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Assessment of Patients with β-Thalassemia Major, Undergoing Tertiary Care at a Regional Thalassemia Center in Pakistan

PJZ_53_1_245-250

Assessment of Patients with β-Thalassemia Major, Undergoing Tertiary Care at a Regional Thalassemia Center in Pakistan

Yasir Sharif1, Saba Irshad1*, Ammara Muazzam1, Muhammad Hamza Tariq1, Ambreen Kanwal1, Sana Rasheed1, Mabel Baxter Dalrymple2 and Anam Tariq1

1Institute of Biochemistry and Biotechnology, University of the Punjab-54590, Lahore, Pakistan.

2The University of Manchester, Oxford Road, Manchester, M13 9PL, England, United Kingdom.

ABSTRACT

To assess iron overload, disturbed liver and hematological profile and secondary complications in β thalassemia major (BTM) patients, the current study was carried on 408 subjects including 204 patients and 204 controls. For all 408 individuals; complete blood count (CBC), blood group, serum ferritin level and liver function tests were performed. Secondary complications were assessed by physical examination of pallor, splenomegaly, ascites, and hepatomegaly. The average±SD values of patients’ CBCs and liver enzymes were: red blood cells 3.07x 1012±0.769x 1012/L, white blood cells 8.89x 109±2.849x 109/L, hemoglobin 8.01± 1.027 g/dL, platelets 321.68x 109±1.027x 109/L, serum ferritin 2773.3±1071.9ng/mL, alanine transaminase 117.12±32.001U/L, aspartate transaminase 84.77±18.223U/L and bilirubin 1.02±0.139mg/dL. CBC of control group revealed that all of the studied parameters were normal in them and BTM patients showed significant deviation from control in both hematological and hepatic profile (P < 0.05). Examination for secondary complications revealed that Pallor sign was observed in 79.6% of patients, followed by splenomegaly (64.9%) and hepatomegaly (9%). As far as the control group is concerned no complication was found in that group. Current study provides sufficient evidence to justify advanced therapies to overcome secondary complications, iron overload, disturbed hepatic and hematological profile of patients and overall offers insight into improving the quality of treatment for β-thalassemia major patients.


Article Information

Received 30 June 2019

Revised 22 August 2019

Accepted 12 December 2019

Available online 24 December 2020

Authors’ Contribution

YS, SR, AT performed the experimental work. SI supervised and designed the work. MBD reviewed the manuscript. MHT, AM, AK provided technical supports and participated in drafting the manuscript.

Key words

Beta thalassemia major, Serum ferritin, Liver enzymes, Blood cells count, Secondary complications

DOI: https://dx.doi.org/10.17582/journal.pjz/20190630160603

* Corresponding author: saba.ibb@pu.edu.pk

0030-9923/2021/0001-0245 $ 9.00/0

Copyright 2021 Zoological Society of Pakistan



INTRODUCTION

Thalassemia is defined as an inherited disorder of hemoglobin that is portrayed by decreased synthesis of at least one of the globin chains, prompting imbalanced globin synthesis. β thalassemia is due to the imperfection in β globulin chain generation and reaches from clinically quiet heterogeneous thalassemia minor to extreme transfusion-dependent thalassemia major (Desouky et al., 2009; Omar et al., 2005).

It is estimated that hemoglobinopathies has 270 million carriers worldwide. Out of this large number, 80 to 90 million carriers are of β thalassemia (Williams et al., 2012). As per the recent information, 0.3 to 0.4 million kids experience the serious issue of hemoglobin defect during childbirth, of which, 23,000 are affected with β-thalassemia. Eminently, proof recommends that feasible 90% of these kids are conceived in low pay zones of the world (Kountouris et al., 2014; Williams et al., 2012). In Pakistan nearly 9.8 million carriers of β-thalassemia exist with 5-7% carrier rate (Ansari et al., 2012). β thalassemia major ultimately causes anemia which is both hypochromic and microcytic in nature, in which mean corpuscular hemoglobin (MCH) and mean corpuscular volume (MCV) is lower than the normal persons (Karmi et al., 2016). Degradation of erythrocytes and repetitive blood transfusion results in iron accumulation in different essential organs like pancreas, spleen, endocrine organs, liver and heart (Rasool et al., 2016; Shanaki et al., 2016). Iron overload in hepatocytes causes damage to the liver which can be checked by measuring the level of liver enzymes that is enhanced in toxicity of liver, induced by iron accumulation within it. Untreated thalassemia ultimately leads to a collection secondary complications including hepatosplenomegaly, pallor, poor musculature, jaundice, leg ulcer, growth retardation, masses development due to hematopoiesis, genum valgum, skeleton changes (Galanello et al., 2010), ascites, edema, haemosiderosis (severe iron accumulation in blood), splenomegaly (Taher et al., 2010), heart diseases, cirrhosis, pseudoxanthoma elasticum and hepatocellular carcinoma (Borgna Pignatti et al., 2005). The aim of the current study is to assess various hepatic biochemical, hematological parameters and secondary complications in β thalassemia major (BTM) patients.

