Correspondent: Trinita Diyah Permatasari
Email: [email protected] �
INTRODUCTION
Beta
thalassemia major is caused by a homozygous mutation (beta-zero thalassemia) of
the beta-globin gene, resulting in the total absence of beta chains. It
manifests clinically as jaundice, growth retardation, hepatosplenomegaly,
endocrine abnormalities, and severe anemia requiring life-long blood
transfusions. The condition in between these two types is called
beta-thalassemia intermedia with mild to moderate clinical symptoms (Bajwa and
Basit, 2022). The
infant with β-thalasemia major usually can be seen within the first year
of life and early childhood with pallor, failure to thrive, variable degree of
jaundice, looks weakness and fatigue, recurrent infection, abdominal
enlargement due hepatosplenomegaly and slow growth during puberty (Hamizah, et
al., 2017).
The prevalence of thalassemia
carriers in Indonesia reaches 3-8%, which means that 3-8 out of 100 people are
thalassemia carriers (Indonesia, 2012). The number of cases of
thalassemia major in Indonesia has increased from 2012 to 2018. In 2012 there
were 4,896 cases of thalassemia, and in 2018 there were 8,761 cases (Indonesia, 2012).
Patients with β thalassemia major require
regular blood transfusions throughout their lives to maintain haemoglobin
levels above 9-10.5 g/dL to suppress ineffective erythropoiesis activity in the
bone marrow and prevent growth disorders (Ouadghiri et al., 2023). However, repeated blood
transfusions can result in iron overload due to the continuous accumulation of
iron, while the body's ability to excrete iron is limited (Ganz & Nemeth, 2023). In addition, the excess iron
experienced by patients with beta-thalassemia major is also caused by increased
iron absorption in the gastrointestinal tract due to ineffective
erythropoiesis. (Basu et al., 2021) . Excess iron accumulation is
toxic to tissues and can cause heart failure, cirrhosis, growth disorders, and
endocrine disorders (Pietrangelo & Torbenson, 2024). Therefore, in addition to repeated
transfusion therapy, patients with β thalassemia major also require iron
chelation therapy to reduce excess iron. This therapy is carried out by
excreting iron through urine or faeces using chelating agents (Cappellini
et al., 2014).
Ferritin is considered the major iron
storage protein which maintains a large iron core in its cavity and has
ferroxidase activity (Arosio
et al., 2017) ). Serum ferritin examination
is one of the tests that is often performed to measure the number of iron
stores in thalassemia patients undergoing transfusion therapy. Beta thalassemia major patients should
maintain their serum ferritin levels below 1500 ng/ml to minimize the possible
complication of iron overload (Karunaratna et al., 2017).
Iron chelation therapy's challenge is
achieving adherence to a lifelong treatment regimen (Chat
Chai et al., 2021). Poor adherence to treatment
can increase disease conditions or even death. The level of adherence to
long-term therapy in chronic diseases in developed countries is around 50%,
while in developing countries, it can be worse. Usage
of Deferiprone or Deferasirox as oral chelator is more preferable due to its
ease of use, with several studies presenting higher compliance rate in patient
with oral chelator compared to injection chelator (Wahidiyat et al., 2018).
In Indonesia, few studies have
examined the relationship between the level of adherence to iron chelation and
serum ferritin levels in patients with thalassemia beta major. This study aimed
to determine the relationship between the level of adherence to iron chelation
and serum ferritin levels in patients with thalassemia beta major at Kediri
District General Hospital.
METHODS
This type of research is observational analytic with a cross-sectional
design. The research was conducted at the SMF Pediatrics (IKA) Regional General
Hospital (RSUD) Kediri Regency in December 2022-January 2023. The
population in this study were all patients aged 1-18 years who were diagnosed
with β thalassemia major at SMF IKA RSUD Kediri Regency. The study sample
was 17 thalassemia major thalassemia patients. The sample was taken using a
purposive sampling method based on inclusion criteria, namely pediatric
patients aged 1- 18 years old who had self-examination and was diagnosed with
β-thalassemia major, had blood transfusions ≥ 10 times at SMF IKA
RSUD Kediri Regency, and their parents gave their consent to participate in the
study and the exclusion criteria were patients with fever characterized by an
increase in temperature ≥ 380 C, acute infection, chronic inflammation,
splenectomy, and malignancy based on medical records and physical examination.
This study has received Ethical Clearance from the Research Ethics Committee of
Kediri District Hospital.
