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How to screen, evaluate and treat hypothyroidism
in homozygous β-thalassemia (β-thal) patients
Abstract
Hypothyroidism denotes deficient production of thyroid hormone by the thyroid gland and can be primary (abnormality in thyroid gland itself) or secon-
dary/central (as a result of hypothalamic or pituitary disease). The term "subclinical hypothyroidism" is used to define low grade primary thyroid gland
dysfunction with mild increase of thyroid-stimulating hormone (TSH) concentration in the presence of normal serum free thyroxine (FT4). The diagnosis
of hypothyroidism is primarily based on clinical symptoms and measurement of TSH and FT4 concentrations. In the general population, common causes
of primary hypothyroidism are autoimmune thyroiditis as well as the consequence of therapeutic interventions, mainly thyroid surgery or radioiodine
therapy. The pathophysiology of thyroid disorders in homozygous
β
-thalassemia (
β
-thal) patients is substantially different from that in healthy people.
Body and organ iron overload are responsible for over 90% of morbidity and mortality in this population. Endocrinopathies are often managed by the
caring physician. However, in more severe cases such as patients with insulin-dependent diabetes, adrenal insufficiency, disorders of gonadal hormones,
hyperthyroidism or hypothyroidism, endocrine consultation for evaluation and prompt therapy is needed. This report summarizes the recommendations
of the advisory members of the International Network on Endocrine Complications in Thalassemia and Adolescent Medicine (ICET-A) for the screening,
diagnosis and treatment of hypothyroidism in patients with
β
-thalassemias. It is expected that these recommendations will foster the diagnosis and mana-
gement of hypothyroidism in thalassemia communities and clinics for the benefit of the patients.
Key words: Thalassemia, hypothyroidism, screening, diagnosis, treatment, recommendations.
Vincenzo De Sanctis 1, Ashraf T. Soliman 2, Duran Canatan 3, Mohamed A. Yassin 4, Shahina Daar 5, Heba Elsedfy 6, Salvatore Di Maio 7,
Rania Elalaily 8, Giuseppe Millimaggi 9, Christos Kattamis 10
1Pediatric and Adolescent Outpatient Clinic, Quisisana Hospital, Ferrara, Italy;
2Departments of Pediatrics, University of Alexandria, Alexandria, Egypt;
3Director of Thalassemia Diagnosis Center of Mediterranean Blood Diseases Foundation, Antalya, Turkey;
4National Center for Cancer Care and Research, Medical Oncology Hematology Section HMC, Doha, Qatar;
5Department of Haematology, College of Medicine and Health Sciences, Sultan Qaboos University, Sultanate of Oman;
6Department of Pediatrics, Ain Shams University, Cairo, Egypt;
7Emeritus Director in Pediatrics, Children’s Hospital “Santobono-Pausilipon”, Naples, Italy;
8Department of Primary Health Care, Abu Nakhla Hospital, Doha, Qatar;
9Radiology Unit, Quisisana Hospital, Ferrara, Italy;
10 First Department of Paediatrics, National Kapodistrian University of Athens, Athens, Greece.
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Rivista Italiana di Medicina dell’Adolescenza - Volume 17, n. 1, 2019
104
Background
The routine management of patients with hae-
moglobinopathies, especially
β
-thalassaemias (
β
-
thal) and other transfusion-dependent chronic
anaemias involves the administration of frequent
blood transfusions.
This leads to gradual accumulation of iron in
various tissues and organs basically the heart,
liver and endocrine glands. Without effective iron
chelation therapy, patients die from complica-
tions of the heart, liver and endocrine glands (1).
Based on the needs of annual blood consump-
tion,
β
-thal is further characterized as Transfu-
sion Dependent Thalassemia (TDT) and Non-
Transfusion Dependent Thalassemia (NTDT).
Patients with TDT require regular, lifelong blood
transfusions for survival, starting from the first 2-
3 years of life [the “classic form” of homozygous
β
-thalassemia or “thalassemia major” (
β
-thal
major)] (1).
Hypothyroidism is a clinical disorder defined as
failure of the thyroid gland to produce enough
thyroid hormone to meet the metabolic demands
of the body. In community surveys on healthy
people, the prevalence of primary hypothyroidi-
sm varied from 0.1 to 2 % (2).
In
β
-thal major patients the reported prevalence
of primary hypothyroidism ranges from 4% to
35% or more, based on the level of serum TSH
and FT4/ thyroxine (T4).
