|Year : 2021 | Volume
| Issue : 1 | Page : 17-22
Serum ferritin and hematological indices in thalassemia minor and nontransfusion dependent hemoghlobinopathy
Mehdi Dehghani1, Parisa Karimzadeh2, Nazanin Azadeh2, Alirea Rezvani1, Ali Kashkooe2
1 Department of Hematology and Medical Oncology, Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
2 Department of Hematology and Medical Oncology, Shiraz University of Medical Sciences, Shiraz, Iran
|Date of Submission||17-Apr-2020|
|Date of Acceptance||15-Aug-2020|
|Date of Web Publication||21-Jun-2021|
Dr. Mehdi Dehghani
Department of Hematology and Medical Oncology, Hematology Research Center, Shiraz University of Medical Sciences, Shiraz
Source of Support: None, Conflict of Interest: None
BACKGROUND: Iron deficiency is not common in thalassemia minor and nontransfusion dependent hemoglobinophaties. The majority of these patients have normal-to-high serum ferritin.
OBJECTIVES: The aims of the study were to evaluate serum ferritin levels in alpha and beta thalassemia minor and intermedia and in, hemoglobin H disease, and sickle cell anemia, and to investigate the effect of iron consumption on increasing serum ferritin levels and the role of Mentzer and Srivastava indices in patients with thalassemia minor and low serum ferritin levels.
MATERIALS AND METHODS: In this study, 204 patients with alpha-thalassemia minor, beta-thalassemia minor, nontransfusion-dependent thalassemia intermediate, and sickle cell disease were studied. Serum ferritin levels, Mentzer, Srivastava, and Bordbar's formula were measured using erythrocyte indices.
RESULTS: Irrespective of iron deficiency status, which was 5.9% and was more common in women, total iron intake was 39%. Iron deficiency status was 3.3% in alpha thalassemia, 9.8% in beta-thalassemia, and 4.5% in sickle cell disease. High and very high serum ferritin levels are more common in beta intermediate thalassemia and sickle cell anemia. Mentzer and Srivastava indices were not significant for differentiating thalassemia minor and iron deficiency, but the Bordbar's formula in thalassemia minor with iron deficiency was statistically significant (119.75).
CONCLUSION: Patients with minor thalassemia and nontransfusion dependent hemoglobinopathy had a lower prevalence of iron deficiency according due to due to serum ferritin levels compared to the general population. High and very high ferritin is more common in intermediate thalassemia, hemoglobin H, and sickle cell patients.
Keywords: Ferritin, hemoglobin H, intermediate thalassemia, Mentzer index, minor thalassemia, Srivastava index
|How to cite this article:|
Dehghani M, Karimzadeh P, Azadeh N, Rezvani A, Kashkooe A. Serum ferritin and hematological indices in thalassemia minor and nontransfusion dependent hemoghlobinopathy. Iraqi J Hematol 2021;10:17-22
|How to cite this URL:|
Dehghani M, Karimzadeh P, Azadeh N, Rezvani A, Kashkooe A. Serum ferritin and hematological indices in thalassemia minor and nontransfusion dependent hemoghlobinopathy. Iraqi J Hematol [serial online] 2021 [cited 2021 Jul 30];10:17-22. Available from: https://www.ijhonline.org/text.asp?2021/10/1/17/318765
| Introduction|| |
Thalassemia is a disorder of haemoglobin, in which the production of natural hemoglobin is partially or completely impaired. Alpha- and beta-thalassemia has spread widely from the Mediterranean region to Southeast Asia and the Middle East. In Iran, the prevalence of carriers is higher in the north around the Caspian Sea and also near the Persian Gulf in the south (about 10%). Although beta-thalassemia is much more common than alpha thalassemia, alpha-thalassemia is still one of the main health problems in Iran., Iron deficiency and beta-thalassemia carriers are the two main causes of microcytosis, and the distinction between these conditions is of therapeutic importance as well as important implications for thalassemia carrier screening.
Most patients with alpha and beta-thalassemia (minor, intermediate, and major thalassemia) had normal and high serum ferritin levels. Especially in thalassemia major and intermediate iron overload is a major problem with serious consequences. The long-term effect of high serum ferritin in all types of alpha-thalassemia as well as in beta-thalassemia minor, which may sometimes be high, is unknown.
