with low ferritin level in younger age group (<=25 years) p=0.001. While poor nutrition is a significant risk factor among older age group (>25 years) p= 0.000. In conclusion, low ferritin with normal hemoglobin is a hidden disorder which

Annals of Tropical Medicine & Public Health http://doi.org/10.36295/ASRO.2021.24225

Ghazzay et al (2020): Low ferritin with normal hemoglobin Feb 2021 Vol. 24 Issue 2

needs to be addressed bygeneral practitioners and physicians when diagnosis and treatmentis considered.It is accepted that individuals with low serum ferritin with normal hemoglobin or CBC will develop iron-deficiency anemia in the weeks or months following diagnosis, thus, evaluation of iron storage in at-risk patients should prompt early initiation of irontherapy and relief of symptoms.

Keywords: serum ferritin, normal hemoglobin, iron deficiency anemia How to cite this article: Ghazzay H, Jasim MA, et al (2021): Low ferritin with normal hemoglobin, a common neglected and hidden haematological disorder, Ann Trop Med & Public Health; 24(S2): SP24225. DOI: http://doi.org/10.36295/ASRO.2021.24225

Introduction; Globally, Iron deficiency is the most prevalent nutritionalinsufficiency that results in anemia.World Health Organization (WHO) has defined anemia level according to sex as lower than 130 g/L for men and below 120 g/L for women[1]. There are several forms of anemia and these cannot be differentiated from each other by the hemoglobin concentration alone.Iron deficiency per se markedly higher in prevalence than iron deficiency anemia[2]. In Western countries there are many studies that have shown that 11–33% of young women have iron deficiency after menarche.Among menstruating women,the prevalence of iron deficiency is constantly high 9– 22%, but after menopause the prevalence settles to around 1.4–4% [3-5]. Gender is a risk for iron deficiency anemia and 25–40% of females are expected to develop it during life time[2, 5]. Iron deficiency may be severe despite a normal hemoglobin concentration and with normal complete blood count (CBC) parameters.

There is a misunderstanding not in the community alone, but even in many practicing doctors that iron deficiency is only clinically significant if the patient is anemic. In reality these claims are scientifically baseless, because many studies in females, adolescents and youth have proven that a person who is iron deficient may have one or more symptoms of anemia such as chronic fatigue, hair loss, headache, dizziness, palpitations, shortness of breath by doing simple tasks (walking short distances, climbing stairs, doing housework), sleep disturbances restless legs, pica (desire to chew ice or non-food items,) and loss of interest in work, relationships, and intimacy[6]. In addition, it is accepted that individuals with low ferritin will develop iron-deficiency anemia in weeks or months following diagnosis if they are not treated with iron supplementation[7]. Two factors encourage early management of iron deficiency; simplicity of treatment and deleterious effect of the deficiency on life quality, screening for iron deficiency in at-risk populations( women with heavy menstruation, pregnancy, frequent or excessive blood donation, fibroids, digestive tract disease (including ), patient on certain medications, such as pain relievers with aspirin, and also as a result of poisoning from lead, toxic chemicals or alcohol abuse) is an important aspect of health maintenance.

The serum ferritin concentration (cut off <30 ng/L) is the most sensitive and specific indicator used for identification of iron deficiency [3, 8]. Because of the anticipated high rate of iron deficiency among menstruating women, neither hemoglobin level nor the complete blood count (CBC), can identify iron deficiency without

Annals of Tropical Medicine & Public Health http://doi.org/10.36295/ASRO.2021.24225

Ghazzay et al (2020): Low ferritin with normal hemoglobin Feb 2021 Vol. 24 Issue 2

anemia. Our study aims to highlight the importance of low serum ferritinlevel without anemia and to make it familiar observation among physicians and general practitioners because it is easy to be missed while the patient has long-standing suffering of obscure general weakness.

Materials and Methods This observational studywas conducted during the period from November 2018 to February 2020. Five milliliter of peripheral blood sample was collected from120 patients who visited the internal medicine outpatientclinic of Al-Ramadi Teaching hospital in Anbar Governorate, west of Iraq. The cases were females aged between 13-45 years. The study inclusion conditions were; symptomatic patients with different complains such as fatigue, hair loss, dizziness, headache, palpitation and chest pain, associated with low serum ferritin <30 ng/L and Hemoglobin ≤ 12 g/dL. Exclusion criteria: Abnormal CBC, Family history of hemoglobinopathy disorders, patients on iron treatment, patient with chronic kidney disease, heart diseases, liver disease, and malignancy are excluded from this study. Full medical history with clinical examination was done for all patients.

