Relationship between Short Stature and Serum Ferritin in Children

with Beta Thalassemia Major

S. M. Lubis

and B. Lubis

Pediatric Endocrinology Division, Department of Child Health, Medical

School, Universitas Sumatera Utara, Medan, Sumatera Utara, Indonesia

Pediatric Hematology-Oncology Division, Department of Child Health,

Medical School, Universitas Sumatera Utara, Medan, Indonesia

Keyword: Short Stature, Serum Ferritin, Children, Beta Thalassemia.

Abstract: Short stature has been recognized in thalassemia major patients for many years and continue to be common

problems despite regular transfusion and chelation therapy. The aim of this study was to determine the

relationship between short stature and serum ferritin in children with beta thalassemia major. A cross sectional

study was carried out in children with beta thalassemia major who met the inclusion criteria and selected

based on consecutive sampling, aged less than 18 years, and regularly visited Thalassemia Day-Care Centre

at H. Adam Malik and Universitas Sumatera Utara General Hospital. This study was conducted in March to

May 2018. Data was collected through the questionnaire, anthropometric measurements, and blood test

analysis. Descriptive statistics and chi-square test were performed, p<0.05 was considered as significant level.

There were 56 children were recruited in this study, females and males comprised 27 (48.2%) and 29 (51.8%)

respectively, 60.2% of subjects had short stature and 14.3% had severe thinness. The mean serum ferritin

levels were 5081.41±4503.65 ng/mL. Age at diagnosis was 40±33.61 months. This study found there was no

significant association between serum ferritin levels with short stature but significant association was

identified between age at diagnosis and short stature.

1 INTRODUCTION

Thalassemia as the most common genetic disorder

worldwide is regarded as a serious problem in public

health issues especially in Asia region (Ansari Sh et

al., 2014).Almost 100,000 patients with major

thalassemia need regular transfusions. Regular red

blood cell (RBC) expansion, permit normal

development throughout childhood, and extend

survival (Hashemi A et al., 2011). Transfusions

result in iron overload, which is fatal without

treatment in the second decade of life. Iron-chelating

therapy for iron overload is one important part of

major thalassemia treatment in last 20 years

(Hashemi A et al., 2011).Although morbidity and

mortality of the thalassemia major has been

significantly in the light of modern medical

treatment, however, it could influence various

aspects of patients’ life (Ansari Sh et al., 2014).

Many complications of beta thalassemia major

are the result of increased iron deposition from

repeated blood transfusion. The accumulation of iron

in different tissues causes organ damage affecting

mainly endocrine glands, heart, and liver. The most

prominent endocrine complication is growth

retardation and failure of normal pubertal

development. Growth failure has been attributed to

growth hormone (GH) hypothalamic and/or

pituitary, insulin-like growth factor 1 (IGF-1),

insulin-like growth factor binding protein 3

(IGFBP3) deficiency, hypothyroidism, delayed

sexual maturation and to bone disorders caused by

iron-chelating toxicity. Short stature in children with

beta thalassemia major could be due to GH-IGF-1

axis dysfunction and iron-chelating induced bone

dysplasia (Nasr MR., 2012).

Malnutrition is a significant cause of growth

retardation in thalassemic children living in poor

countries. In these children, inadequate nutrient

intake (zinc, folic acid, vitamin D, carotenoids, and

retinol binding proteins) contribute significantly to

their growth impairment (De Sanctis V et al., 2014).

The aim of this paper was to determine the

relationship between short stature and serum ferritin

in children with beta thalassemia major.

Lubis, S. and Lubis, B.

Relationship between Short Stature and Serum Ferritin in Children with Beta Thalassemia Major.

DOI: 10.5220/0010098908910897

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

891-897

ISBN: 978-989-758-449-7

891

2 METHODS

This cross sectional study was conducted in March

to May 2018. Subjects were selected by using

consecutive sampling that met the inclusion criteria

and regularly visited Thalassemia Day-Care Centre

at H. Adam Malik and Universitas Sumatera Utara

General Hospital. The inclusion criteria were

children with beta thalassemia major aged less than

18 years with regarding two years blood transfusion

and received blood transfusion regularly, and

exclusion criteria were having genetic disease such

as Down syndrome and chronic illness (malignancy,

tuberculosis, chronic hepatitis, congenital heart

disease, chronic renal failure, primary skeletal

disorders, diabetes mellitus). Serum ferritin level

was measured using the

chemiluminescentmicroparticle immunoassay

(CMIA).

