Ferritin and Vitamin D levels and its relation to bone diseases in thalassemic adults: A hospital-based retrospective cohort study

Reem Jameel Tharwat; Saud Balilah; Hatem M Habib; Nada H Mahmoud; Fatema S Beek; Fatema K Almadani; Sarah A Elmaghraby; Duha D Al-Loqmani; Hibah A Al-Mahdi

doi:10.4103/joah.joah_56_18

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ORIGINAL ARTICLE

Year : 2019 | Volume : 10 | Issue : 1 | Page : 15-22

Ferritin and Vitamin D levels and its relation to bone diseases in thalassemic adults: A hospital-based retrospective cohort study

Reem Jameel Tharwat¹, Saud Balilah², Hatem M Habib³, Nada H Mahmoud¹, Fatema S Beek¹, Fatema K Almadani¹, Sarah A Elmaghraby¹, Duha D Al-Loqmani¹, Hibah A Al-Mahdi¹
¹ Medical Interns, Taibah University, Al-maddina, KSA
² Consultant Hematologist, King Fahad Hospital, Al-maddina, KSA
³ OBGYNE Resident, Department of OBGYNE, Maternity Hospital, Al-maddina, KSA

Date of Web Publication

30-Apr-2019

Correspondence Address:
Dr. Reem Jameel Tharwat
Beir Othman, Sodisah Al-Ansarriah, Al-Maddina
KSA

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/joah.joah_56_18

Abstract

BACKGROUND: Thalassemia complications affecting different body systems, including osteoporosis and bone fracture. Although numerous studies are available in the literature, little is known about this subject in Saudi Arabia.
OBJECTIVES: The study aimed to describe the characteristics of thalassemia patients in Madinah City, Saudi Arabia and to assess the prevalence of bone disease among them with an emphasis on Vitamin D and Ferritin level.
SUBJECTS AND METHODS: A hospital-based retrospective cohort study was designed. The study was carried out on 69 β thalassemia patients from King Fahd Hospital in Madinah, Saudi Arabia from 2015 to 2017. The study extracted patients' data related to their personal, clinical, laboratory, and complications. Data on DEXA scan were also obtained for 20 of the studied patients. The prevalence rate of bone fracture among the studied patients was calculated, and other collected data were tabulated in number and percentage for categorical variables and mean and standard deviation for quantitative variables.
RESULTS: All the studied patients were of β thalassemia patients. Two-thirds of them were anemic (66.7%). The prevalence of bone fractures was 14.5% (95% confidence interval = 8.1–24.7), iron overload of >1000 was found in 62 patients (89.9%) and ferritin level of <10 ng was found in 19 patients (27.5%). Vitamin D level was ranging from 10 to 24 ng in 39.1% and from 25 to 80 ng in 11.6% of studied patients. Furthermore, the Z score value was <−2 of the spine in 83.7% of 20 patients underwent DEXA scan in our study. Among these 20 patients, the mean Z score value of the femur was − 2.1.
CONCLUSIONS: The prevalence of bone fracture among thalassemia patients in Madinah City, Saudi Arabia was relatively high accounting for 14.5% of the studied patients. Low level of Vitamin D and high iron overload and ferritin level was prevalent among the studied patients. Further studies from multiple centers and cities are needed to more understanding of this important issue.

Keywords: Ferritin, retrospective, Saudi Arabia, thalassemia, Vitamin D

How to cite this article:
Tharwat RJ, Balilah S, Habib HM, Mahmoud NH, Beek FS, Almadani FK, Elmaghraby SA, Al-Loqmani DD, Al-Mahdi HA. Ferritin and Vitamin D levels and its relation to bone diseases in thalassemic adults: A hospital-based retrospective cohort study. J Appl Hematol 2019;10:15-22

How to cite this URL:
Tharwat RJ, Balilah S, Habib HM, Mahmoud NH, Beek FS, Almadani FK, Elmaghraby SA, Al-Loqmani DD, Al-Mahdi HA. Ferritin and Vitamin D levels and its relation to bone diseases in thalassemic adults: A hospital-based retrospective cohort study. J Appl Hematol [serial online] 2019 [cited 2023 May 29];10:15-22. Available from: https://www.jahjournal.org/text.asp?2019/10/1/15/257470

