2. • Thyroid follicular epithelial cells convert thyroglobulin into thyroxine (T4) and
lesser amounts of triiodothyronine (T3).
• T4 and T3 are released into the systemic circulation, where most of these peptides
are reversibly bound to circulating plasma proteins, such as thyroxine-binding
globulin and transthyretin.
• The binding proteins act as a buffer that maintains the serum unbound (“free”) T3
and T4 concentrations within narrow limits, while ensuring that the hormones are
readily available to the tissues.
• In the periphery, the majority of free T4 is deiodinated to T3; the latter binds to
thyroid hormone nuclear receptors in target cells with tenfold greater affinity than
does T4 and has proportionately greater activity. Binding of thyroid hormone to its
nuclear thyroid hormone receptor (TR) results in the assembly of a multiprotein
hormone-receptor complex on thyroid hormone response elements (TREs) in
target genes, up regulating their transcription.
3. • Thyroid hormone has diverse cellular effects, including the stimulation of carbohydrate and lipid
catabolism and protein synthesis in a wide range of cells. The net result is an increase in the basal
metabolic rate. In addition, thyroid hormone has a critical role in brain development in the fetus and
neonate.
• The function of the thyroid gland can be inhibited by a variety of chemical agents, collectively
referred to as goitrogens.
• Because they suppress T3 and T4 synthesis, the level of TSH increases, and subsequent
hyperplastic enlargement of the gland (goiter) follows.
• The antithyroid agent propylthiouracil inhibits the oxidation of iodide and thus blocks the production
of thyroid hormones; parenthetically, propylthiouracil also inhibits the peripheral deiodination of
circulating T4 into T3, thus ameliorating symptoms of thyroid hormone excess. Iodide, when given in
large doses to individuals with thyroid hyperfunction, also blocks the release of thyroid hormones by
inhibiting the proteolysis of thyroglobulin. Thus, thyroid hormone is synthesized and incorporated
into colloid, but it is not released into the blood.
4. • The thyroid gland follicles also contain a population of
parafollicular cells, or C cells, which synthesize and secrete the
hormone calcitonin. This hormone promotes the absorption of
calcium by the skeletal system and inhibits the resorption of
bone by osteoclasts.
• Diseases of the thyroid include conditions associated with
excessive release of thyroid hormones (hyperthyroidism),
thyroid hormone deficiency (hypothyroidism), and mass lesions
of the thyroid. We will first consider the clinical consequences of
disturbed thyroid function, and then turn to the disorders that
generate these problems.
5. Hyperthyroidism
• Thyrotoxicosis is a hypermetabolic state caused by elevated circulating levels of free T3 and
T4. Because it is caused most commonly by hyperfunction of the thyroid gland, it is often referred to
as hyperthyroidism. However, in certain conditions the oversupply is related to either excessive
release of preformed thyroid hormone (e.g., in thyroiditis) or to an extrathyroidal source, rather than
hyperfunction of the gland.
• Thus, strictly speaking, hyperthyroidism is only one (albeit the most common) cause of
thyrotoxicosis. The terms primary and secondary hyperthyroidism are sometimes used to designate
hyperthyroidism arising from an intrinsic thyroid abnormality and that arising from processes outside
of the thyroid, such as a TSH-secreting pituitary tumor, respectively.
• With this caveat, we follow the common practice of using the terms thyrotoxicosis and
hyperthyroidism interchangeably.
• The three most common causes of thyrotoxicosis are associated with hyperfunction of the
gland and include the following:
• • Diffuse hyperplasia of the thyroid associated with Graves disease (approximately 85% of cases)
• • Hyperfunctional multinodular goiter
• • Hyperfunctional thyroid adenoma
6. • Excessive levels of thyroid hormone result in an
increase in the basal metabolic rate. The skin of
thyrotoxic patients tends to be soft, warm, and flushed
because of increased blood flow and peripheral
vasodilation, adaptations that serve to increase heat
loss. Heat intolerance is common. Sweating is
increased because of higher levels of calorigenesis.