Blood samples obtained for following laboratory tests: complete blood count done by Swelab Alfa® auto analyzer (Sweden), reticulocyte count, serum iron, Total Iron Binding Capacity(TIBC) done by spectrophotometry using a kit supplied by BIOLABO® Company(France) and serum ferritin done MiniVidas® machine (BioMérieux, France) using its costume kit, other tests like ECG,TFT, Hb-electrophoresis and testing for fecal occult blood whenever indicated. Documented agreement was requested from all patients.

Statistical analysis: The statistical analysis was performed with SPSS Statistics software (version 24.0, Chicago, USA). Normality of datadistribution was evaluated. Variables displaying a normal distribution were expressed as mean ± SD. Frequency distribution Tables and Chi squared test were performed to compare between the groups for the whole study. The level of Statistical significance was set when the p-value was less than 0.05

Results Thedemographic, clinical and laboratory (age, marital status, parity, Hb level and serum ferritin) characteristics of the one hundred twenty patients,are shown in Table 1.

Table 1: Characteristics of the study sample including age, marital status, parity, Hb level and serum ferritin

variables No. (120) % (100) Age groups(years): <=25 25 20.8 26-35 41 34.2

Annals of Tropical Medicine & Public Health http://doi.org/10.36295/ASRO.2021.24225

Ghazzay et al (2020): Low ferritin with normal hemoglobin Feb 2021 Vol. 24 Issue 2

36+ 54 45.0

Mean± SD 32.6±8.9 Marital status: Married 63 52.5 Non- married 57 47.5 Parity: Multipara 61 50.8 nulliparous 59 49.2 Hemoglobin level: 12-12.9 87 72.5 13-13.9 27 22.5 ≥ 14 6 5.0 Mean± SD 12.7±0.6 Ferritin level: <10 50 41.7 10-19.9 61 50.8 ≥ 20 9 7.5 Mean± SD 11.3±5.5

The age group of the study sample ranged between 13 and 45 years, most of them (45.0%) 36 years and older. Hemoglobin levels ranged between 12.0 and 14.8 gm/dl, however, 72.5% of the patients had Hb level of 12.0- 12.9 gm/dl.While the patients' ferritin levels ranged (2.1- 26 ng/L) and more than 50% of the patients had a level of 10-19.9 ng/L. (Table 1).

Table 2 illustrates the different symptoms among 120 patients with low serum ferritin and normal hemoglobin. Fatigue is the commonest symptomthat present in ninety five patients (79.2%), followed by hair loss 88(73.3%), dizziness 84(70.0%), headache 79 (65.8% ), poor concentration 74 (61.7% ), palpitation72(60.0% ) , chest pain 67 (55.8% ) and legs pain (47.5% ).

Table 2: Symptoms complained by non-anemic patients with low ferritin (n=120).

symptoms No. % Fatigue 95 79.2 hair falling 88 73.3 Dizziness 84 70.0 Headache 79 65.8 Poor concentration 74 61.7

Annals of Tropical Medicine & Public Health http://doi.org/10.36295/ASRO.2021.24225

Ghazzay et al (2020): Low ferritin with normal hemoglobin Feb 2021 Vol. 24 Issue 2

Palpitation 72 60.0 Chest pain 67 55.8 Legs pain 57 47.5

Table 3 shows the risk factors among the symptomatic subjects according to age groups. It was found that low serum ferritin in 120 females is positively correlated with heavy menstrual bleeding (65%), poor nutrition (81.7%) , too much Tea and Coffee intake (67.5%) and low economic status (49.2% ).Heavy menstrual bleeding is significantly associated with low ferritin level in younger age group (<=25 years) p=0.001. While poor nutrition is a significant risk factor among older age group (>25 years) p= 0.000. Low economic status is also significantly associated with low ferritin level.