Introduction

Thalassemia is congenital hemolytic anemia caused by reduced or absent synthesis of one or more globin chains of hemoglobin. It has two types such as alpha and beta. β thalassemia represents the most common type and it is also the most common single gene disorder worldwide.^[1] β Thalassemia has subtypes, β thalassemia major (β TM), β thalassemia intermedia (β TI), and E-β thalassemia (E-β).^[2] Thalassemia used to have a special geographical distribution known as a thalassemia belt affecting mainly parts of Africa and Asia, but nowadays as a result of migration, it has a worldwide distribution. In Saudi Arabia, it is mainly around the coastal cities of the Red Sea and in the Eastern province around Qateef, Jubail, Dammam, and Hofuf.^[3] The total worldwide incidence of thalassemia is 1 in 100,000.^[4] whereas in Saudi Arabia, it is one of the most common congenital hemolytic anemia with the prevalence of 3.22% for thalassemia trait and 0.07% for thalassemia disease.^[5] It is associated with many complications that affect patient's life at many levels, either from the mutation itself or as a consequence from the treatment.^[5] Bone diseases among thalassemic patients are a newly growing problem play a major role in the thalassemia morbidity causes, despite the continuity of blood transfusion treatment.^[6] The prevalence and correlated causes of bone diseases among thalassemic patients were investigated in many studies around the world, yet the etiology of bone disease in thalassemia is poorly understood and it has been linked to many risk factors such as gender, ineffective erythropoiesis, iron overload, treatment with desferrioxamine, Vitamin D concentrations, and the influence of endocrinopathies, such as hypogonadism and growth hormone deficiency, and thalassemia genotypes.^[2] In one of the studies, one third to one-half of beta-thalassemia patients have been reported to develop fractures of long bones as a result of minor trauma, especially in the group of beta TM.^[7] In another study at Shiraz, Iran reported that thalassemia patients showed significant lower lumbar bone marrow density (BMD) and BMC values compared with controlled patients.^[8] In a retrospective study that was done in Italy on 70 β-thalassemia, adult patients with a mean follow-up of 20 years showed 26 out of 70 with osteoporosis and 27 out of 70 with osteopenia.^[9] On the other hand, a longitudinal study was done in Victoria, Australia on 277 participants with transfusion-dependent thalassemia to see the relationships between BMD and risk factors for osteoporosis, they reported a marked decrease in BMD all over the body, especially in the femoral neck in patients with transfusion-dependent thalassemia, and 11.6% of all participants had bone fractures. However, the study showed a gender discrepancy in higher rates of prevalence of fractures and BMD loss in male patients.^[10] Due to the scarcity of researches about bone diseases in thalassemic patients in our region, we will be focusing in our study on the prevalence of bone diseases among thalassemic which is low bone mass, and pathologic fractures, and it is possible risk factors in general and the levels of ferritin and Vitamin D in specific.

Aim

The aim of this study is to correlate between the prevalence of bone disease in thalassemia patients and the level of Vitamin D and ferritin.

Objectives

To describe the characteristics of thalassemia patients in Madinah City, Saudi Arabia
To assess the prevalence of bone disease among the studied patients
To find the relation between Vitamin D and ferritin level with bone disease in thalassemia patients.

Subjects and Methods

This is a retrospective study done on thalassemia patients seen in King Fahd hospital from 2015 to 2017.

Data were extracted from hospital records. Approval was obtained from the ethical committee of the hospital; the confidentiality and privacy of the collected data were ensured by using anonymous data entry and analysis. The aim of this study was to describe the characteristics of the studied patients, to assess the prevalence of bone fractures among them, and to correlate between the prevalence of bone disease in thalassemia patient and the level of Vitamin D and Ferritin. All selected patients in the study were actively involved in attending the hematology clinic or admission to medical wards at King Fahad hospital. The variables were obtained from the records to involve this study will be age, sex, height, weight, time since diagnosis, mean hematological values (total hemoglobin, fetal hemoglobin, MCV, platelet, WBCs, bilirubin, and iron), bone crisis per annum, hospitalization, blood transfusion, and hip replacement). Patients whom recorded to have bone disease were used in calculating the overall prevalence and their 95% confidence interval (CI) was estimated.

