M. A. F. EL-HAZMI ET AL.

Diabetes Mellitus in Children Suffering from

/?-Thalassaemia
by M. A. F. El-Hazmi,* A. Al-Swailem,** I. Al-Fawaz,*** A. S. Warsey,| and Abdulmohsen Al-Swailemtt
* Department of Medical Biochemistry, College of Medicine, King Saud University, Riyadh, Saudi Arabia
**Ministry of Health, Riyadh, Saudi Arabia
***Department of Paediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
^Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia
f t Maternity & Children Hospital, Riyadh, Saudi Arabia

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Summary
Insulin-dependent diabetes mellitus ( I D D M ) is a frequent complication in patients with (J-thalassaemia
major. It is believed to be a consequence of the damage inflicted by iron overload to the pancreatic P-cell.
Liver disorders and genetic influences seem to be additional predisposing factors to diabetes mellitus in
patients with p-thalassaemia. Ethnic variations are frequently reported on prevalence and complications
of diabetes mellitus in the (J-thalassaemia patients.
We investigated 50 Saudi children ( < 1 5 years) with P-thalassaemia major and 50 p-thalassaemia
minor, and age- and sex-matched controls for the prevalence of diabetes mellitus, and its relation to
hitherto claimed predisposing factors. Fasting blood glucose, plasma insulin level, liver function tests,
plasma ferritin, iron, and transferrin were assessed in each patient and glucose tolerance was evaluated.
Results in patients with p-thalassaemia major were compared with those obtained for P-thalassaemia
minor and the controls.
The results showed moderate elevation of ferritin level in the majority of the p-thalassaemia major
despite desferroxamine therapy. Either hyperinsulinaemia or hypoinsulinaemia was encountered in the
majority of these patients. The prevalence of diabetes mellitus was 6 per cent compared to 2 per cent in the
P-thalassaemia minor and normal children. Impaired glucose tolerance ( I G T ) occurred at a significantly
higher (24 per cent) frequency in the p-thalassaemia major compared to 2 and 0 per cent in the
P-thalassaemia minor patients and normal controls, respectively. The prevalence of diabetes mellitus was
significantly lower in the Saudi thalassaemic patients compared to the results obtained from patients of
other ethnic groups reported in literature. Liver function abnormalities were more frequent in this group
than in the p-thalassaemia minor and the controls. It appears from the inference of our results that
combinations of factors including iron overload and liver damage, predispose the p-thalassaemia major
patients to f5-cell damage and, hence, to impaired glucose tolerance.

Introduction transmitted by blood transfusion.1 Regular trans-

Beta-thalassaemia major patients frequently suffer
from several complications secondary to the anaemic
state, blood transfusion requirements, and iron over-
load (Fig. 1). Serious complications include develop-
ment of skeletal abnormalities due to marrow hyper-
plasia, endocrine, and other organ dysfunctions
resulting from iron overload and/or viral infections
Acknowledgement
This study was supported in part by King Abdulaziz City for
Science and Technology (KACST), and partly by King Saud
University.
Correspondence: Professor M. A. F. El-Hazmi, Department
of Medical Biochemistry (30), College of Medicine, King
Saud University, P.O. Box 2925, Riyadh 11461, Saudi
Arabia.
fusions, however, remain the treatment of choice to
maintain a high haemoglobin level, and to improve
clinical condition and survical rates of the patients.
Insulin-dependent diabetes mellitus (IDDM) is one
of the frequent complications reported in the
/?-thalassaemia major and is believed to be a con-
sequence of pancreatic and/or liver damage caused by
the iron overload.1""3 Ethnic variations affect the
frequency of diabetes mellitus among patients with
/J-thalassaemia major and suggest a role for environ-
mental and genetic factors in the aetiology of
IDDM.4-6
We investigated Saudi patients with /J-thalassaemia
major to determine the frequency of IDDM and
compared the results with those obtained in
/?-thalassaemia minor patients and normal controls.

Journal of Tropical Pediatrics Vol. 40 October 1994 ) Oxford University Press 1994 261
 M. A. F. EL-HAZM1 ET AL.

Complications in B-Thal Patients

6-Thalassaemia

Cardiomegaly

Increased Iron Chronic Anaemia

Absorption

Marrow
Hyperplasia
Iron Overload Increased Transfusion
Requirements
Skeletal
Defects
Endocrine Viral Infection

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Delects

Hyperinsulinaemia Chronic Liver

Disease

• Delayed Growth
• Delayed Puberty B Cell Damage fl Cell Exhaustion
• Hypothyroidism
• Hyperthyroidism
• Hypogonadism
Impaired Diabetes Mellitus
GTT

FIG 1. Flow chart of the possible mechanism leading to complications in /?-thalassaemia patients.