The wide variation has been attributed to several
factors, such as patients’ genotype, age, ethnic
variations, efficiency of protocols for transfusions
and chelation, and compliance to treatment (3-6).
There is no significant difference of prevalence in
males versus females.
Thyroid failure develops, more frequently, after
the second decade of life (7). However, it may
occur earlier in developing countries, due to
higher iron overloading (8-12).
Since no expert consensus or guidance for scree-
ning, diagnosis and management of hypothyroi-
dism in TDT patients is available, a group of the
International Network on Endocrine Complica-
tions in Thalassemia and Adolescent Medicine
(ICET-A) experts prepared this document based
on the principles of clinical evidence.
The essential recommendations for appropriate
and tailored management of hypothyroidism for
clinicians treating
β
-thal major patients with
hypothyroidism are also proposed.
Evaluation System and Gra-
ding for Recommendations
The recommendations are graded according to
the ACP (American College of Physician) system
for evidence and recommendations (13). Using
this system, the strength of each clinical recom-
mendation is graded as: Strong, Weak, or No for
Insufficient Evidence and for the quality of evi-
dence as Strong, Moderate, Low, or Insufficient.
When to screen?
Screening can be defined as the application of a
test to detect a potential disease or condition in a
person who is asymptomatic at the time of
testing (14). To be effective, the benefit from a
screening programme must outweigh the harm,
both physical and psychological, caused by the
test, diagnostic procedures and treatment.
The following individuals are at high-risk for
development of hypothyroidism as reported by
several professional societies and expert panels,
and are recommended for targeted screening:
subjects with a history of thyroid disease, thyroid
surgery or radiation to the neck, a family history
of thyroid disease, patients with goiter, or high
antithyroid peroxidase antibodies (TPOAb),
and/or antithyroglobulin antibodies (TgAb).
In addition, pregnant women or women wishing
to have children with assisted reproductive tech-
nologies, women over the age of 60, those with
type 1 diabetes mellitus, or presence or history
of autoimmune disease, hyperprolactinemia,
dyslipidemia, or taking drugs affecting thyroid
function such as amiodarone. Interested readers
can further refer to recent comprehensive
reviews and statements on the detection and
treatment of thyroid dysfunctions in children
and adults (15-23).
Recommendation 1
Hypothyroidism in
β
-thal major patients may
develop gradually, and the subtle and non-speci-
fic symptoms and signs of the disease may be
attributed to other illnesses. Proper screening can
lead to early diagnosis of thyroid disorders. The-
refore, we recommend checking thyroid function
annually (or more frequently, if indicated), star-
ting from the second decade of life and earlier in
non-chelated iron overloaded patients. Any
further medical decision must be personalized.
Strong recommendation. Moderate quality
evidence.
105
V. De Sanctis, AT. Soliman, D. Canatan, MA Yassin, S. Daar, H. Elsedfy, S. Di Maio, R. Elalaily, G. Millimaggi, C. Kattamis
How to screen, evaluate and treat hypothyroidism in homozygous β-thalassemia (β-thal) patients
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The combination of low FT4 and inappropriately
low TSH should be confirmed on two separate
determinations although some patients with CH
have slightly high TSH levels (7, 16, 33-35).
Several mechanisms have been suggested to
explain the differences and paradoxical values of
TSH: hypoadrenalism raising TSH, decreased
secretion of somatostatin from hypothalamus
leading to increased secretion of TSH and redu-
ced biological and receptor binding activity of
TSH. CH patients with predominant hypothala-
mic defect have high serum immunoreactive
TSH levels that are devoid of full biological acti-
vity. In these cases, TSH elevations are similar to
those generally found in subclinical or mild pri-
mary hypothyroidism and may lead to misdia-
gnosis (16).
The prevalence of CH is particularly high in young
adults with
β
-thal major patients (7, 34, 35).
Recommendation 3
TSH is useful in the identification of overt pri-
mary hypothyroidism (TSH >10 mIU/L, FT4
below normal range) and for distinguishing
between primary versus CH (TSH levels are low,
normal and sometime slightly elevated). Speciali-
st endocrine consultation is also recommended.
Patients with TSH levels between 4.5 and 10
mIU/L and normal serum free T4 levels (subcli-
nical hypothyroidism) should be carefully eva-
luated and monitored.
Strong recommendation. Strong quality evi-
dence.