The data entry and analysis were performed using SPSS (version 21.0, IBM Corp., Armonk, NY, USA). The prevalence of the studied characteristics presented and tabulated in the form of number and percentages for categorical variables and mean and standard deviation for quantitative variables.

Results

The study population includes patients with thalassemia in Madina, Saudi Arabia. A sample of (69) patients were selected randomly. [Table 1] shows their properties according to their personal data.

Table 1: Distribution of the sample study to the personal data

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It is clear from the previous table that almost 55% of the thalassemia patients were male, whereas 45% of them were female. Moreover, their distribution according to their ages almost 50% of them were <20 years old, almost 44% of them were between 20 and 30 years old, almost 9% of them were between 31 and 40 years old, and almost 3% of them were >40 years old. Moreover, their distribution according to nationality, almost 73% of them were non-Saudi, whereas almost 28% of them were Saudis.

[Figure 1] concludes all the previous results.

Figure 1: Personal data

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The study tool

The questionnaire consists of five sections as follows:

Section 1: consists of the patient's personal data such as gender, age and nationality
Section 2: (Laboratory) consists of several questions such as thalassemia type, ferritin level, Vitamin D levels, Hb level, and Hb electrophoresis
Section 3: (Endocrine panel) consists of several questions such as alkaline phosphate, TSH, T3, T4, calcium, and phosphorus
Section 4: (Complications) consists of several questions such as hypogonadism, HIV, Hepatitis C, Hepatitis B, DM, heart diseases, hepatomegaly, liver cirrhosis, the use of iron chelator, using of combined chelator
Section 5: (Bone diseases) consists of several questions such as bone fractures, previous diagnosis, DEXA scan done, Z value (spine), and Z value (femur).

Statistical methods

The statistical analysis program (SPSS version. 21) was been used in the study in data entry and analysis, with the use of necessary statistical methods to achieve the objectives of the study.

Results

First: Laboratory

[Table 2] shows the patients distribution according to type of thalassemia, ferritin level, Vitamin D levels, and Hb level.

Table 2: The patients distribution according to: Type of thalassemia, ferritin level, Vitamin D levels, and hemoglobin level

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Note that all patients with thalassemia in the study sample of the type of beta, and we note that the vast majority of them increase the level of ferritin about 1000, while almost 1% of them the level of ferrite is <1000.

As for their distribution according to Vitamin D levels, almost 39% of thalassemia patients had a Vitamin D level between (10 and 24 ng) while almost 28% of them had a Vitamin D level < (10 ng), and almost 12% of them had a Vitamin D level between (25 and 80 ng).

Moreover their distribution according to Hb level, almost 67% of thalassemia patients had a Hb level between (8 and 10 g/dl) while almost 30% of them had Hb level < (8 g/dl), and almost 3% of them had Hb level between (10 and 12 g/dl).

Second: Endocrine panel

[Table 3] shows the patients distribution according to alkaline phosphate, TSH, T3, T4, Calcium, phosphorus, and GH.

Table 3: The patients distribution according to: Alkaline phosphate, thyroid-stimulating hormone, triiodothyronine, thyroxine, calcium, phosphorus, and growth hormone

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Note from the previous table that:

Almost 57% of thalassemia patients had alkaline phosphate between 44 and 147 IU/L (0.73 and 2.45 microkat/L), while almost 35% had alkaline phosphate more than 147 and 1.4% below 44 IU/L (<0.73 microkat/L)
Almost 64% of thalassemia patients had TSH between 0.4 and 4.0 mIU/L, while almost 17% had TSH >4.0 mIU/L
Almost 64% of thalassemia patients had T3 between1.54 and 3.08 nmol/L (100–200 ng/dL), while almost 17% had T3 above 3.08 nmol/L (200 ng/dL)
Almost 74% of thalassemia patients had T4 between 4.5 and 11.2 mcg/dL, while almost 6% had T4 above 11.2 mcg/dL
Almost 70% of thalassemia patients had calcium between 8.9-10.1 mg/dL, while almost 28% had calcium <8.9 mg/dL
Almost 48% of thalassemia patients had phosphorus between 2.5 and 4.5 mg/dL, while almost 35% had phosphorus >4.5 mg/dL, and 13% had phosphorus below 2.5 mg/dL
Almost 82% of thalassemia patients had Normal GH, while 13% had GH below 5 ng/mL (226 pmol/L), and almost 6% had GH >5 ng/mL (226 pmol/L).

