Ocular Abnormalities in Correlation with Multi-transfused in

Children with Beta Thalassemia Major

B. Lubis

and S. M. Lubis

Pediatric Hematology-Oncology Division, Department of Child Health, Medical School, Universitas Sumatera Utara,

Medan, Sumatera Utara, Indonesia

Pediatric Endocrinology Division, Department of Child Health, Medical School, Universitas Sumatera Utara, Medan,

Sumatera Utara, Indonesia

Keyword: Ocular Abnormalities, Children, Beta Thalassemia Major.

Abstract: Thalassemia is the commonest haemoglobinopathies worldwide. Repeated blood transfusion lead to

hemosiderosis which affects all the organ in the body including eyes. The aim of this study was to evaluate

ocular abnormalities in children with beta thalassemia major who have received multiple blood transfusions.

A cross-sectional study was conducted in the Thalassemia day-care centre of a tertiary care at H. Adam

Malik Hospital Medan, Indonesia. Visual aquity, anterior segment, fundus, and retina were evaluated to

screen ocular abnormalities. There were 37 patients with beta thalassemia major, male and female were 20

(51.3%) and 17 (48.7%), respectively, age 3 to 18 years. All patients received regular blood transfusions,

but only 28 patients (78.4%) received iron chelation therapy. Opthalmologic examinations showed ocular

abnormalities in 15 subjects (40.4%), cataract in 3 patients (8.1%), papil edema in 10 patients (27%), and

papil atrophy in 2 patients (5.4%). Decreased visual acuity was observed in 8 patient (21.6%).

Hyperpigmentation in bulbar conjunctiva were seen in 12 patients (32.4%). There was no significant

correlation between ocular abnormalities and multiple transfusions. Regular ophthalmologic evaluations

was needed to detect retinopathy and early changes in their ocular system for a better quality of life in

thalassemic patients.

1 INTRODUCTION

Thalassemia is a severe genetic blood disorders

caused by a mutation in the globin gene. Abnormal

globin chains lead to the excessive destruction of red

blood (Vichinsky EP, 2005). Beta thalassemia major

is one of the most common hemoglobinopathy.

Management of thalassemia major consist of regular

blood transfusions therapy throughout the life,

getting natural development and growth, reducing

hyperplasia of erythroid tissue and deformities of

skeleton (Cao A, 2010; Langhi D et al., 2016).

Although transfusions can prevent death and decease

mortality, iron accumulated from repeated blood

transfusion and enhanced iron absorption by

gastrointestinal tract can lead to organ damage such

as heart, liver, endocrine gland, and skeletal system

(Propper RD, 1980).

Mechanism of ocular manifestations in

thalassemia is multifactorial such as regular blood

transfusion therapy which causes iron overload. Iron

chelating agents chelate other metals suchs as

Copper, zinc, nickel, and cobalt essential for normal

retinal function causing several ocular abnormalities.

Deficiency micronutrients like zinc, vitamins like

vitamin B

can also lead to ocular manifestations.

Iron deposition in eye can lead to several ocular

abnormalities as a result of the disease itself or as

side effects of iron chelators and include ocular

surface disorders, cataract, angioid streak, retinal

venous tortuosity, retinal pigment epithelium (RPE)

degeneration and mottling, optic neuropathy, and

decreased visual acuity (Taher A et al., 2006; Arden

GB et al., 1984; Gartaganis S et al., 1989).

This study was conducted to assess the

prevalence of ocular abnormalities in multi-

transfused beta-thalassemia patients and to

determine their relationship with serum ferritin level.

2 METHODS

A cross-sectional study was conducted in the

Thalassemia day-care centre of a tertiary care H.

898

Lubis, B. and Lubis, S.

Ocular Abnormalities in Correlation with Multi-transfused in Children with Beta Thalassemia Major.