Table 3:Risk factors of low ferritin in non- anemic patients according to age

Age group

<=25 >25 Total Risk factor P value (n=25) (n=95) (n=120) Menstrual bleeding: 23 (92.0) 55 (57.9) 78 (65.0) Heavy 0.001* 2 (8.0) 40 (42.1) 42 (35.0) Normal Nutritional status: 13 (52.0) 9 (9.5) 22 (18.3) Good 0.000* 12 (48.0) 86 (90.5) 98 (81.7) Poor Tea consumption: 17 (68.0) 64 (67.4) 81 (67.5) 25 Heavy 8 (32.0) 17 (17.9) (20.8) 0.06 Mild 0 (0.0) 14 (14.7) 14 (11.7) Nil **Economic status: 14 (56.0) 6 (6.3) 20 (16.7) 41 High 1 (4.0) 40 (42.1) (34.2) 59 0.000* Moderate 10 (40.0) 49 (51.6) (49.2) Low

Annals of Tropical Medicine & Public Health http://doi.org/10.36295/ASRO.2021.24225

Ghazzay et al (2020): Low ferritin with normal hemoglobin Feb 2021 Vol. 24 Issue 2

Family history of low ferritin: 2 (8.0) 2 (2.1) 4 (3.3) Yes 0.144 23 (92.0) 93 (97.9) 116 (96.7) No **High income More than 1.5 Million ID/month, Moderate 0.5 -1.5 Million ID/month, Low income less than 0.5 Million ID/month

Discussion Anemia is a common syndrome which is easily identified by naked eye since it give a pale appearance of skin and mucus membrane color. Anemia due to iron deficiency is the most prevalent form and results from by iron inadequacy as the name suggests [9]. Iron deficiency passes into two stages; pre-latent, latent before leading to the final destiny which is anemia. At the pre-latent and latent stage, ferritin and serum iron are reduced respectively without change in hemoglobin level [10, 11]. The late development of anemia in the course of iron deficiency give false impression to the medical professional about adequacy of iron store. Iron is involved in many biological function other than its vital function in oxygen transport in red blood cellshemoglobin, such as deoxyribonucleic acid (DNA) synthesis, electron transport and function of many enzymes[12].These function will be impaired upon deficiency of iron with subsequent symptoms development[13].Iron level is very tightly regulated through regulation of its uptake and loss. Iron is stored in bone marrow as ferritin and the later level in blood is a reflection of the body store[14].It is a fact the menstruating women have normally lower hemoglobin and ferritin level than men and non-menstruating women[15].

The USA Centers for Disease Control and Prevention (CDC) has defined heavy bleeding in a plain language that can be easily comprehend by female of all educational level and cultural background as “changing tampon or pad in less than every two hours or pass clots the size of a quarter or larger, that is heavy bleeding or if lasts more than 7 days [16]. In our work we found a very strong inverse association between heavy menstrual bleeding and ferritin level. The average amount of blood loss during each cycle is about 80 ml, though the range is wide from 30 to 180 ml, and this amount is much larger in heavy menstrual cycles [17], this is typically associated with a mean loss of iron of 3.2 mg for a loss of 80 ml [17]. Another factor, in our work, that has a positive correlation with ferritin level is economic status. It is well known that food of animal sources have more iron which is readily absorbable, however it is expensive when compared to vegetable sources[18].

It is not surprising to detect significant number of female with reduced ferritin as a measure of Iron store. The deleterious effect of forcible displacement over three years' period have two-fold Negative effect on ferritin.Firstly, displacement is associated with reduced income and consequent reduction in food quality, secondly, stress, caused by displacement, is known to cause ‘heavy menses’ that is poorly appreciated by the suffering females.What complicates Iron deficiency in our community is the tradition of drinking tea and coffee which impairs iron absorption from non hemesources [19, 20]. All the iron deficiency associated symptoms are

Annals of Tropical Medicine & Public Health http://doi.org/10.36295/ASRO.2021.24225

Ghazzay et al (2020): Low ferritin with normal hemoglobin Feb 2021 Vol. 24 Issue 2

associated with serious physical social and mental grief complications such as heart failurePrevious studies have shown that iron deficiency is a common nutritional disorder all over the world specially in the developing countries [21]. Worldwide, iron deficiency is responsible for 841,000 fatalities and 35,057,000 disability- adjusted life years lost, almost two third of the iron deficiency burden occur Africa and deprived parts , while North America has just more than one percent of the global problem [22]

Conclusion Iron deficiency is a common nutritional problem that has been overlooked since hemoglobin was used as surrogate marker which lacks sensitivity and specificity. Patients with vague symptoms such as tiredness and poor concentration should be screened for iron deficiency regardless of hemoglobin status.