Third: Complications

[Table 4] shows the patients distribution according to hypogonadism, HIV, Hepatitis C, Hepatitis B, DM, heart diseases, hepatomegaly, liver cirrhosis, use of iron chelator, and use of combined chelator.

Table 4: The patients distribution according to: Hypogonadism, human immunodeficiency virus, hepatitis C, hepatitis B, diabetes mellitus, heart diseases, hepatomegaly, liver cirrhosis, use of iron chelator, and use of combined chelator

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Note from the previous table that:

Almost 2.9% of thalassemia patients suffer from hypothyroidism, while 97.1% do not suffer from hypothyroidism
All patients with thalassemia do not suffer from HIV
Almost 33.3% of thalassemia patients suffer from Hepatitis C, whereas 66.7% do not suffer from Hepatitis C
Almost 1.4% of thalassemia patients suffer from Hepatitis B, whereas 98.6% do not suffer from Hepatitis B
Almost 5.8% of thalassemia patients suffer from DM, whereas 94.2% do not suffer from DM
Almost 2.9% of thalassemia patients suffer from heart diseases, whereas 97.1% do not suffer from heart diseases
Almost 11.6% of thalassemia patients suffer from Hepatomegaly, whereas 88.4% do not suffer from hepatomegaly
All patients with thalassemia do not suffer from liver cirrhosis
Almost 87% of thalassemia patients use of iron chelator, whereas 13% do not use iron chelator
Almost 47.8% of thalassemia patients use of combined chelator, whereas 52.2% do not use of combined chelator.

Fourth: Bone diseases section

[Table 5] shows the patients distribution according to bone fractures, previous diagnosis, and DEXA scan done.

Table 5: The patients distribution according to: Bone fractures, previous diagnosis, and DEXA scan done

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Note from the previous table that:

Almost 14.5% of thalassemia patients suffer from bone fractures, whereas 85.5% do not suffer from bone fractures
Almost 8.7% of thalassemia patients had a previous diagnosis of the disease, whereas 91.3% do not have previous diagnosis of the disease
Almost 8.7% of thalassemia patients had DEXA scan, whereas 71% do not have DEXA scan.

[Table 6] shows the Z value (spine) for thalassemia patients who performed the DEXA scan:

Table 6: The Z value (spine) for thalassemia patients who performed the DEXA

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[Table 7] shows the Z value (femur) for thalassemia patients who performed the DEXA scan:

Table 7: The Z value (femur) for thalassemia patients who performed the DEXA scan

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Discussion

Thalassemia is congenital hemolytic anemia with β thalassemia represents the most common type worldwide.^[1] Thalassemia complications affecting different body systems, including osteoporosis and bone fracture. Although numerous studies are available in the literature, little is known about this subject in Saudi Arabia. The present retrospective study was conducted on 69 β thalassemia patients from King Fahd Hospital in Madinah, Saudi Arabia from 2015 to 2017, and aimed to describe the characteristics of thalassemia patients in the studied region, to assess the prevalence of bone disease among them with an emphasis on the Vitamin D and Ferritin level.

All the studied patients were of β thalassemia patients. The prevalence rates of β thalassemia and sickle cell disease in Saudi Arabia are considered one of the highest compared to surrounding countries in the Middle East (0.05% and 4.50%, respectively).^[11] Furthermore, β thalassemia represents the most common type worldwide.^[1] The total worldwide incidence of thalassemia is 1 in 100,000,^[4] whereas in Saudi Arabia, it is one of the most common congenital hemolytic anemia with the prevalence of 3.22% for thalassemia trait, and 0.07% for thalassemia disease.^[5]. Regional variations have been reported in the prevalence of β thalassemia within Saudi Arabia. The regions of the highest prevalence are arranged geographically along a belt from west to east, starting from the Western region (Baha, Jazan, and Makkah) toward the Eastern region.^[12] It is mainly around the coastal cities of the Red Sea and in the Eastern province around Qateef, Jubail, Dammam, and Hofuf.^[3] Studies from other Arab countries showed that the frequency of β thalassemia trait, in general, falls within the range of 2.0%–10.0%.^[13]