The study included a questionnaire for parents or

guardians and anthropometric measurements. The

questionnaires requested information about the age

at diagnosis, history of thalassemia in family, get

iron chelating agent, frequency of blood transfusion

in a year, and social- economic data. Anthropometric

measurements included body weight (in Kg), was

measured to the nearest 0.1 Kg by digital machine.

Height (in cm) was measured to the nearest 0.1cm by

using stadiometer. All instruments were validated

following the manufacturer’s protocol. Body mass

index (BMI) was calculated as weight (kg) /height

(meter) (Ogden CL et al., 2010).Then, the subjects

were categorized based on World Health

Organization (WHO) reference of Children Growth

Chart which is recognized as z- scores (standard

deviation scores). Short stature was assessed by

using Growth Chart Center for Disease Control

(CDC) 2000 for boys and girls.

This study was approved by The Ethics

Committee of The Medical School, Universitas

Sumatera Utara, Medan, Sumatera Utara, Indonesia.

All parents or guardians gave written informed

consent that the results of this study would be used

for scientific research purposes.

2.1 Statistical Analysis

Data were analyzed using SPSS software version 24

(SPSS Inc., Chicago, IL, USA). Quantitative

variables were expressed as mean±standard

deviation (SD). The descriptive statistics were used

to analyze socio demographic characteristics of the

subjects. The relationship between short stature and

serum ferritin level was used chi-square test, p<0.05

was considered as significant level.

3 RESULTS

There were 56 children were recruited in this study,

females was 27 (48.2%) and male was 29 (51.8%),

respectively. Characteristics of children in this study

are given in Table 1. Short stature was found in 34

(60.7%) and normal stature was in 22 (39.3%)

subjects. Most thalassemia children had normal

nutritional status, but 14,3% subjects were thinness

(BMI <-2 SD) and 14.3% are severe thinness (BMI

<-3 SD). Family history of thalassemia was found

only in 12 (21.4%) subjects, but it is possible that the

number of subjects who had a family history of

thalassemia is actually more than that reported by

parents in the questionnaire, because some are not

diagnosed or have not screened. Most subjects were

diagnosed with beta thalassemia major at over 2

years of age. Around 87.5% of subjects had parental

income of 5-10 million rupiah in a month.

Table 1. Characteristics of Children in this Study

n (%)

Age (years) 9.46±4.44

Age at diagnosis

< 6 months 7 (12.5)

6 months to 2 years 12 (21.4)

>2 years 37 (66.1)

Sex:

Male

27 (48.2)

Female 29 (51.8)

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

892

Table 1. Characteristics of Children in this Study (cont.)

Body weight (Kg) 23.63±8.77

Body height (cm) 121.41±19.07

BMI (kg/m

) 15.50±2.16

Family history of thalassemia

Yes 12(21.4%)

No 44(78.6%)

Father’sEducation

level

Elementaryschool 9 (16.1)

Middle school 11 (19.6)

Seniorhighschool 31 (55.4)

University 5 (8.9)

Mother’s education level

Elementaryschool 9 (16.1)

Middle school 14 (25.0)

Seniorhighschool 27 (48.2)

University 6 (10.7)

Parental income (Rupiah)

< 5 million 49 (87.5)

5-10million 6 (10.7)

> 10million 1 (1.8)

Nutritional status (body mass index)

Normal 40 (71.4)

Thinness (<-2 SD) 8 (14.3)

Severethinness (<-3

SD)

8 (14.3)

Stature

Normal 22 (39.3)

Short stature 34 (60.7)

BMI: Body mass index. Data are means ± SD, or percentages.

Table 2 showed serum ferritin levels in most subjects

were above 2000 ng/mL, hemoglobin levels before

transfusion of most children between 5-7 g/dL, most

subjects received blood transfussions every month,

and 17 (30.4%) subjects did not use iron chelating

therapy.

Table 2. Variables Characteristics

n(%)

Ferritin Level (ng/mL)

<1000 7 (12.5)

1000-2000 12 (21.4)

>2000 37 (66.1)

Haemoglobin level before transfussion (g/dL)

<5 6 (10.7)

5-7 44 (78.6)

Relationship between Short Stature and Serum Ferritin in Children with Beta Thalassemia Major

893

Table 2. Variables Characteristics (cont.)