The data collection instrument in this study used the Medication
Adherence Scale-8 (MMAS-8) questionnaire. MMAS-8. The level of adherence is
divided into 2, namely the adherent category if the total score of the MMAS-8
questionnaire is equal to 6-<8 (a combination of moderate and high degrees)
and the category of non-adherence if the total score of the MMAS-8
questionnaire is less than 6. Meanwhile, data on the patient's serum ferritin
level is taken from secondary data derived from medical records. Data analysis to
determine the correlation between the two variables using the Spearman
correlation test with a significance value of p <0.05. The statistical processing computer
program Statistical Package for Social Science (SPSS) 26.0 is used.
RESULTS AND DISCUSSION
There were 17 samples of beta thalassemia major patients who met the inclusion and
exclusion criteria. The general characteristics of β thalassemia major
patients at Kediri District Hospital are shown in Table 1.
Table 1. General Characteristics of Beta
Thalassemia,
Major Patients at Kediri District Hospital
|
Sample Characteristics
|
Amount (n)
|
Percentage (%)
|
|
Gender
|
|
|
|
Man
|
7
|
41.18%
|
|
Woman
|
10
|
58.82%
|
|
Age
|
|
|
|
<5 years
|
2
|
11.77%
|
|
5 - <10 years
|
4
|
23.54%
|
|
10 - < 15 years
|
3
|
17.64%
|
|
15 - <18 years
|
8
|
47.05%
|
|
TB/U
|
|
|
|
Normal
|
7
|
29.41%
|
|
Short
|
10
|
70.59%
|
|
Abdomen Examination
|
|
|
|
Splenomegaly
|
5
|
41.18%
|
|
Hepatosplenomegaly
|
12
|
58.82%
|
|
Classification Therapy
|
|
|
|
Deferiprone
|
10
|
58.82%
|
|
Deferasirox
|
7
|
41.18%
|
Based
on the study's results, the adherence level and serum ferritin level are shown
in Table 2. The results of the Spearman correlation test between the adherence
level of iron chelation treatment and ferritin levels are shown in Table 3.
Table 2. Values
of ferritin levels and MDA levels
|
Sample Characteristics
|
Amount (n)
|
Percentage (%)
|
|
Compliance Level
|
|
|
|
Obey
|
2
|
11.76
|
|
Not obey
|
15
|
88.24%
|
|
Ferritin Levels
|
|
|
|
< 1000ng/mL
|
2
|
11.76%
|
|
1000-2000ng/mL
|
2
|
11.76%
|
|
>2000ng/mL
|
13
|
76.48%
|
The level of adherence to iron chelation treatment
and serum ferritin levels had a p-value of 0.01 <α 0.05 and an r-value
of -0.559, so it can be concluded that the level of adherence to iron chelation
treatment and serum ferritin levels had a significant and moderate correlation.
Table 3. Results of the Spearman Correlation Test
on Adherence and ferritin levels
|
Compliance Level
|
Serum
Ferritin Levels
|
|
R -0.559
|
|
p.s. 0.01
|
|
n 17
|
Characteristics of the sample
based on the data obtained showed that the number of female samples was more
than male. Namely, ten samples (66.7%) were female, and seven (33.3%) were
male. According to Mendel's law, thalassemia is passed from parent to child in
an autosomal recessive manner. The pattern of autosomal recessive inheritance
is a horizontal line so that
there are many sufferers in one generation, but not for every generation. At conception, each sib of an affected individual has a 25%
chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a
carrier. Heterozygotes (i.e., carriers) may be slightly anemic but
are clinically asymptomatic (Origa, 2021). The characteristics of the sample based on age obtained the highest
number of samples aged 15-<18 years with eight samples (47.05%). Patients
with β thalassemia major usually appear normal at birth. Symptoms will be
found in children aged 2 to 6 years (Cappellini et al., 2014).
The characteristics of the sample according to
height per age were ten samples (58.82%) with short height and seven samples
(41.18%) of normal height. The anterior pituitary gland is very sensitive to
iron accumulation, so it interferes with the secretion of hormones. If there is
an accumulation of iron in the anterior pituitary, it will interfere with the
synthesis and secretion of Growth Hormone (GH) so that the growth of people
with thalassemia can be disrupted (Joshi & Phatarpekar, 2013). In addition, iron buildup can interfere with
osteoid maturation and precipitate into hydroxyapatite crystals, disrupting
normal bone metabolism (Moiz et al., 2018).