In the present study, all patients were of β thalassemia. More than half of them were male (55.1%), and the majority of them (84%) were <31 years old. About three-fourth of the studied patients were of non-Saudi nationality. The same age and sex characteristics of β thalassemia were also reported in previous similar regional^{[11],[12],[13]} and international^[14] studies. In a study of clinical profile of 53 thalassemia patients, observing the relationship between the patients with their verity ages and sex. Among them, 21 (39.6%) were female and 32 (60.4%) were male. The median age of the studied patients was of 16 years and their mean age was 15.4 ± 7.9. In a previous Saudi study, the predominant age group of patients with thalassemia was ranging from 2 to 30 years.^[11]

The laboratory findings of β thalassemia patients in this study showed iron overload of >1000 in 62 patients (89.9%) and ferritin level of <10 ng in 19 patients (27.5%). Vitamin D level was ranging from 10 to 24 ng in 39.1% and from 25 to 80 ng in 11.6% of the studied patients. Anemic patients with low hemoglobin level were found in 46 (66.7%) of the studied patients. The laboratory findings and diagnostic feature of the diagnosis of β thalassemia patients were more or less similar to the laboratory profile of our studied patients.^[15] Anemia is always a severe complication in thalassemia. Early iron kinetic studies indicated the presence of ineffective erythropoiesis and shortened red cell survival. It has been demonstrated that there are at least two populations of red cells-one which is rapidly destroyed and another with longer survival.^[16] The osmotic fragility of the erythrocytes is markedly decreased. Some cells resisthemolysis in 0.1% saline solution.^[17]

In thalassemia patients, bone disease becomes an important cause of morbidity. Problems include osteoporosis, rickets, scoliosis, spinal deformities, nerve compression, and fractures.^{[18],[19],[20]} Impaired calcium homeostasis is thought to be a consequence of iron overload seen in β-thalassemic transfused patients. Both defective synthesis of 25 OH Vitamin D and/or hypoparathyroidism have been described in these patients and negatively affect their bone metabolism.^{[20],[21],[22],[23],[24]} In North America, Thalassemia Clinical Research Network surveyed 361 patients with thalassemia and reported that 12.8% of the patients had Vitamin D concentrations <27 nmol/L and 82% <75 nmol/L, regardless of the thalassemia syndrome.

The endocrine manifestation of thalassemia patients in the present study showed TSH level of more than 4 mlU/L in 17.4% the studied patients, T₃ more than 200 ng/dl in 17.4% of patients, and T₄ more than 11.2 μg/dl in 5.8% of the studied 69 patients. Growth hormone showed low level <5 ng/ml (226 pmol/L) in 9 patients (13%). Poor growth and multiple endocrine disorders, including hypogonadotropic hypogonadism, growth hormone deficiency, and diabetes, are known complications in β TM and are responsible for iron overload.^[25] Even with iron chelation, the rate of endocrinopathies remains high among these patients with hypogonadism reported in approximately 40%–60% of the patients, short stature in 30% and diabetes in 5%–14%.^[26] In the present study, however, the hypogonadism was found in only two patients (2.9%). The use of iron chelator in this study was reached up to 87% of the studied patients and using combined chelator was detected in less than half of the studied 69 patients (47.8%). High serum ferritin levels during puberty are a risk factor for hypogonadism, and high serum ferritin levels during the first decade of life predict final short stature. It remains to be determined whether improving chelation by earlier initiation of chelation by the use of deferoxamine (DFO) by the combined use of DFO and deferiprone will lead to better growth and sexual development without DFO toxicity.^[27]

Diabetes mellitus and cardiovascular complication were representing were found in 4 patients (5.8%), and 2 patients (2.9%). Diabetes mellitus is a major endocrinopathy for patients with TM. Although diabetes mellitus is multifactorial, iron loading is its primary cause and its management poses a clinical challenge. Detecting the pre-diabetes stage is critical because clinical diabetes can potentially be reversed or prevented.^[28] Patients with chronic anemia increase their cardiac output to maintain oxygen delivery, resulting in increased cardiac dimensions, and heart disease.^[29] Furthermore, iron cardiomyopathy, may be the result of into iron uptake, iron storage, and iron toxicity.^[30] The heart takes up physiologic amounts of iron through transferrin receptors, but this process is tightly regulated and does not lead to iron overload. When transferrin-binding capacity is exceeded, circulating low molecular weight non-transferrin-bound iron species appear.