Recommendation 4
During the last 2 decades advances in our under-
standing of thyroid physiology in pregnancy have
led to the appreciation of the adverse effects of
SH on both the mother and child. Trimester-spe-
cific reference ranges for TSH and T4 (total or
free) should be established in each antenatal
hospital setting (23). If TSH trimester-specific
laboratory reference ranges are not available, the
following reference range upper limits are recom-
mended: first trimester, 2.5 mIU/L; second trime-
ster, 3.0 mIU/L; third trimester, 3.5 mIU/L (23).
Specialist advice is also recommended.
Strong recommendation. Moderate quality
evidence.
Recommendation 5
An initial raised serum TSH with FT4 within the
reference range should be reinvestigated after a
Recommendation 2
Screening for thyroid disorders during pre-
gnancy has been a long-disputed issue. Universal
screening and targeted high-risk case-finding
have their own advantages and disadvantages.
Nevertheless, as thyroid dysfunction may be
unmasked during pregnancy it is prudent to
recommend that all
β
-thal major women patients
be screened for thyroid function before pre-
gnancy and be followed up closely, according to
published guidelines (17, 18, 20, 21).
Strong recommendation. Moderate quality
evidence.
How to diagnose hypothyroidism?
Primary hypothyroidism is confirmed by an
increase in the serum thyrotropin TSH concen-
tration above the upper limit of the laboratory’s
reference range in the presence of low FT4 (5-7).
The normal range of TSH levels, at early morning
assessment in thyroid disease-free individuals,
has been traditionally accepted as 0.45-4.5 mIU/L
(24), with a median value of 1.4 mIU/L (25).
This corresponds to the 2.5th to ~ 97.5th per-
centile of TSH distribution curve in most popu-
lations (20, 21). Third-generation TSH immuno-
metric assays have very high sensitivity and spe-
cificity (26-28).
Patients with primary hypothyroidism have a
TSH level >10 mIU/L coupled with a reduction in
the serum FT4 or total T4 concentration below
the reference range (16-19). Subclinical hypothy-
roidism (SH) is a combination of high TSH with
normal FT4 level.
Two types of SH have been reported in
β
-thal
major patients: Type A (normal FT4, TSH 5-10
mIU/ml) and Type B (normal FT4, basal TSH >
10 mIU/ml) (29).
In general, both healthy individuals and those
with SH have a circadian fluctuation in serum
TSH concentration, with a nadir in the early
afternoon and approximately 30% higher con-
centrations during the hours of darkness (around
2.00 am) (30, 31).
Sub-biochemical primary hypothyroidism, con-
sists of an enhanced TSH response to thyrotropin
releasing hormone (TRH) test in the presence of
normal TSH and FT4 (32).
Central hypothyroidism (CH) is thyroid hypo-
function caused by insufficient stimulation by TSH
of an otherwise normal thyroid gland. The diagno-
sis of CH is generally made biochemically by the
combined determination of serum TSH and FT4.
106
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Rivista Italiana di Medicina dell’Adolescenza - Volume 17, n. 1, 2019
3-4 month interval. Repeat TSH testing is impor-
tant to differentiate between SH, transient increa-
se of TSH, or a biochemical error.
Moderate recommendation. Moderate quality
evidence.
Recommendation 6
Thyroid tests may be compromised in the pre-
sence of more severe non-thyroidal comorbidity
such as infection (pneumonia, sepsis), trauma,
malignancy, heart failure, myocardial infarction,
and diabetic ketoacidosis. Repeating blood tests
when the patient has recovered is strictly recom-
mended.
Strong recommendation. Strong quality evi-
dence.
Clinical manifestations and
other diagnostic parameters
The severity of clinical manifestations generally
reflects the degree of thyroid dysfunction and the
time course of development of hypothyroidism.
The clinical presentation of patients with SH may
be subtle, without any symptoms, and may be
detected simply during routine screening of thy-
roid function.
β
-thal patients with primary
hypothyroidism may present with short stature,
delayed puberty, fatigue, cold intolerance, wei-
ght gain, and dry skin (36). In
β
-thal patients
with severe primary hypothyroidism, cardiac fai-
lure and pericardial effusion have been reported
(36). The clinical manifestations of CH are usual-
ly milder than those observed in primary
hypothyroidism.
Recommendation 7
Measurement of serum thyroid autoantibodies
are not strictly necessary for routine testing in
subjects with
β
-thal major (37, 38). Any further
medical decision must be made considering
patient circumstances.
Moderate recommendation. Moderate quality
evidence.