 

MATERIALS AND METHODS

A total of 408 samples were collected, out of which 204 were β-thalassemia major patients and the 204 were healthy blood donors (controls). All these patients (already diagnosed with BTM by CBC test, hemoglobin electrophoresis and family history whilst the complicated cases were diagnosed through molecular identification methods) and controls were enrolled in Sundas blood bank and thalassemia center, situated in Lahore, Pakistan. We investigated several parameters from patients’ medical records including history, age, gender, blood group and frequency of blood transfusions. Informed consent form was taken from each patient while the study was approved by ethical committee of University of the Punjab, Lahore. To study secondary complications, physical examinations like pallor, splenomegaly, ascites and hepatomegaly were performed and then following blood tests were conducted.

For CBC parameters (hemoglobin level, WBC, RBC and platelets count) 3cc sample was collected in EDTA vacutainer tube and CBC was performed on Sysmex anlayser (Sysmex kx-21). The sample was suctioned into the Sysmex; passed between two terminals through a gap, so thin that just a single cell can sit back. The impedance changes as a cell go through. The adjustment in impedance results in cell check and volume (Ike et al., 2010). The ferritin was measured on ‘Architect 1000 SR’ the architect ferritin estimation is an immunoassay which determine the presence of ferritin in serum using chemiluminescent microparticle immunoassay (CMIA) technology. ABO and Rh Blood grouping of thalassemia patients was performed using antisera A, B and Anti D (Reid et al., 2004).

To perform the hepatic biochemical profile which includes liver function tests (LFTs), the samples were collected in red top vacutainer tubes to obtain serum. The above tests were analyzed using Thermoscientifc kits, on Spinlab 300 spectrophotometer. Total bilirubin was performed by photometric test using 2, 4-dichloroaniline (DCA). At the end, absorbance was taken at 546 nm. alanine transaminase (ALT) and aspartate transaminase (AST) were measured by enzymatic colorimetric method and absorbance for the test was taken at 340 nm. To analyze the data statistically, SPSS 18.0 software was used. An estimation of p ≤ 0.05 was taken as statistically significant.

 

RESULTS

In the current study, the mean age of β thalassemia major (BTM) patients was 6.34 ± 2.272 (Mean± Standard Deviation) years which was 32.84± 3.915 years in normal blood donors. Among 204 patients, 139 were male whilst 65 were female and in controls group, 161 were male and 43 female. This depicts male to female ratio 2.13:1 in BTM patients whilst it was 3.74:1 in the control group.

The age of first blood transfusion in patients was observed 1.2 years in male and 1.3 years in female. 119 (58.34%) patients were undergoing blood transfusions on a monthly basis, followed by 69 (33.82%) patients, undergoing transfusions after every three weeks. Whereas 9 (4.41%) and 7 (3.43%) patients received blood transfusions fortnightly and weekly, respectively (Table I). Blood grouping showed that “B” blood group was the most common among both BTM patients and controls. Out of 204, 15 and 16 subjects were found to be negative for Rh antigen in patients and control groups, respectively (Table II).

 

Table I. Frequency of blood transfusion in BTM patients (n=204).

Frequency of transfusion

Number of Patients

Total

Female (% within gender)

Male (% within gender)

Weekly

03(4.6%)

04(2.88%)

07(3.43%)

Fortnightly

05(7.69%)

04(2.88%)

09(4.41%)

3 weeks

20(30.77%)

49(35.25%)

69(33.82%)

Monthly

37(56.92%)

82(58.99%)

119(58.33%)

 

Table II. Blood grouping in patients and controls.

Blood Group

Controls (n= 204)

Patients (n= 204)

O+

57(27.94%)

59(28.92%)

A+

43(21.07%)

37(18.14%)

B+

72(35.29%)

73(35.78%)

AB+

16(7.84%)

20(9.80)

O-

5(2.45%)

6(2.94%)

A-

4(1.96%)

2(0.98%)

B-

6(2.94%)

5(2.45%)

AB-

1(0.49%)

2(0.98%)

Total Rh-

16(7.84%)

15(7.35%)

Total Rh+

188(92.16%)

189(92.64%)

 

Table III. Hepatic biochemical and hematological profile of patients and controls.