DOI: 10.5220/0010099508980903

In Proceedings of the International Conference of Science, Technology, Engineering, Environmental and Ramiﬁcation Researches (ICOSTEERR 2018) - Research in Industry 4.0, pages

898-903

ISBN: 978-989-758-449-7

Adam Malik Hospital Medan, Indonesia. Thirty

seven children were included in this study. Inclusion

criteria were children with beta thalassemia major

with the age less than 18 years with regarding two

years blood transfusion. Subjects have received

packed red cell transfusions with a dosage of 15 ml/

Kg BW to maintain haemoglobin concentration after

transfusion at levels greater than 11 g/dL for at least

2 years were enrolled in the study. Haemoglobin was

measured before each transfusion and the serum

ferritin levels was measured in all patients at 6-

monthly intervals. The records were kept at the

thalassemia day-care centre.

Ophthalmological assessment was assessed by

Pediatric Ophthalmologist, included a detailed

history of visual problems and visual aquity

screening. Anterior segment was examined by using

slit lamp and posterior segment screening was

evaluated by using multimodal imaging in

ophthalmology like indirect retinoscopy, optical

coherence tomography (OCT) or fundus photo.

Subjects who had history of corneal disease, using

contact lens, ocular trauma, previous ocular surgery,

and those taking topical medications were excluded

in this study.

2.1 Statistical Analysis

The relationship between serum ferritin level and

ocular abnormalities was analysed using Chi square

test. Spearman test was used to determine the

correlation between frequency and volume of

transfusion with serum ferritin level. Statistical

calculation was done using Statistical Package for

Social Science (SPSS) version 24.0 at 95%

confidence interval and P-value of <0.05 was

considered as statistically significant.

3 RESULTS

There were thirty seven thalassemia subjects with

the age 3–18 years were included in this study, there

were 20 subjects (51.3%) were male and 17 subjects

(48.7%) were female. Baseline characteristics of

subjects were shown in Table 1. The dominant

ethnic in this study was Javanese (59.8%). All

subjects received regular blood transfusion, but only

28 patients (78.4%) received iron chelation therapy,

and others (21.6%) without iron chelation

treatments. Median age at diagnosis was 31.0 (3.0-

180.0) months. Only 5 (13.5%) subjects had serum

ferritin levels was less than 1000 ng/mL, and 32

subjects (86.5%) was more than 1000 ng/

Table 1. Baseline characteristics of subjects

n (%)

Age, year

5-10

>10

Gender

Male

Female

20 (51.3)

17 (48.7)

Ethnicity

Acehnese

Javanese

Karonese

Melayunese

Padangnese

Sundanese

Chinese

2 (5.4)

22 (59.8)

3 (8)

2 (5.4)

6 (16)

1 (2.7)

Ocular Abnormalities in Correlation with Multi-transfused in Children with Beta Thalassemia Major

899

Table 1: Baseline characteristics of subjects

Table 2: Ocular abnormalities findings

n (%)

Characteristics of bulbar conjunctiva

Normal 25 (67.6)

Hyperpigmentation 12 (32.4)

Characteristics of camera oculi anterior

Normal 30 (81.1)

Hyperpigemtation 7 (18.9)

Visual acuity

Normal 29 (78.4)

Decrease 8 (21.6)

Ocular abnormalities

None 22 (59.5)

Papil edema 10 (27)

Complicated cataract 3 (8.1)

Papil atrophy 2 (5.4)

Mean body weight, kg (mean ±SD)

24.5 (8.8)

Mean body height, cm (mean ±SD) 123.6 (18.9)

Mean BMI, kg/m

(mean ±SD)

15.4 (2.2)

Median age at diagnosis, month (min-max) 31.0 (3.0-180.0)

Iron chelating agent

Exjade

Ferriprox

None

13 (35.1)

16 (43.3)

8 (21.6)

Serum ferritin level

< 1000 ng/mL

5 (13.5)

1000-5000 ng/mL 20 (54.1)

5000-10000 ng/mL

8 (21.6)

>10.000 ng/mL 4 (10.8)

Median serum ferritin level, ng/mL ((Min –

max)

2842.0 (430.8-31285.4)

Median transfusion volume, mL (min-max)

175.0 (10.0-525.0)

Median transfusion frequency, time (min-

max)

12.0 (3.0-48.0)

ICOSTEERR 2018 - International Conference of Science, Technology, Engineering, Environmental and Ramiﬁcation Researches

900

The association between serum ferritin levels and

ocular abnormalities has been shown in Table 3.