Recommendation 8
Thyroid ultrasound should be considered as an
additional parameter for the diagnosis of thyroid
disorders. Reduced echogenicity, diffuse spotty
echogenicity, dyshomogeneity of the thyroid
parenchyma and nodules in young adult patients
have been reported (39-43).
Strong recommendation. Moderate quality
evidence.
What are the risk factors for the
development of hypothyroidism in
homozygous
β
-thal?
The pathophysiology of thyroid disorders in
patients with
β
-thal is substantially different
from that in the general population.
In
β
-thal patients, thyroid dysfunction appears to
be primarily due to toxicity of the excess
unbound iron within cells or in plasma, genera-
ting reactive oxygen species, leading to lipid
peroxidation and generation of both unsaturated
(malondialdehyde and hydroxynonenal) and
saturated (hexanal) aldehydes. Both have been
implicated in producing cellular dysfunction,
cytotoxicity and cell death (44-46). Apart from
iron overload, other factors responsible for organ
damage have been recognized, including chronic
hypoxia due to anaemia (47) that may potentiate
the toxicity of iron deposition in endocrine
glands.
Recommendation 9
The easiest and cheapest methods available for
assessment of body iron levels are biochemical
measurements of serum ferritin (SF) trend and
transferrin saturation. In the absence of confoun-
ding factors, such as inflammation, vitamin C
deficiency, oxidative stress, hepatocyte dysfunc-
tion, and increased cell death, SF levels correlate
with the size of cellular iron stores (48-50).
Strong recommendation. Strong quality evi-
dence.
Recommendation 10
Several magnetic resonance imaging (MRI) tech-
niques have been developed for the assessment of
liver iron concentration (LIC), each with advanta-
ges and limitations. However, the assessment of
LIC by MRI may guide clinicians for further dia-
gnostic and therapeutic workup (51, 52).
Strong recommendation. Moderate quality
evidence.
How to treat and monitor
hypothyroidism?
All patients with primary hypothyroidism with
TSH >10 mIU/L should be treated. The synthetic
thyroid hormone levothyroxine (L-T4) is a cost-
effective treatment of hypothyroidism, with few
side effects. On average, approximately 70%-
107
V. De Sanctis, AT. Soliman, D. Canatan, MA Yassin, S. Daar, H. Elsedfy, S. Di Maio, R. Elalaily, G. Millimaggi, C. Kattamis
How to screen, evaluate and treat hypothyroidism in homozygous β-thalassemia (β-thal) patients
Endo-Thal
80% of the available tablet dose is absorbed by
the euthyroid individual. The absorption rate
may diminish in the hypothyroid patient.
Absorption is maximal when the stomach is
empty, reflecting the importance of gastric aci-
dity in the process (53, 54).
The recommended daily dose of L-T4 is 1.6– 1.7
μg/kg body weight for most patients and should
be taken on an empty stomach, in the morning,
30–60 min prior to breakfast (18-22). Patients
who have difficulty with morning levothyroxine
dosing may find bedtime dosing an effective
alternative (55, 56). Serum T4 concentrations
peak 2 to 4 hours after an oral dose and remain
above normal for approximately 6 hours in
patients receiving daily replacement therapy.
The long half-life of thyroxine of about 7 days
allows treatment with a single daily tablet (53).
A minimum gap of 4 hours should be maintained
between administration of thyroxine and drugs
that are known to interfere with its absorption
(53, 54).
Considering half-life and distribution of L-T4,
and the pituitary loop, L-T4 therapy should be
monitored by measuring TSH and FT4 levels,
6 to 8 weeks after each dose modification.
Dosage should be adjusted based on clinical
response and laboratory parameters.
In primary hypothyroidism, treatment is monito-
red with serum TSH, which should be maintai-
ned in the upper half of the normal range.
In patients with central hypothyroidism, treat-
ment is tailored according to free or total T4 levels,
which should be maintained in the upper half of
the normal range (57). Further dose adjustment
should be guided individually by relief of symp-
toms and tolerance of the medication dosage.
After euthyroidism is achieved, follow-up interval
can be increased to 6 months and then annually.
Lifelong monitoring is required to check com-
pliance and to take account of variations in dosa-
ge requirements (16, 18-22).
Poor adherence to L-T4 therapy is the most com-
mon cause of persistently elevated TSH levels in
patients on adequate doses of thyroid hormone.