Parameter

Controls (n= 204)

Patients (n= 204)

P value

Mean ± S.D (Range)

Mean ± S.D (Range)

Bilirubin (mg/dL)

0.96 ±0.20 (0.7-1.3)

1.02 ±0.13 (0.8-1.7)

<0.001

Alanine transaminase (IU/L)

33.15 ±3.71 (20-50)

117.12 ±32.00 (35-220)

<0.001

Aspartate transaminase (IU/L)

30.01 ±9.58 (10-50)

84.77 ±18.22 (30-140)

<0.001

Hemoglobin (g/dL)

14.29 ±0.87 (12.7-17.1)

8.01 ±1.02 (4.5-10.4)

<0.001

Serum ferritin (ng/mL)

154.7 ±30.5 (90-250)

2773.3 ±1071.9 (1081-9817)

<0.001

White blood cells x 109/L

7.53 ±4.99 (2.5-77.4)

8.89 ±2.84 (4.2-16.3)

<0.005

Red blood cells x 1012/L

4.73 ±0.44 (4.6-5.2)

3.07 ±.769 (2.1-5.2)

<0.001

Platelets x 109/L

313.14 ±39.27 (230-420)

321.68 ±1.02 (109-654)

<0.005

 

Hepatic biochemical profile showed that the mean level of bilirubin, alanine transaminase (ALT) and aspartate transaminase (AST) was significantly increased in BTM patients. Average value of bilirubin was 0.96 ±0.206 mg/dL in the control group which was raised to 1.02 ±0.139 mg/dL in patients group (P<0.001). ALT and AST concentration was also raised in BTM patients with a mean value of 33.15 ±3.71 IU/L and 30.01 ±9.583 IU/L (in controls) to 117.12 ±32.001 IU/L (P<0.001) and 84.77 ±18.223 IU/L (P<0.001), respectively (Table III).

Data from hematological profile of BTM patients showed that their mean serum ferritin level was 2773.3 ±1071.9 ng/mL that was significantly higher (as expected) than the mean value of normal donors i.e. 154.7 ±30.5 ng/mL. Contrary to this, mean level of hemoglobin and red blood cells (RBCs) was significantly reduced to 8.01±1.027 g/dL (P<0.001) and 3.07± 0.769x 1012/L (P<0.001) respectively which had a mean value of 14.29± 0.876 g/dL and 4.73± 0.445x 1012/L in control group. The mean values of white blood cells (WBCs) and platelets count in donors were 7.53 ±4.999 x 109/L and 313.14 ±39.27 x 109/L correspondingly that was significantly enhanced to 8.89 ±2.849 x 109/L (P<0.005) and 321.68 ±1.027 x 109/L (P<0.005) in BTM patients (Table III).

In regard to secondary complications, 79.66% patients presented pallor condition. Splenomegaly and hepatomegaly were dominant sign and seen in 64.9% and 9% patients respectively. Ascites, edema and Jaundice was also seen rarely in patients however bruises, central nervous system (CNS) disorders and lymphadenopathy was not inspected in any of the BTM patient (Fig. 1).

 

DISCUSSION

β-thalassemia is a genetic disorder with global prevalence, that ultimately results in death. Treatment of this disease includes blood transfusion, usage of antioxidants, chelation therapies and inducers of fetal haemoglobin. Typically, transfusions and chelation are most commonly administered; however, frequent blood transfusions increase the risk of transmission of infections.


 

The mean age of the patients of β thalassemia was 6.34±2.272 years which was consistent with the literature (Ansari et al., 2012; Ishaq et al., 2012). Serum ferritin level in 204 patients was greater than 1000μg/L with a mean Ferritin level of 2773.32 ±1071.908 ng/mL that is also comparable with previous studies where reported ferritin level was 3225 ± 1594 ng/mL (Munir et al., 2012) and 3682 ± 1693 ng/mL (Kandhari et al., 2005). Increased intestinal iron absorption, repeated blood transfusions, peripheral hemolysis and ineffective erythropoiesis are unavoidably linked to iron accumulation within different organs like liver, kidney, heart and endocrine glands (Rasool et al., 2016; Shanaki et al., 2016). This iron accumulation leads to liver fibrosis, endocrine abnormalities, heart disease and cirrhosis (Origa, 2017). In our study bilirubin level was found to be increased as compared to the control group, which is also similar to the previous studies (Kumar et al., 2017; Mohammad et al., 2012). This disarrangement of bilirubin is owing to peripheral hemolysis, that is quick to the point that it surpasses the liver ability to utilize the bilirubin, prompting increased bilirubin (Cappellini et al., 2018), that is because of decline in function of enzyme cytochrome c oxidase, disrupting the respiration by mitochondria (Al Haddad, 2012). According to Suman et al. (2017) when the number of blood transfusions crosses 30 and serum ferritin level gets more than 1000 ng/mL and it ultimately results in derangement of liver enzymes. As in all of the patient’s serum ferritin level was more than 1000 ng/mL, therefore, two of the most important enzymes of liver i.e. ALT and AST were examined to be increases in our BTM group, high ALT and AST has also been reported previously (Mansi et al., 2008; Mohammad et al., 2012; Shams et al., 2010). Barton (2007) also examined that there was a positive correlation between serum ferritin and liver enzymes.