The prevalence of hyperpigmentation in bulbar

conjunctiva and camera oculi anterior were 8

(66.7%) and 3 (42.9%), respectively, in subjects who

had serum ferritin levels between 1000-5000 ng/ml.

Visual acquity decreased in 8 (21.6%) in subjects,

we also found 3 subjetcs with cataract, but there

were no significant association between serum

ferritin levels and hyperpigmentation, vivisual

acquity, and cataract in our subjects.

Table 4 showed the correlation between

frequency and volume of transfusion with serum

ferritin level. There was significant association

between blood volume of transfussion and serum

ferritin levels (p<0. 05), but there was no significant

association between frequency of transfussion with

serum ferritin levels.

Table 3. Association between serum ferritin level and ocular abnormalities

Category of serum

ferritin level

Bulbar conjunctiva p

Normal (%) Hyperpigmentation (%)

<1000 3 (12.0) 2 (16.7) 0.428

1000-5000 12 (48.0) 8 (66.7)

5000-10000 6 (24.0) 2 (16.7)

>10000 4 (16.0) 0 (0.0)

Camera oculi anterior

Normal (%) Hyperpigmentation (%)

<1000 4 (13.3) 1 (14.3) 0.920

1000-5000 17 (56.7) 3 (42.9)

5000-10000 6 (20.0) 2 (28.6)

>10000 3 (10.0) 1 (14.3)

Visual acuity

Normal (%) Decreased (%)

<1000 3 (10.3) 2 (25.0) 0.283

1000-5000 17 (58.6) 3 (37.5)

5000-10000

>10000

5 (17.2)

4 (13.8)

3 (37.5)

0 (0.0)

Ocular abnor

alities

None (%) Oedema of

papilla (%)

Complicated

cataract (%)

Atrophy of

papilla (%)

<1000 3 (10.3) 2 (25.0) 0 (0.0) 0 (0.0) 0.632

1000-5000 17(58.6) 3 (37.5) 1 (33.3) 2 (100.0)

5000-10000 5 (17.2) 3 (37.5) 1 (33.3) 2 (100.0)

>10000 4 (13.8) 0 (0.0) 1 (33.3) 0 (0.0)

Ocular abnormalities

Complicated cataract (%) No cataract (%)

<1000 0 (0.0) 1 (8.3) 0.541

1000-5000 1 (33.3) 8 (66.7)

5000-10000 1 (33.3) 2 (16.7)

>10000 1 (33.3) 2 (16.7)

*Chi square test

Table 4. Correlation between frequency and volume of transfusion with serum ferritin level

Mean

Frequency of transfusion, time

Serum ferritin level, n

/mL

17.6

5033.2

0.199 0.239

Volume of blood transfusion, mL

Serum ferritin level, n

/mL

188.7

5033.2

0.544 <0.001

*Spearman test

Ocular Abnormalities in Correlation with Multi-transfused in Children with Beta Thalassemia Major

901

4 DISCUSSION

Thalassemic patients are on lifelong blood

transfusion therapy. Multiple or repeated blood

transfusions lead to siderosis and adverse ocular

changes may occur as a result of the disease or due

to iron overload and chelation therapy. Adverse

retinal effects may occur as a result of the iron

chelators or the disease itself and include the

following: Retinal pigment epithelium (RPE)

degeneration, RPE mottling, retinal venous

tortuosity and vitrretinal hemorrhages. Thalassemic

patients may present with decresed visual acuity,

color vision anomalies, hyperpigmentasi, papil

edema, papil athrophy, thinning and tortuosity of

retinal vessels, vitreo-retinal hemorrhages, night

blindness, cataracts, visual field defect and optic

neuropathy. Thalassemia major may also be

associated with a nonproliferative pigmentary

retinopathy due to liberation of free iron as a result

of hemolysis (Gartaganis S et al., 1989; Wong RW

et al., 2001).