This study was designed to evaluate serum ferritin levels in alpha minor thalassemia and beta minor thalassemia, intermediate, hemoglobin H disease, and sickle cell anemia. In addition, the effect of iron consumption on increasing serum ferritin levels and the role of Mentzer and Srivastava indices in patients with thalassemia minor and low serum ferritin levels were investigated.
| Materials and Methods|| |
We prospectively analyzed the complete blood count, serum ferritin level, and hemoglobin electrophoresis results of adult patients who were referred to the hematology clinic of Shiraz University of Medical Sciences over a 2 years' period (from March 2013 to February 2015). All patients with all alpha-thalassemia variant and beta minor thalassemia and nontransfusion dependent intermediate thalassemia and sickle cell anemia were included. The assessment of thalassemia and sickle cell anemia was based on diagnostic and standard references. Diagnosis of beta-thalassemia minor was based on HbA2 >3.5% and for alpha thalassemia, including hemoglobin H, minor and silent carrier diagnosis was made if HbA2 was <3.5% with a normal to high serum ferritin level or persistent microcytosis in patients with low ferritin level after treatment by iron supplement and also hemoglobin DNA analysis in these patients were assigned minor or silent carrier alpha-thalassemia with or without iron deficiency. Review peripheral blood with supravital stain for golf ball morphology was done in patients suspicious to hemoglobin H disease. Beta intermediate thalassemia and sickle cell anemia were diagnosed by hemoglobin electrophoresis. The serum ferritin level was measured by the ELISA method in fasting state. Patients with iron deficiency and minor thalassemia were diagnosed if serum ferritin was <15 ng/ml. We consider normal serum ferritin between 30 and 50 ng/ml for female subjects and 50–100 ng/ml for the adult male., Mentzer Index was defined as mean corpuscular volume/red blood cell (MCV/RBC) and Srivastava Index as mean corpuscular hemoglobin (MCH/RBC count) in all minor thalassemia patients with and without iron deficiency, hemoglobin H, intermediate thalassemia and sickle cell anemia. All patients with chronic disease, inflammation, liver, and kidney disease were excluded from the study because serum ferritin levels were not reliable at this time.
All statistical analysis was performed, using descriptive statistics and independent t-test. Pearson's Chi-square test was used to calculate the association between the variables. P < 0.05 were considered to be statistically significant. All statistical analyses were conducted using SPSS version 22.0 (SPSS Inc., Chicago, Illinois, U.S.A.).
| Results|| |
Data of two hundred and four participants, including 55 men (27%) and one hundred and forty-nine women (73%), were collected. The median age was 30.08 ± 14.63 years (ranges: 15–83 years). Seventy-eight patients (39%) were taking iron supplements, and one hundred and twenty-two (61%) were not taking iron supplements, and in four cases, iron supplementation was unknown. The demographic data and serum ferritin levels are shown in [Table 1].
|Table 1: Red blood cell indices in studied subjects in relation to hemoglobinopathies|
Click here to view
Iron consumption was higher in women than in men. In men 11.3% and in women 49.3% and in all patients, iron supplementation was 39%. Sixty-one percent of patients had no history of iron supplementation in the past 2 years. However, with the exception of sickle cell anemia, other hemoglobinopathies have the characteristics of microcytic and hypochromic anemia in their laboratory data.
Using serum ferritin below 15 ng/ml in men and women as the cut-off point for iron deficiency, 12 patients (5.9%) showed iron deficiency, and the rest (94.1%) had a normal range or high serum ferritin level. Iron deficiency was more common in women than men; 12 women (8.1%) had < 15 ng/ml of ferritin compared to men. This means that due to the physiological condition of women and iron loss during menstruation and pregnancy, they are generally prone to iron deficiency.