Materials and Methods
The study group included 50 /?-thalassaemia major
patients (male 28; female 22), 50 /?-thalassaemia minor
patients (male 28; female 22), and 50 normal children
(male 28; female 22). The />-thalassaemia patients were
regularly attending either the King Khalid University
Ferritin
1,400
B-Thal. major B-Thal.minor Control
FIG 2. Distribution of ferritin level in /Mhalassaemia
major and minor patients, and controls. The hori-
zontal line (—) indicates the mean value.
Hospital or the Central Hospital, Riyadh. The dia-
gnosis of the thalassaemic state was based on the
clinical symptoms, hypochromic-microcytic state,
reduced red cell indices, discriminant factors, Hb A2
level, and where possible determination of a//?-globin
chain ratio. 7 All patients and controls were subjected
to physical examination and fasting blood samples
were drawn in EDTA or heparin tubes. Fresh blood
was used to prepare slides for red cell morphological
studies and to determine the value of haematological
parameters and red cell indices using Coulter Counter
ZF6 with a haemoglobinometer attachment. The red
cells were separated from the plasma by centrifugation
and haemolysates were prepared from fresh red cells
by addition of cold distilled water. The haemolysate
was used to study the haemoglobin phenotypes using
electrophoresis at alkaline 8 and acids pH 9 , Hb A2 and
Hb F levels were estimated using the Helena Thai
Column and Helena Quiplates, respectively. The
plasma was used for the determination of glucose level
and liver function tests, using Autoanalyzer American
Monitor 'Parallel System', insulin, and ferritin using
radioimmune assay kits from Amersham and trans-
ferrin by radio immuno-diffusion (Behring).
The diagnosis of diabetes mellitus was based on the
recommendation of World Health Organization using
fasting and 2-h post-prandial blood glucose level.10
The results of the /?-tha!assaemia major and minor
patients, and controls were entered in the computer at

262 Journal of Tropical Pediatrics Vol.40 October 1994

M. A. F. EL-HAZMI ET AL.

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6-Thal.major B-Thal.minor ntrol 6-Thal.major 6-Thal.minor Control

Iron Transferrin (g/l)

FIG 3. Distribution of transferrin and iron levels in /i-thalassaemia major and minor patients and control. The
horizontal line (—) indicates the mean value.

King Saud University Computer Centre, and the mean
and standard deviations were calculated using the
Statistical Analysis System (SAS). The significance of
the difference in the mean of parameters in any two
groups was determined by applying the student t-test.
P value less then 0.05 was considered statistically
significant. The ferritin level was correlated with other
biochemical parameters using the General Linear
Model (GLM) Program.
Results
All patients with /i-thalassaemia major were on regular
(monthly) blood transfusion regimens while there were
no transfusion requirements in the /J-thalassaemia
minor patients and controls. The distribution of

B-Thal. major 6-Thal.minor Control

DM(%) 6 2 *
IGT%) 24 2 0

FBS (mmol/l) Hb A 1 c Insulin (U/ml)

I ADM(%) AIGT%) I
FIG 4. Levels of fasting blood glucose, insulin and
Hb A l c in /3-thalassaemia major and minor patients, FIG 5. Prevalence (per cent) of IDDM and IGT in
and controls. The horizontal line (—) indicates the /?-thalassaemia major and minor patients, and con-
mean value. trols.

Journal of Tropical Pediatrics Vol.40 October 1994 263

 M A . F EL-HAZM1 ET AL.

TABLE 1
Liver function tests in /J-thalassaemia patients
/J-Thal /?-Tha!
(major) (minor) Normal

T. Bil (itmol/l) 14.5±8.5 13.6+16.0 6.9 + 6.7

D. Bil (/iinol//) 2.2+1.7 2.5+1.6 0.6 + 0.9
Cholesterol (mmol//) 3.04+1.1 4.0± 1.1 3.9+1.1
Triglyceride (mmol//) 1.5±0.7 1.4 + 0.9 0.9 + 0.6
T. protein (g//) 66.6+15.8 70.3 + 9.6 66.3 + 11.6
Albumin (g//) 38.6 + 6.2 42.7 + 5.4 43.0 + 3.4
Alkaline phos (U//) 239.1 ±147.0 192.7 + 98.6 217.0+122
SGPT (U/0 107.4 + 89.8 29.5 ±31.0 19.6 + 29.8
SGOT (U//) 89.8 + 122.3 46.8 + 43.0 30.9 + 43.0
LDH (U//) 168.0 + 96.1 153.1+98.3 11.1 + 17.3

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14,

12

1o

6.