References 1. Nieves Garcia-Casal, M., et al., WHO Hemoglobin Thresholds to Define Anemia in Clinical Medicine and Public Health: A Scoping Exercise. Current Developments in Nutrition, 2020. 4(Supplement_2): p. 189-189. 2. Looker, A.C., et al., Prevalence of iron deficiency in the United States. Jama, 1997. 277(12): p. 973- 976. 3. Clenin, G.E., The treatment of iron deficiency without anaemia (in otherwise healthy persons). Swiss Med Wkly, 2017. 147: p. w14434. 4. Lopez, A., et al., Iron deficiency anaemia. Lancet, 2016. 387(10021): p. 907-16. 5. Greer, J.P., Wintrobe's Clinical HematologyWintrobe's Clinical Hematology. Thirteenth edition ed2013: LWW. 2312. 6. Pavord, S., et al., UK guidelines on the management of iron deficiency in pregnancy. Br J Haematol, 2012. 156(5): p. 588-600. 7. Patterson, A.J., W.J. Brown, and D.C. Roberts, Dietary and supplement treatment of iron deficiency results in improvements in general health and fatigue in Australian women of childbearing age. J Am Coll Nutr, 2001. 20(4): p. 337-42. 8. Camaschella, C., Iron-deficiency anemia. N Engl J Med, 2015. 372(19): p. 1832-43. 9. Friedman, A.J., Iron Deficiency Anemia in Women Across the Life Span. Journal of Women's Health, 2012. 21(12): p. 1282-1289. 10. Leonard, A.J., et al., A study of the effects of latent iron deficiency on measures of cognition: a pilot randomised controlled trial of iron supplementation in young women. Nutrients, 2014. 6(6): p. 2419- 2435. 11. Hausmann, K., [Latent and manifest iron deficiency conditions. Diagnostic and therapeutic developments]. Z Gesamte Inn Med, 1984. 39(8): p. 142-52.

Annals of Tropical Medicine & Public Health http://doi.org/10.36295/ASRO.2021.24225

Ghazzay et al (2020): Low ferritin with normal hemoglobin Feb 2021 Vol. 24 Issue 2

12. Abbaspour, N., R. Hurrell, and R. Kelishadi, Review on iron and its importance for human health. Journal of research in medical sciences : the official journal of Isfahan University of Medical Sciences, 2014. 19(2): p. 164-174. 13. Oliveira, F., S. Rocha, and R. Fernandes, Iron metabolism: from health to disease. Journal of clinical laboratory analysis, 2014. 28(3): p. 210-218. 14. Wang, J. and K. Pantopoulos, Regulation of cellular iron metabolism. Biochemical Journal, 2011. 434(3): p. 365-381. 15. Rushton, D.H. and J.H. Barth, What is the evidence for gender differences in ferritin and haemoglobin? Crit Rev Oncol Hematol, 2010. 73(1): p. 1-9. 16. Prevention, C.f.D.C.a. Heavy Menstrual Bleeding. December 20, 2017 [cited 2020 4 May]; Available from: https://www.cdc.gov/ncbddd/blooddisorders/women/menorrhagia.html. 17. Ofojekwu, M.-J.N., et al., Hemoglobin and Serum Iron Concentrations in Menstruating Nulliparous Women in Jos, Nigeria. Laboratory Medicine, 2013. 44(2): p. 121-124. 18. West, A.-R. and P.-S. Oates, Mechanisms of heme iron absorption: current questions and controversies. World journal of gastroenterology, 2008. 14(26): p. 4101-4110. 19. Zijp, I.M., O. Korver, and L.B. Tijburg, Effect of tea and other dietary factors on iron absorption. Crit Rev Food Sci Nutr, 2000. 40(5): p. 371-98. 20. Sharp, P.A., Intestinal Iron Absorption: Regulation by Dietary & Systemic Factors. International Journal for Vitamin and Nutrition Research, 2010. 80(45): p. 231-242. 21. Berger, J. and J.C. Dillon, [Control of iron deficiency in developing countries]. Sante, 2002. 12(1): p. 22-30. 22. Stoltzfus, R.J., Iron deficiency: global prevalence and consequences. Food Nutr Bull, 2003. 24(4 Suppl): p. S99-103.

Annals of Tropical Medicine & Public Health http://doi.org/10.36295/ASRO.2021.24225