Heightened catabolic metabolism results in weight loss
despite increased appetite.
7. • Cardiac manifestations are among the earliest and most consistent features. Individuals
with hyperthyroidism can have elevated cardiac contractility and cardiac output, in
response to increased peripheral oxygen requirements. Tachycardia, palpitations, and
cardiomegaly are common. Arrhythmias, particularly atrial fibrillation, occur frequently and
are more common in older patients. Congestive heart failure may develop, especially in
older patients with preexisting cardiac disease.
• Myocardial changes, such as focal lymphocytic and eosinophilic infiltrates, mild fibrosis,
myofibril fatty change, and an increase in size and number of mitochondria, have been
described. Some individuals with thyrotoxicosis develop reversible left ventricular
dysfunction and “low-output” heart failure, so-called thyrotoxic or hyperthyroid
cardiomyopathy.
• • Overactivity of the sympathetic nervous system produces tremor, hyperactivity,
emotional lability, anxiety, inability to concentrate, and insomnia. Proximal muscle
weakness and decreased muscle mass are common (thyroid myopathy). In the
gastrointestinal system, sympathetic hyperstimulation of the gut results in hypermotility,
diarrhea, and malabsorption.
8. • • Ocular changes often call attention to hyperthyroidism. A wide, staring
gaze and lid lag are present because of sympathetic overstimulation of the
superior tarsal muscle (also known as Mьller’s muscle), which functions
alongside the levator palpebrae superioris muscle to raise the upper
eyelid. However, true thyroid ophthalmopathy associated with proptosis
occurs only in Graves disease .
• • The skeletal system is also affected. Thyroid hormone stimulates bone
resorption, increasing porosity of cortical bone and reducing the volume of
trabecular bone. The net effect is osteoporosis and an increased risk of
fractures in patients with chronic hyperthyroidism. Other findings include
atrophy of skeletal muscle, with fatty infiltration and focal interstitial
lymphocytic infiltrates; minimal liver enlargement due to fatty changes in
the hepatocytes; and generalized lymphoid hyperplasia and
lymphadenopathy in patients with Graves disease.
9. • Thyroid storm refers to the abrupt onset of severe hyperthyroidism. This condition occurs
most commonly in patients with underlying Graves disease and probably results from an
acute elevation in catecholamine levels, as might be encountered during infection,
surgery, cessation of antithyroid medication, or any form of stress.
• Patients are often febrile and present with tachycardia out of proportion to the fever.
Thyroid storm is a medical emergency. A significant number of untreated patients die of
cardiac arrhythmias.
• • Apathetic hyperthyroidism refers to thyrotoxicosis occurring in older adults, in whom
advanced age and various co-morbidities may blunt the features of thyroid hormone
excess that typically bring younger patients to attention. The diagnosis of thyrotoxicosis in
these individuals is often made during laboratory work-up for unexplained weight loss or
worsening cardiovascular disease.
10. • A goitre is an enlargement of the thyroid gland. It may be congenital or acquired. Thyroid function
may be normal (euthyroid), underactive (hypothyroid), or overactive (hyperthyroidism). Enlargement
is usually
• to increased pituitary secretion of TSH, but may, in certain cases, be due to an infi ltrative process
that may be either infl ammatory or neoplastic.
• Congenital goitre
• The commonest causes of congenital goitre are due to the transplacental
• transmission of factors that interfere with foetal thyroid function from the
• mother to the foetus:
• • maternal antithyroid drugs;
• • maternal iodine exposure;
• • maternal hyperthyroidism (Graves’s disease).
12. • Simple (colloid) goitre
• This is a euthyroid, non-toxic goitre of unknown cause. It is not associated with disturbance of
thyroid function and is not associated with either inflammation or neoplasia. Thyroid function tests
and radioisotope scans are normal. It is most common in girls during or around the peripubertal
years. Treatment is not needed, although follow-up is recommended.