Characteristics of the samples according to
abdominal examination found β thalassemia major patients with splenomegaly
without hepatomegaly in 5 samples (29.41%) and hepatosplenomegaly in 12 samples
(70.59%). Splenomegaly occurs due to extramedullary erythropoiesis (Andriastuti et al., 2016). Severe anaemia in patients with β thalassemia
major causes the kidneys to release erythropoietin. This hormone stimulates the
bone marrow to produce more red blood cells resulting in ineffective
erythropoiesis. Increased erythropoiesis results in bone marrow hyperplasia and
expansion, resulting in bone deformities. Erythropoietin also stimulates
extramedullary hematopoietic tissue in the liver and spleen, causing
hepatosplenomegaly. Based on the data obtained, ten samples (58.82%) received
Deferiprone iron chelation therapy. Moreover, seven samples (41.18%) received
Deferasirox therapy. Deferiprone is superior in controlling or reducing myocardial
iron load (as proven by T2* MRI) (Wahidiyat et al., 2019). Deferasirox is effective in improving myocardial and hepatic siderosis.(Ansari et al., 2017). Iron chelation therapy is urgently needed in
patients with β thalassemia major with repeated blood transfusions (Permono et al., 2012). Iron chelation should be started when ferritin
levels rise above 1000 ng/mL or the patient has received 10-20 units of PRC (Prabhu et al., 2009).
From the results of this study, 15 samples
(88.24%) were non-adherent in consuming iron chelation, and two samples
(11.76%) were obedient. The sample's adherence level was assessed from the
Medication Adherence Scale-8 (MMAS-8) questionnaire. So it can be said that the
level of adherence to consumption of iron chelation in patients with β
thalassemia major at RSUD dr. Kediri district is low. Many factors influence
the level of treatment adherence. There are several barriers to adherence to
therapy, namely poor communication between patients and drug providers,
insufficient knowledge about the drug and how to use it, feeling unsure of the
importance of treatment, and fear of side effects of the drug. To improve
medication adherence, better communication and better information on the
disease and its medication appeared to be the crucial concepts for patients (Kvarnstr�m et al., 2021).
From the results of this study, the lowest
ferritin level was 725.2 ng/mL, and the highest ferritin level was 2986.7
ng/mL. Research subjects who had ferritin levels <1000 ng/mL in 2 samples
(11.76%), 1000-1000 ng/ml in 2 samples (11.76%) and > 2000 ng/mL in 13
samples (76.48%) ). Normal ferritin values range from 20�400 ng/mL (CDC, 2020). The
ferritin levels of the study subjects were far above the normal range. Iron
overload is called iron overload if the ferritin level is more than the normal
value [20]. So the research subject has excess iron. Repeated blood
transfusions, ineffective erythropoiesis, and increased iron absorption through
digestion cause iron overload in patients with β thalassemia major. In
contrast, the body's ability to excrete iron is limited (Cappellini et al., 2014).
Therapy obtained by patients with β
thalassemia major apart from routine blood transfusions is chelation therapy to
excrete iron and administration of vitamin C and vitamin E, which are used as
antioxidants. Optimal administration of iron chelation can reduce iron deposits
in patients with thalassemia (Safitri et al., 2015). However, the lack of adherence to taking the iron
chelating drugs given can be a factor that causes this therapy not to be
optimal. When repeated blood transfusions are carried out without taking
regular iron chelation therapy, it can cause a significant increase in ferritin
levels (Satria et al., 2016). This is consistent with previous research, which
stated that the non-adherent group in iron chelation treatment had ferritin
levels ≥ 1000 ng/ml (Chat Chai et al., 2021). High serum ferritin levels were associated with
higher liver and cardiac iron load and the patients with� irregular use of iron
chelating agents were more likely to have higher cardiac iron load (Sobhani et al., 2019).
The results of data analysis using the Spearman
correlation test on the level of adherence to iron chelation treatment with
serum ferritin levels in patients with thalassemia beta major at Kediri
District General Hospital obtained a p-value of 0.01 and an r-value of -0.559.
This shows that there is a significant correlation between the level of
adherence to iron chelation treatment and serum ferritin levels in patients
with thalassemia beta major and has a moderate
correlation. This is consistent with
previous research, which states that the higher the adherence to iron chelation
treatment, the lower the serum ferritin level. Low adherence in chronic
diseases is influenced by lack of knowledge about the causative disease, lack of
awareness of the reasons for treatment, anxiety about taking drugs in the long
term, fear of side effects of treatment, regimen and type of drug given, age,
and the poor doctor-patient relationship (Triwardhani et al., 2022).
CONCLUSION
Based on the
results of the conducted research, it can be concluded that there is a
significant relationship between the level of compliance with iron chelation
therapy and serum ferritin levels with a p-value of 0.01 and a moderate correlation (r=-0.559) in patients with
beta-thalassemia major at Kediri Regional General Hospital.
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Received: 20-04-2023 �������������������� ������������� Accepted: 24-05-2023 �������������������� ������������� Published: 10-06-2023����� 