NORMAL LFT

LIVER DISEASE

B-TRAL B-THAL CONTROL B-THAL S-THAL CONTROI

MAJOR MINOR MAJOR MINOR
( 4— Mean value )
FIG 6. Distribution of SGOT and SGPT in
/?-thalassaemia major and minor patients and con-
trols.
ferritin, transferrin, and iron levels in these patients are
presented in Fig. 2 and 3, respectively. The ferritin and
transferrin level were significantly higher in the
/?-thalassaemia major patients compared to the
/Mhalassaemia minor patients and controls
The level of fasting glucose, insulin and Hb Alc. in
the two groups of /?-thalassaemia patients and the
controls are presented in Fig. 4. The insulin level was
significantly lower in the /?-thalassaemia major
patients compared to the controls and the
/J-thalassaemia minor. A wide range for insulin was
obtained in the latter group. The mean of Hb A lc and
3O
eo lie
FIG 7. Oral glucose tolerance results in /J-thalassaemia
major patients with normal and abnormal liver
function tests. A—A and O—O are the mean values
in patients with liver disease and normal liver func-
tions respectively. |—|indicates the upper range. Lower
range is not shown.
fasting glucose were significantly higher in the
/?-thalassaemia major patients. The prevalence of
impaired glucose tolerance (IGT) and diabetes melli-
tus, as judged from the elevated fasting blood glucose
level, elevated HbA l c and abnormal oral glucose
tolerance test are presented in Fig. 5. Three of the
/5-thalassaemia major children were suffering from
diabetes mellitus and required insulin for treatment.
There was no history of diabetes mellitus in their
families. The frequency of IDDM in /!-thalassaemia
major (6 per cent) was higher than in normal (2 per

264 Journal of Tropical Pediatrics Vol. 40 October 1994

M. A. F. EL-HAZM1 ET AL.
cent) children and in /?-thalassaemia minor (2 per cent)
patients. The IGT was encountered in 24 per cent
patients suffering from /J-thalassaemia major com-
pared to 2 per cent /?-thalassaemia minor patients and
none of the control group.
The values of liver function tests are presented in
Table 1. The major abnormalities were in the level of
transaminases and lactate dehydrogenase in the
/J-thalassaemia major patients. The distribution of
individual values of serum glutamate oxalo-acetate
transaminase (SGOT) and serum glutamate pyruvate
transaminase (SGPT) are shown in Fig. 6.
The /)-thalassaemia major patients with normal and
abnormal liver function tests were grouped separately
and glucose tolerance test was performed. Oral
glucose tolerance test in patients with normal and
abnormal liver function tests are presented in Fig. 7.
The ferritin level was correlated with blood glucose
level, but no correlation could be demonstrated.
Discussion
The development of IDDM is considered as a major
complication of the /Mhalassaemia major. The aetio-
pathogenesis are believed to involve iron overload,
perhaps through formation of iron radicals, thus
producing liver damage and endocrine
derangement. 111 In addition, viral infections of the
liver may give rise to hepatitis, cirrhosis and insulin
resistance.2 Familial predisposition to IDDM further
elevates the frequency and results in individual varia-
tions. The patients with /9-thalassaemia major and
family history of diabetes mellitus have a higher
chance of acquiring the disease, compared to those
jS-thalassaemia patients without the history of diabetes
mellitus.
In this study, diabetes mellitus was encountered in 6
and 2 per cent of the /J-thalassaemia major and minor
patients, respectively. Impaired glucose tolerance was
significantly higher in the /J-thalassaemia major com-
pared /?-thalassaemia minor patients and no impaired
glucose tolerance was encountered in the normal
children. A high percentage of the thalassaemia major
were found to have insulin deficiency. On the other
hand, elevated insulin levels were encountered in 4 per
cent of these patients. This is believed to be due to
insulin insensitivity produced by iron overload that is
compensated by increase in insulin secretion 11 that
consequently lead to exhaustion of the /?-cells and
finally to IDDM. 5
In Italy, a prevalence of IDDM of 6 per cent was
reported for the /?-thalassaemia major in one study 2
and a prevalence of 21 per cent in another study.
Impaired oral glucose tolerance was found in 38 per
cent of these patients. Before initiation of chelation
therapy, the overall prevalence of diabetes in the
patients over 11 years of age was 23 per cent. 12 " 14
Subsequent studies showed that iron chelation lead to
lower prevalence of IDDM.
Journal of Tropical Pediatrics Vol. 40 October 1994
A major finding in our patients was a high
prevalence of liver function test abnormalities. These
may have been acquired from blood transfusions, but
more likely from viral infection, due to high frequency
of the latter in Saudi Arabia.' 5 The liver abnormalities
and /?-cell destruction could account for both, the high
frequency of insulin deficiency in the /?-thalassaemia
and hence the impaired glucose tolerance, and the
development of the IDDM. It has been suggested that
as the management of /J-thalassaemia improves,
longer survival of the patients will be associated with
the complications of the disease, one being IDDM.
Furthermore, the complications associated with
IDDM such as neuropathy, nephropathy and oph-
thalmological defects may further add to the health
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problems of adult /?-thalassaemia patients.
In the light of the results of this study, we strongly
suggest surveillance and follow-up of patients with
/3-thalassaemia for liver and endocrine disorders in
order to detect and prevent or alleviate associated
complications.
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266 Journal of Tropical Pediatrics Vol.40 October 1994