The prevalence of hepatitis C among the studied patients was high representing about 33.3% of the cohort. On the other hand, however, the prevalence of hepatitis B was very low, and it was found in only one patient (1.4%). The prevalence in the present study for hepatitis C virus (HCV) was lower than those reported by recent reports carried out in Oman (41%).^[31] in Egypt (37.11%),^[32] and in Pakistan (55.7%).^[33] In a recent meta-analysis study, the overall prevalence of HCV in thalassemia patients was 19% (95% CI: 16–21) in Iranian thalassemia patients.^[34]

Viral hepatitis among thalassemia patients may be the result of repeated blood. In the present study, 72.5% of the studied patients were of nonSaudi nationality, and this may explain this unexpected higher level of HCV among the cohort. This explanation may be supported by the prevalence of hepatitis in another earlier Saudi study where the prevalence HCV and hepatitis B virus (HBV) among Saudi patients with hemoglobinopathies was 3.7%.^[35] Viral hepatitis plays an important role in the prognosis of thalassemia patients. The diagnosis of HBV-or HCV-related chronic hepatitis is required to detect patients who have a high risk of developing liver complications and who may benefit by antiviral therapy.^[36]

Conclusion

The prevalence of bone fracture in the present study was 14.5% (95% CI = 8.1–24.7) as it was detected in 10 of the studied 69 patients. Previous diagnosis of bone diseases in these patients was reported by 6 patients accounting for (8.7%). The report from North America indicates a high prevalence of fractures among patients with thalassemia (Major) (16.6%) and TI (12.1%). The high prevalence of fracture in both β and α thalassemia showed a strong association with bone mass and identified factors that may contribute to the pathogenesis of bone disease in thalassemia.^[2] The related studies indicate that bone disease and fracture in thalassemia in the form of low bone mass remains a frequent, debilitating and poorly understood problem, even among well-transfused and chelated pre-pubertal and adult patients,^{[37],[38],[39]} although some other studies have attributed low level of fracture to the optimized blood transfusion and chelation regimens.^[7]

Vitamin D deficiency (VDD) has also been implicated in bone diseases and fractures in thalassemia patients. Patients with VDD are known to have significantly lower BMD and a positive nonlinear relationship was found between 25-OH D and BMD Z-score.^[40] In our study, Vitamin D level was ranging from 10 to 24 ng in 39.1% and from 25 to 80 ng in 11.6% of the studied patients. Furthermore, the Z s core value was <−2 of the spine in 83.7% of 20 patients underwent DEXA scan in this study. Among these 20 patients, the mean Z score value of the femur was −2.1. A report from the USA on 96 patients with thalassemia revealed that 70 (73%) were either deficient (<20 ng/ml, 43%) or insufficient (20–29 ng/ml, 30%).^[41] In Tehran, 37.2% of 220 thalassemia patients had VDD (<27 nmol/L).^[42] A report from North India^[43] and another from Thailand^[44] showed VDD prevalence of 80% and 90% in thalassemia patients, respectively.

According to available knowledge, the study is the first to describe the characteristics of thalassemia patients in Madinah City, Saudi Arabia, to assess the prevalence of bone disease among these patients with an emphasis on the Vitamin D and Ferritin level adding new data to Saudi literature concerning this issue. Hospital-based data have the advantage of ensuring high data quality coming from the studied hospital.

In summary, the prevalence of bone fracture among thalassemia patients in Madinah City, Saudi Arabia was relatively high accounting for 14.5% of the studied patients. Low level of Vitamin D and high iron overload and ferritin level was prevalent among the studied patients. Further studies from multiple centers and cities are needed to identify optimal management strategies for future surveillance of this disease.

Acknowledgment

The authors would like to thank all staff in the King Fahd Hospital for their help and cooperation.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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Figures

[Figure 1]

Tables

[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]

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