>7 6 (10.7)

Transfussion frequency

Every week 2 (3.6)

Every 2 weeks 19 (33.9)

Every 3 weeks 6 (10.7)

Every month 24 (42.9)

More than 1 month 5 (8.9)

Iron-chelating agent

Deferiprone 21 (37.5)

Deferasirox 18 (32.1)

Without therapy 17 (30.4)

The relationship between short stature and serum

ferritin levels and other variables characteristics can

be seen in Table 3. There was no significant

relationship between short stature and serum ferritin

levels and with other characteristic variables, but this

study reported a significant relationship between

short stature and age at diagnosis.

Table 3. Association between short stature with serum ferritin and other characteristics

Normal Short stature p

Age

<5 4 5 0.328

5-10 12 13

>10 6 16

Age at diagnosis

< 6 months 6 1

0.003

6 months to 2 years 7 5

>2 years 9 28

Sex: Male 11 16 0.830

Female 11 18

Family history of thalassemia

Yes 18 26 0.634

No 4 8

Parental income (Rupiah)

< 5 million 19 30 0.440

5-10 million 2 4

> 10 million 1 0

Nutritional status (body mass index)

Normal 15 25 0.799

Thinness (<-2 SD) 4 4

Severe thinness (<-3 SD) 3 5

Ferritin Level (ng/mL)

<1000 1 6 0.296

1000-2000 6 6

>2000 15 22

Haemoglobin level before transfussion (mg/dL)

<5 2 4 0.893

5-7 18 26

>7 2 4

Transfussion frequency

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

894

Table 3. Association between short stature with serum ferritin and other characteristics (cont.)

Every week 1 1 0.062

Every 2 weeks 5 14

Every 3 weeks 0 6

Every month 14 10

More than 1 month 2 3

Iron-chelating agent

Deferiprone 8 13 0.849

Deferasirox 8 10

Without therapy 6 11

Associations are considered significant when p< 0.05.

4 DISCUSSION

Beta thalassemia major is a severe early-onset form

of beta-thalassemia characterized by severe anemia

requiring regular red blood cell transfusions, it

usually cause severe anemia with several health

problems like enlarged spleen, bone deformities,

short stature, diabetes, hepatitis infection, and

requires regular life-long transfusion, therapy, and

medical supervision. Thalassemia affects the growth

of the thalassemic patients (Al-saleheQAA et al.,

2015). Other risk factors that might affect growth

disorders in thalassemia children are low hemoglobin

level pre-transfusion, high ferritin level, not optimal

used iron chelating agent, low social- economic level

and increasing age of thalassemia children. Long-

term blood transfusion and chelating agent

administrations can improve quality of life of the

thalassemic children and decrease deaths due to heart

failure. Growth characteristics in children with

thalassemia major commonly show normal condition

in the first 10 years but growth retardation may occur

after 10 years (Al-salehe QAA et al., 2015; Fadlyana

E et al., 2017).

A total of 56 subjects who met the inclusion

criteria were involved in this study. The results

showed that 60.7% subjects were reported short

stature. The proportion of short stature in this study

was similar to the previous studies that found the

incidence of short stature,as in study that was

conducted on Iranian thalassemic patients the

incidence of short stature were 52.3% (Badfar G et

al., 2017),and other countries reported the prevalence

of short stature to be 30-60% (HamidahA et al., 2001;

Shlomit et al., 2005; Borgna-Pignatti C et al., 1985;

Gomber S, 2006). Butlower incidence was found in a

study by Shamshirsaz et al that reported the incidence

of short stature in thalassemic children was 39.3%

(Shamshirsaz AA et al., 2003).Difference in

prevalence of short stature in patients living in

various countries could be due to genetic

susceptibility to the toxic effects of iron overload in

endocrine gland and serum ferritin. It may also

indicate differences in quality of care, follow-up and

treatment, quality of blood transfusion, chelation

therapy type (regular or irregular) and beginning of

iron chelating therapy.