β thalassemia is a genetic disease of hemoglobin, therefore, it leads to the acute form of anemia, in which the body lacks healthy RBCs and hemoglobin (Malloy et al., 1937). In our study mean hemoglobin level in BTM patient was also lower than the healthy blood donors, that is also in line with previous studies (Ayyash et al., 2018; Bashir et al., 2010). As β thalassemia is characterized by irregularity in hemoglobin level it causes a decrease in concentration of RBCs in BTM patients. In the current study, the concentration of RBCs was observed to be lower than the normal people, which are also reported in previously published data (Akula, 2017; Munir et al., 2013). Contrary to RBCs, WBCs and platelets were described to be increased in the patient group of current study, which is also in cohort with previous studies (Ayyash et al., 2018; Munir et al., 2013).

Repeated blood transfusion ultimately results in an array of secondary complications. Although our analysis shows that a few patients were suffering from edema, ascites, jaundice and lymphadenopathy, other secondary complications were evident. Pallor, hemochromatosis, splenomegaly and hepatomegaly were observed among the patient group. Furthermore, the current study showed that pallor is present in almost 80% patient, illustrative of pallor appearance as a validated test for diagnosis of β-thalassemia (Yalcin et al., 2007). In the current study, 64.9% of the total patients exhibited the complication of splenomegaly which is in line with previously reported occurrence of 63.2% (Shah et al., 2005) and 64.9% (Chaudhary et al., 2012). Hepatomegaly is another complication of untreated β-thalassemia, in which manifestation varies from 27.37% (Din et al., 2014) to 74.8% (Saeed et al., 2015) but in the current study it was found in 9% of the total patients. Coincidence of different secondary complications revealed that pallor sign was the most prevalent and this condition with splenomegaly are linked to anemic, hemolytic and iron overload in BTM patients.

β-thalassemia patients require a regular transfusion of foreign blood for their survival in our study most of the patients (58.33%) received blood transfusion every month, followed by 33.82% (69 patients) who are being transfused every 3rd week. Moreover, it is found that blood group B was predominant, in both patients and controls. This is consistent with a study from Faisalabad, Punjab, in which B blood group was most common (Munir et al., 2013). Previous data from Lahore, Punjab, reported “O” as the principal blood group affected by β-thalassemia (Nazir et al., 2014), and from Jamshoro, Sindh, blood group “A” was the most prevalent blood group (Laghari et al., 2018). In terms of the Rh antigen, less than 8.0% (patients and controls) were found negative for Rh antigen which is also in accordance with previous studies of Pakistan (Laghari et al., 2018; Nazir et al., 2014).

 

CONCLUSION

The present study concluded that a large number of β-thalassemia major patients undergo tertiary care, requiring regular transfusion of blood and other treatment. This study recommend proper iron chelation therapy (to reduce secondary complications), as serum ferritin levels among the patients exceeded the normal range. Iron chelation therapy assists in preventing the accumulation of excess iron in organs throughout the body, in order to maintain their proper function. Furthermore, as thalassemia major patients have elevated levels of HbF for protective purpose thus HbF enhancing drugs such as hydroxyurea, could present therapeutic potential. In conclusion, the current study provides sufficient evidence to justify advanced therapies to overcome secondary complications, iron overload, disturbed hepatic and hematological profile of patients, inform changes to present public health policies and overall offers insight into improving the quality of treatment for β-thalassemia major patients.

 

ACKNOWLEDGMENT

Sundas Foundation (blood bank and thalassemia center) provided free interaction with patients who provided their data and donated blood for further blood testing.

 

Declaration of interests

Authors have no conflicts of interest to disclose and assure that all authors have read/approved the manuscript.

 

Funding statement

The study was funded by Institute of Biochemistry and Biotechnology, University of the Punjab and Sundas Foundation, Lahore.

 

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