This study was conducted to detect various

ocular changes in patients who were on regular

transfusion and iron chelating agent. We evaluated

37 thalasemic children with ocular abnormalities in

15 patients (40.5%), such as visual acquity

decreased in 8 patients (21.6%). There was no

significant correlation between serum ferritin levels

and edema and athropy papil, and cataract. Other

studies reported ocular abnormalities were found in

41.3%, 36%, and 38% (Gartaganis S et al., 1989;

Dewan P et al.2011; Soecinelli R et al., 1990).

Difference results of ocular abnormalities that had

been reported in previous studies may be due to

differences in parameters used to evaluate ocular

abnormalities, it is difficult to make an accurate

comparison. Ocular changes were seen more in

children above 10 years of age and was less in

children below 5 years of age. This clearly shows

that longer the duration of the illness more are the

eye changes.

Decreased visual aquity was observed in 8

patients (21.6%), this result was almost same with

other studies that reported the insidence of decreased

visual acquity was about 15.5–30% in thalassemic

patients (Taher A et al., 2006; Gartaganis S et al.,

1989). The presence of ocular abnormalities was

correlated with serum ferrin levels and multiple

transfusion. This study reported ocular abnormalities

were found in 16 (84%) subjects with the serum

ferritin levels were more than 1000, and less than

1000 ng/mL in 3 subjects (16%). Iron causes

oxidative damage to protein, lipids, and DNA

through the generation of free radicals in the Fenton

reaction and it has been shown to disrupt the blood-

retinal barrier. Iron may play a role in the

pathogenesis of retinal degeneration as a source of

free radical damage. Iron toxicity from multiple

blood transfusions may contribute to beta-

thalassemia retinopathy. Iron is important

component of many metabolic processes, but

appropriate regulation is necessary to prevent

toxicity (Liaska A et al., 2016; Song D et al., 2013).

The limitations in our study were that very few

children with thalassemia use iron chelating therapy

due to low their low socio-economic level, and we

could not evaluate the effect of chelation therapy on

the ocular abnormality especially on the retina in

thalassemic children. We did not correlate the ocular

abnormalities with frequency and volume of blood

transfusion in our subjects. Our study has same

limitations, we did not compare the ocular

abnormalities with frequency and volume blood

transfusion therapy for thalassemic patients,

differences between iron chelation regimen and

there is a possibility that their ocular abnormalities

could have occurred before first time blood

transfusion treatment. Overall, the correlation

between ocular abnormality and frequency and

volume blood transfusion has not been established in

present study, hence, further prospective

investigations with a large sample of thalassemia

patients are suggested.

5 CONCLUSION

The ocular abnormalities in our subjects were

asymptomatic, but 15 subjects (40.4%) was revealed

ocular abnormalities. We did not find any significant

correlation between ocular abnormalities with serum

ferritin levels and multiple transfusion, but a

significant association was found between volume of

blood transfussion and serum ferritin levels. Since

life expectancy in patients with beta thalassemia

major increases, it is necessary to screen for ocular

abnormalities in all children with thalassemia to

improve the quality of life of thalassemic patients.

ACKNOWLEDGMENT

The authors wish to thank the children and parents

of thalassemia patients in one day care center (ODC)

- H. Adam Malik Hospital Medan and dr Balqis D

ICOSTEERR 2018 - International Conference of Science, Technology, Engineering, Environmental and Ramiﬁcation Researches

902

Sulistyowati Pediatric Ophthalmologist - for their

cooperation.

This study has been granted by TALENTA 2018

University of Sumatera Utara.The authors declare

not having any proprietary interest in the materials

described in the article. There are no conflicts of

interest.

All procedures performed in studies involving

human participants were in accordance with the

ethical standards of the institutional and national

research committee and with the 1964 Helsinki

declaration and its later amendments or comparable

ethical standards.

Informed consent was obtained from all

individual participants included in the study.

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