Serum ferritin levels were measured in patients with thalassemia minor and nontransfusion dependent hemoglobinopathies. The lowest serum ferritin level was observed in minor alpha-thalassemia (8.29 ng/ml). Severe iron deficiency, according to serum ferritin level <15 ng/ml was more common in beta-thalassemia minor and was observed in ten patients (9. 7%). Only one sickle cell patient had serum ferritin level <15 ng/ml, but the serum ferritin <15 ng/ml was not observed in the patients with intermediate beta-thalassemia and hemoglobin H disease [Table 2].
|Table 2: Ferritin level in minor thalassemia and nontransfusion dependent hemoglobinopathy|
Click here to view
Iron deficiency status was also assessed according to the type of hemoglobinopathy. The prevalence in this study was 3.3% in alpha thalassemia, 9.8% in beta-thalassemia, and 4.5% in sickle cell disease. However, all patients with hemoglobin H disease and beta intermediate thalassemia had normal-to-high serum ferritin levels, and there was no evidence of iron deficiency. All patients in the last two groups had moderate-to-high serum ferritin levels [Figure 1].
|Figure 1: Serum ferritin levels in patients based on iron supplementation or not|
Click here to view
We also assessed the group with minor thalassemia with low iron storage and iron deficiency anemia. This group of patients includes those who have a negative iron balance; ferritin is between 16 and 50 ng/ml in men and between 16 and 30 ng/ml in women.
In patients with minor alpha and beta-thalassemia, ten women (8.3%) and two men (6.1%) had low iron stores. With the exception of minor beta- and alpha-thalassemia other patients never receive iron supplementation after being diagnosed with hemoglobinopathy. The highest levels of ferritin were observed in nontransfusion dependent beta-thalassemia intermediate, and the second and third levels were related to hemoglobin H and sickle cell, respectively. This difference was statistically significant (P = 0.011).
Iron intake and serum ferritin levels were compared in different types of hemoglobinopathy. However, the relationship between patients using iron and serum ferritin levels was not statistically significant (P = 0.806). This means that high serum ferritin in minor thalassemia and nontransfused hemoglobinopathy may be due to long-term gastrointestinal absorption instead of iron supplementation in the short term.
Hematological indices including Mentzer Index, Srivastava Index and new formula by Bordbar et al. were evaluated in minor thalassemia with or without iron deficiency and other hemoglobinopathies. The mean of the Mentzer index in sickle cell anemia was 21, which was higher than other hemoglobinopathy; after that beta intermediate thalassemia had a higher Mentzer index with an average index of 18.93.
In the evaluation of the Srivastava index, patients with sickle cell and then in intermediate thalassemia, have more Srivastava index with mean index: 6.67 and 5.64, respectively. Bordbar's new formula is a good indicator for guessing minor thalassemia before hemoglobin electrophoresis with significant indicators for its diagnosis.
This is a good indicator for borderline conditions in beta and alpha thalassemia. There was no significant difference in the evaluation of patients with minor thalassemia and iron deficiency in Mentzer and Srivastava index, but in Bordbar's formula significant difference was observed in minor thalassemia with iron deficiency. The mean Bordbar's formula for these patients was 119.75 [Table 3].
|Table 3: Mentzer, Srivastava index and Bordbar's formula in minor thalassemia, intermediate thalaasmia, hemoglobin H, sickle cell|
Click here to view
Ferritin >100 ng in men and more than 50 ng in women, as well as above 1000 ng/ml in patients without iron intake and blood transfusion, were evaluated as indicators of increased iron absorption. Of these, 115 patients (56.37%) were included in this group. Most patients are in beta-thalassemia minor (66.01%). Nine patients (4.41%) had more than 1000 ng/ml ferritin. However, high serum ferritin levels are more common in intermediate thalassemia and sickle cell anemia [Table 4].
|Table 4: The frequency of high serum ferritin of studied subjects in relation to gender|
Click here to view
| Discussion|| |
The aim of this study was to determine the level of serum ferritin and iron deficiency by determining the level of serum ferritin in minor thalassemia and nontransfusion dependent hemoglobinopathy regardless of iron intake. We examined other hematological parameters, including Mentzer and Srivastava index in patients with concomitant thalassemia minor and low serum ferritin levels, to improve the diagnosis of iron deficiency patients with minor thalassemia.
Most patients referred to the hematology clinic with signs and symptoms of anemia were female (73%), which means that minor thalassemia and nontransfusion dependent thalassemia are more common in women in this area or might be due to the severity of the symptoms in women, so they come to our centers more often. In the study of Kolahi et al., minor thalassemia was not more common in women than men in Iran.
More than 50% of all patients were in beta-thalassemia. In previous studies, it is clear that beta-thalassemia is more common in Iran than alpha-thalassemia and other hemoglobinopathies.