• Multinodular goitre
• • Rare.
• • A fi rm goitre with single or multiple palpable nodules.
• • Thyroid function studies usually normal, although TSH and anti-thyroid antibody titres may be
elevated. Abnormalities on thyroid US and areas of reduced uptake on radioisotope scanning may
be seen.
13. • Hyperthyroidism (thyrotoxicosis)
• • Thyrotoxicosis: refers to the clinical, physiological, and biochemical findings that result when the
tissues are exposed to excess thyroid hormones.
• • Hyperthyroidism: denotes those conditions resulting in hyperfunction of the thyroid gland leading
to a state of thyrotoxicosis.
• Causes of thyrotoxicosis
• Due to hyperthyroidism
• • Excessive thyroid stimulation:
• • Graves’s disease
• • Hashimoto’s disease (Hasitoxicosis;
• • neonatal (transient) thyrotoxicosis
• • pituitary thyroid hormone resistance (excess TSH)
• • McCune–Albright syndrome
• • hCG-secreting tumours
• • Thyroid nodules (autonomous):
• • toxic nodule/multinodular goitre
• • thyroid adenoma/carcinoma
14. • Not due to hyperthyroidism
• • Thyroiditis:
• • subacute
• • drug-induced
• • Exogenous thyroid hormones
15.
16. • History
• Shelley is a 14-year-old girl who is referred to the paediatric outpatient department because she has noticed a swelling in
her neck. She has lost 3 kg in the last 2 months and is having trouble sleeping. In addition, Shelley’s mum says she has
been much more anxious and ‘shaky’ than normal for the past few weeks and she thinks that Shelley’s eyes are bigger than
normal. She started her periods 2 years ago. These were regular but in the last few months they have become irregular.
Shelley’s mum has type 2 diabetes and her aunt has an underactive thyroid. No other diseases run in the family. She is on
no medication.
• Examination Shelley appears restless and has mild exophthalmos. Her hands are sweaty and tremulous. Her heart rate is
150 beats/min and blood pressure is 134/70 mmHg. Examination of her neck reveals a large smooth goitre in the midline of
the anterior neck. Her height is 161 cm (50th centile) and weight is 41 kg (9th centile).
• Investigatins Normal
• Serum TSH <0.1 mU/L 0.4–4.0 mU/L
• Serum free thyroxine (fT4) 55 pmol/L 9–25 pmol/L
• Serum free triiodothyronine (fT3) 27 pmol/L 3.5–7.8 pmol/L
• TSH receptor antibody (TRAb) Positive Negative
17.
18. Clinical features (all causes)
• Thyrotoxicosis may be associated with the following symptoms:
• • hyperactivity/irritability;
• • poor concentration; altered mood; insomnia;
• • heat intolerance/fatigue/muscle weakness/wasting;
• • weight loss despite increased appetite;
• • altered bowel habit—diarrhoea;
• • menstrual irregularity;
• • sinus tachycardia; increased pulse pressure;
• • hyperreflexia; fi ne tremor;
• • pruritis.
19. • A diagnosis of hyperthyroidism is made using bothclinical and laboratory
findings. The measurement of
• serum TSH concentration is the most useful single screening test for
hyperthyroidism, because its levels are
• decreased even at the earliest stages, when the disease may still be
subclinical. A low TSH value is usually confirmed with measurement of free
T4, which is predictably increased. In occasional patients, hyperthyroidism
results predominantly from increased circulating levels of T3 (“T3
• toxicosis”). In these cases, free T4 levels may be decreased, and direct
measurement of serum T3 may be useful. In rare cases of pituitary-
associated (secondary) hyperthyroidism, TSH levels are either normal or
raised.
21. • Graves’s disease
• Graves’s disease is an autoimmune disorder with genetic and environmental factors
contributing to susceptibility. Several HLA-DR gene loci (DR3; DQA1*0501) have been
identifi ed as susceptibility loci and there is often a family history of autoimmune thyroid
disease (girls > boys). Graves’s disease occurs due to a predominance of stimulating type
autoantibodies to the TSH receptor.