Normal growth in thalassemic children in the first

10 years depend on hemoglobin levels which are

maintained at above 10–11 g/dL. This condition can

be caused by hypoxia as a major growth disorder

factor (Al-(Wataify AS, 2014). In this study, most

subjects showed average hemoglobin levels before

transfusion was 5–7 g/dLthat foundin 78.6% subjects,

this study also reported that there was no association

between hemoglobin levels before transfusion and the

incidence of short stature (p>0.05). However, a study

that was conducted in Iraq revealed different results

that the hemoglobin levels before transfusion was <9

g/dLwas statistically increase the incidences of short

stature in thalassemic children (Wataify AS,

2014).Differences in results can be caused by a lack

of compliance to attend regular blood transfusion.

Low family income becomes a major factor that

affect the compliance.

Ferritin is an iron storage form in the body, which

releases the required iron when needed. All

thalassemic patients using iron chelator should be

monitored and evaluated regarding serum ferritin

levels (Nesheli HM et al., 2016).Moayeri et al

reported that short stature in thalassemic children was

found with serum ferritin levels more than 2000

ng/mL.It can be caused by not optimal and delayed

iron chelating treatment (Moayeri H et al.,

2006).Another study reported that short stature was

foundwith serum ferritin levels more than 3000

ng/mL (Shalitin S et al., 2005).While other study

reported that high serum ferritin levels in puberty may

cause growth retardation (Jahargidar R et al.,

2017).Causes of growth retardation that usually

becomes remarkable in puberty are chronic anemia-

Relationship between Short Stature and Serum Ferritin in Children with Beta Thalassemia Major

895

related chronic hypoxemia, increased calorie need

due to increased erythropoiesis, growth hormone

deficiency that may develop as a result of toxicity on

hypotalamo-hypophysial level caused by increased

iron load, hypothyroidism, inability to make the

growing spurt because of delayed puberty and

hypogonadism, and psychosocial factors (Yaman A

et al., 2013).

Unlike previous studies, in this study we did not

find significant association between serum ferritin

levels and short stature in our subjects.This can occur

due to a small sample size, measurement errors, or

chelating therapy type. Another possible reason to

explaining the lack of significant association between

serum ferritin levels and short stature is the possible

serum ferritin tolerance. In this study, serum ferritin

levels were measured at a given moment, and its

changes at different times were not determined.

However, short stature was seen in most our subjects

with the serum ferritin levels more than 2000 ng/mL.

Some factors considered as risk factors for having

complication in thalassemia patients were as follows:

Sex, age at diagnosis, age at start of transfusions, age

at start of chelation therapy, intensive and/or early

chelation with desferrioxamine, use of oral chelators,

chronic hepatitis C, and iron-related complications

(Origa R et al., 2016).This study reported a significant

association between age at diagnosis and short stature

(p<0.05), it showed us that the rate of complications

was increased in older patients. This phenomenon

may be a result of early hypothalamic/ pituitary

damage induced by iron overload, and/or by the toxic

effects of iron deposition in tissues. As reported by a

study conducted by Aydinok et al, although the risk

of developing short stature was lower among children

receiving the oral chelator, they reported decreased of

stature in adolescent receive iron chelators after age

10 years for 3 years, therefore, an eventual positive

effect of oral chelators on growth does not seem to be

sufficient when started after age 10 years (Aydinok Y

et al., 2012).Some of our subjects (30.4%) were

without therapy of iron chelator treatment and maybe

it may be caused by lack of parental or children

compliance to protocol treatments that have been

made to patients. Therefore, all thalassemia patients

should be adherence to all treatments such as

regularly transfusion and use iron chelation agents,

and avoidance of iron chelator overdosage clearly

reduced the risk for short stature and other

thalassemia complications.

CONCLUSION

The results of this study demonstrated that there was

nosignificant association between serum ferritin

levels and short stature, but this result showed

significant association between age at diagnosis and

short stature, it means that they are suffering from

growth disorder since the beginning of their life.

Therefore, new planning and policies seem to be

necessary to minimize the complications in patients

with beta thalassemia major. Some of the

recommended plans include improvement of blood

transfusion protocols, chelation therapy, informing

the parents and patients about the complications of

iron overload in the endocrine glands. We suggest

that all patients be examined at an early age in terms

of growth every six months.

ACKNOWLEDGMENTS

The authors gratefully acknowledge that the present

research is supported by Ministry of Research and

Technology and Higher Education Republic of

Indonesia. The support is under the research grant

TALENTA USU of year 2018, contract number

139/UN5.2.3.1/PPM/KP-TALENTA USU/2018.

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