The patients with alpha-thalassemia had higher RBC count and hemoglobin levels in comparison to minor beta-thalassemia and other hemoglobinopathies. The MCV and MCH in beta-thalassemia minor showed the lowest values compared to other cases. The RBC indices in minor alpha-thalassemia and hemoglobin H disease are the same; but in the patients with minor beta-thalassemia, RBC indices were lower compared to intermediate thalassemia. The effect of hydroxyurea in intermediate thalassemia and sickle cell is inevitable and can increase the MCV index.
In this study, lower serum ferritin was observed in beta-thalassemia group, and the highest rate of iron deficiency was about 9.7% in alpha minor thalassemia compared to other groups. In a study by Abrishami and Golshan, the prevalence of iron deficiency anemia was variable, and it depends on age, sex, and geographical area and the frequency of pregnancy. The prevalence of iron deficiency in Iran has been reported from 14.2% in children to 17.4% in women of child-bearing age. The prevalence of iron deficiency in the general population varies depending on age, sex, geographical area, and frequency of pregnancy. The prevalence of iron deficiency in Iran is reported to be 14.2% in children and 17.4% in women of childbearing age.
In this study, the prevalence of iron deficiency in alpha-thalassemia minor was 3.3% and in beta minor thalassemia was 9.9%. In the above studies, the prevalence of iron deficiency in thalassemia minor is lower compared to the general population of Iran. Patients with thalassemia minor are less prone to iron deficiency due to higher iron absorption. As a result, we did not have any iron deficiency patients in intermediate beta-thalassemia and hemoglobin H disease, and iron supplementation should be avoided before examining iron in these groups.
Hepcidin is the main regulator of plasma iron concentration and is rapidly cleared from plasma. Hepcidin deficiency leads to iron overload, and the complete absence of hepcidin can cause inherited hemochromatosis. Ferroportin is the major iron-releasing protein that causes iron to be transported into the plasma via transferrin and located on the surface of cells and enterocytes, macrophages and hepatocytes. Iron release from these macrophages is controlled by ferroportin. The role of the liver in regulating iron is crucial because liver cells sense the body's iron status and regulate hepcidin, and then interact with ferroportin to regulate cellular iron release. Therefore, the physiological response to iron overload under normal conditions may depend on hepcidin, which mediates iron uptake (enterocytes), recycling (macrophage), and storage (liver). Hepcidin deficiency increases ferroportin-mediated iron exports, resulting in increased iron enterocyte uptake and possibly the export of recycled iron to plasma transferrin by macrophages. Hepcidin is also suppressed in thalassemia patients, especially thalassemia major and intermediate beta-thalassemia. In these groups, iron absorption is inappropriately stimulated despite the high load of iron.,
In this study, due to the above mentioned, high and very high levels of serum ferritin (ferritin >1000 ng/ml) and iron overload in intermediate beta-thalassemia and sickle cell anemia were clearly more common. In the thalassemia minor group, the prevalence of iron deficiency was 5.9%, regardless of iron supplementation, which was 39% in thalassemia minor patients who were purchased by patients due to supplementation on their own. Iron supplementation with or without prescription was >30% in this group.
Although patients with transfusion independent intermedia thalassemia have chronic anemia, they have acceptable growth and development. Several pathogenic mechanisms, including ineffective erythropoiesis, extramedullary hematopoiesis, and a secondary drive to increase intestinal iron absorption, distinguish this hemoglobinopathy from others. This is an important factor in increasing serum ferritin in nontransfusion-dependent intermediate thalassemia.
Iron overload and target organ toxicity in nontransfusion-dependent thalassemia and hemoglobin H and other hemoglobinopathies are slower than beta major thalassemia and other transfusion-dependent thalassemia's. Current models for iron metabolism in intermediate thalassemia show that a combination of, ineffective erythropoiesis, anemia and hypoxia results in a compensatory increase in serum erythropoietin levels as well as a decrease in serum hepcidin levels that control ferroportin concentrations on intestinal epithelium. Compared to previous studies in patients with hemoglobin H, the level of ferritin in Omani patients with hemoglobin H is not high, but in Chinese patients with hemoglobin H, as in our patients without iron intake, high levels of serum ferritin were detected. This may be due to genetic diversity.