However, food intake can interfere with L-T4
absorption, with studies showing that fiber sup-
plements, soy protein, coffee and grape fruit can
reduce L-T4 absorption (18-22). Also, some
drugs co-administered with L-T4 interfere with
its absorption, such as calcium carbonate (18,
19, 21). Furthermore, gastrointestinal disorders
(inflammatory bowel disease, celiac disease, lac-
tose intolerance, atrophic gastritis, and Helico-
bacter pylori infection) interfere with L-T4
absorption (18-22, 57). Therefore, the coexisten-
ce of other diseases, which can interfere with L-
T4 absorption should be suspected whenever
high L-T4 doses (> 2 μg/kg of body weight) do
not achieve biochemical control in adherent
patients. Physicians must make the appropriate
adjustments in L-T4 dosage in the face of absorp-
tion variability and drug interactions.
Current guidelines do not recommend routine
thyroid hormone substitution in subjects with
normal FT4 levels and a TSH between 4.5 and 10
mIU/L (58). However, the term SH implies that
patients should be asymptomatic, although
symptoms are difficult to assess, especially in
patients with chronic disease such as
β
-thal. Spe-
cial attention must be paid in patients presenting
clinical features or laboratory findings of reduced
growth velocity, short stature, delayed puberty,
cardiac failure, arrhythmias, or iron overload.
Reversal of SH has been observed in iron over-
loaded
β
-thal major patients after intensive iron
chelation therapy (59-63).
Recommendation 11
L-T4 monotherapy remains the treatment of
choice due to its long half-life and the conve-
nience of a single daily dose, and the assumption
that L-T4 is largely converted to T3 as needed.
It is recommended that the same formulation is
used throughout therapy, to avoid variations in
clinical effectiveness.
Strong recommendation. Moderate quality
evidence.
Recommendation 12
Although there are preliminary studies sugge-
sting that L-T4 dissolved in glycerine and sup-
plied in gelatine capsules may be better absorbed
than standard L-T4 in selected circumstances,
such as concomitant use of proton pump inhibi-
tors, further long-term studies are needed to con-
firm these preliminary observations. Switch to a
gel capsule might be considered in the rare case
of putative allergies to excipients.
Moderate recommendation. Moderate quality
evidence.
Recommendation 13
A trial of thyroid hormone substitution, for seve-
ral months, may be considered in
β
-thal major
patients with SH, taking into consideration a
108
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Rivista Italiana di Medicina dell’Adolescenza - Volume 17, n. 1, 2019
combination of age, patient’s personal history,
complaints, and presence of risk factors.
Weak recommendation. Moderate quality evi-
dence.
Recommendation 14
The American Thyroid Association (ATA) and
the European Thyroid Association guideline Com-
mittees have endeavoured to clarify how to mana-
ge thyroid disorders during pregnancy.
Strong recommendation. Strong quality evi-
dence.
Recommendation 15
Close monitoring of TSH is recommended in
hypothyroid
β
-thal major patients with osteopo-
rosis, as over-dose of L-T4 may negatively affects
bone metabolism and therefore the rate of the
current bone formation or loss.
Strong recommendation. Moderate quality
evidence.
Recommendation 16
In the rare event when there is co-existence of
hypocortisolism with hypothyroidism it is
important to defer any thyroid hormone replace-
ment until prior adequate correction of hypocor-
tisolism.
Strong recommendation. Strong quality evi-
dence.
Conclusions
Hypothyroidism denotes deficient production of
thyroid hormone by the thyroid gland and can
be primary (abnormality in thyroid gland itself)
or secondary/central (as a result of hypothalamic
or pituitary dysfunction). The diagnosis of
hypothyroidism in homozygous
β
-thalassemia
patients is primarily based on measurement of
serum TSH and FT4 concentrations. In the gene-
ral healthy population, common causes of pri-
mary hypothyroidism are autoimmune thyroidi-
tis and therapeutic interventions, such as thyroid
surgery or radioiodine therapy. However, the
etiology in homozygous
β
-thal patients is sub-
stantially different from that in the general popu-
lation. This paper summarizes the recommenda-
tions of the Advisory Members of ICET-A for the
screening, diagnosis and treatment of hypothy-
roidism in patients with
β
-thal. We hope that
these recommendations will foster the diagnosis
and management of hypothyroidism in thalasse-
mia community and clinics for the benefit of the
patients.
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Endo-Thal
Rivista Italiana di Medicina dell’Adolescenza - Volume 17, n. 1, 2019
Correspondence:
Vincenzo De Sanctis, MD
Pediatric and Adolescent Outpatient Clinic
Accredited Quisisana Hospital
44121 Ferrara (Italy)
E-mail: vdesanctis@libero.it