The Mentzer index is a good formula for patients with suspected sickle cell anemia. For patients with suspected sickle cell anemia, they should use before hemoglobin electrophoresis, as these patients have a high Menter index with a mean of 21, but the average Mentzer index in patients with beta-thalassemia intermedia is 18.93.
Similarly, patients with sickle cell and intermediate beta-thalassemia have a higher Srivastava index of 6.67 and 5.64, respectively, compared to other hemoglobinopathies. The best formula for patients with suspected alpha-thalassemia minor and beta-thalassemia minor with or without iron deficiency before hemoglobin electrophoresis is the Bordbar's formula.
This is a good indicator for the diagnosis of minor thalassemia. The average Bordbar's formula for beta-thalassemia minor is 110.15, and for alpha-thalassemia minor is 48.50. This is a good indicator for difficult and borderline cases in minor beta and alpha thalassemia.
Patients with sickle cell anemia have a low Bordbar index with a mean of 4.25. In evaluating patients with thalassemia minor and iron deficiency, Montzer and Srivastava index are not really appropriate because this formula was not significantly different in patients with or without iron deficiency. Significant differences were observed with the Bordbar's formula in minor thalassemia with iron deficiency. The mean Bordbar's formula for beta-thalassemia minor with iron deficiency was 119.75 compared with 110.151 for minor thalassemia without iron deficiency.
| Conclusion|| |
In patients with minor thalassemia and non-transfusion-dependent hemoglobinopathy, the prevalence of iron deficiency is lower due to serum ferritin levels compared to the normal population. High and very high ferritin is more common in intermediate thalassemia and hemoglobin H and sickle cells. In patients with minor thalassemia and iron deficiency, the Mentzer and Srivastava indices are not really good, but the Bordbar formula, is a good option for distinguishing between minor thalassemia and iron deficiency.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Kumar R, Arya V, Agarwal S. Profiling β Thalassemia Mutations in Consanguinity and Nonconsanguinity for Prenatal Screening and Awareness Programme. Adv Hematol 2015;2015:625721.
Bordbar E, Taghipour M, Zucconi BE. Reliability of different RBC indices and formulas in discriminating between β-thalassemia minor and other microcytic hypochromic cases. Mediterr J Hematol Infect Dis 2015;7:e2015022.
Dehbozorgian J, Moghadam M, Daryanoush S, Haghpanah S, Imani Fard J, Aramesh A, et al
. Distribution of alpha-thalassemia mutations in Iranian population. Hematology 2015;20:359-62.
Amid A, Haghi-Ashtiani B, Kirby-Allen M, Haghi-Ashtiani MT. Screening for thalassemia carriers in populations with a high rate of iron deficiency: Revisiting the applicability of the Mentzer Index and the effect of iron deficiency on Hb A2 levels. Hemoglobin 2015;39:141-3.
Kohne E. Hemoglobinopathies: Clinical manifestations, diagnosis, and treatment. Dtsch Arztebl Int 2011;108:532-40.
Bellanger RA. Iron deficiency Anemia in women. US Pharm 2010;35:50-8.
Killip S, Bennett JM, Chambers MD. Iron deficiency anemia. Am Fam Physician 2007;75:671-8.
Kolahi S, Farzin H, Khoshbaten M. Hypochromic microcytic anemia in Northwestern of Tabriz, Iran. Eur J Gen Med 2008;5:178-180.
Abrishami F, Golshan A. Frequency of iron deficiency anemia in girls studying in mashhad high schools. Iran J Ped Hematol Oncol 2013;3:143-8.
Haghshenass M, Mahloudij M, Reinhold JG, Mohammadi N. Iron-deficiency anemia in an Iranian population associated with high intakes of iron. Am J Clin Nutr 1972;25:1143-6.
Rossi E. Hepcidin-the iron regulatory hormone. Clin Biochem Rev 2005;26:47-9.
Nemeth E, Ganz T. The role of hepcidin in iron metabolism. Acta Haematol 2009;122:78-86.
Musallam KM, Taher AT, Rachmilewitz EA. β-thalassemia intermedia: A clinical perspective. Cold Spring Harb Perspect Med 2012;2:a013482.
[Table 1], [Table 2], [Table 3], [Table 4]