• Clinical features
• In addition to those of hyperthyroidism, Graves’s disease is characterized by specifi c
features:
• • Diffuse goitre (majority).
• • Graves’s ophthalmopathy: exophthalmos/proptosis; eyelid lag or retraction; periorbital
oedema/chemosis; ophthalmoplegia/extraocular muscle dysfunction.
• Diagnosis
• Clinical suspicion of Graves’s disease requires confi rmatory blood test:
• • Thyroid function tests: high T4/high T3/low TSH.
• • Thyroid antibody screen: antithyroid peroxidase; anti-thyroglobulin +ve;
• TSH receptor antibody (stimulatory type) +ve; radionucleotide thyroid scan—increased
uptake.
22. • Treatment
• The aims of therapy are to induce remission of Graves’s disease with
antithyroid drugs (carbimazole or propylthiouracil) and, if necessary, to
bring the symptoms of thyrotoxicosis (anxiety, tremor, tachycardia) under
control using a B-blocking agent (propranolol). Two alternative regimens
are practised.
• • Dose titration regimen: antithyroid treatment titrated to achieve normal
thyroid function.
• • Block and replace regimen: antithyroid treatment maintained at the
lowest dose necessary to induce complete thyroid suppression and
therapeutic hypothyroidism. In this situation replacement thyroxine therapy
is also necessary to achieve euthyroidism.
• Antithyroid therapy is usually given for 12–24mths in children, before
considering a trial off treatment. Thyroid function (serum-free T4; TSH
levels) should be monitored at regular intervals (1–3mths).
23. • Neonatal thyrotoxicosis
• • Rare and due to the passive transfer of maternal thyroid
antibodies from a thyrotoxic mother to the foetus.
• • Affected neonates are irritable, flushed, and tachycardic.
Weight gain is poor and cardiac failure may be present.
• • The condition is self-limiting. Supportive treatment, e.g. beta
blocker therapy, is required.
24.
25. • Congenital hypothyroidism
• Hypothyroidism may be due to a number of conditions that result in insufficient secretion of thyroid
hormones. Congenital hypothyroidism is a relatively common condition, occurring in approximately
1/4000 births. It is twice as common in girls than in boys.
• Aetiology
• The causes of congenital hypothyroidism include the following:
• • Thyroid dysgenesis (85%): usually sporadic; resulting in thyroid aplasia/ hypoplasia, ectopic
thyroid (lingual/sublingual).
• • Thyroid hormone biosynthetic defect (15%): hereditary, e.g. Pendred’s syndrome.
• • Iodine deficiency ( common worldwide).
• • Congenital TSH deficiency (rare): associated with other pituitary hormone deficiencies.
26. • Clinical features
• Usually non-specifi c; they are diffi cult to detect in fi rst month of life. They include:
• • umbilical hernia;
• • prolonged jaundice;
• • constipation;
• • hypotonia;
• • hoarse cry;
• • poor feeding;
• • excessive sleepiness;
• • dry skin;
• • coarse faecies;
• • delayed neurodevelopment.
27. • Diagnosis
• In most developed countries there are national neonatal biochemical screening
programmes.
• • Test in 1st week of life.
• • Blood spot—fi lter paper collection (e.g. ‘Guthrie card’).
• • TSH (high) and/or fT4 (low) estimation.
• Thyroid imaging is also recommended to determine whether the cause is due to thyroid
dysgenesis or due to hormone biosynthetic disorder.
• • Thyroid US.
• • Radionucleotide scanning (99Tc or 131I).
28.
29.
30. Case
• The patient was transferred to the Neonatal Intensive Care Unit of the Vittore Buzzi Children’s
Hospital, Milan, about eleven hours after birth, due to the presence of a bilateral anterolateral
cervical mass.
• The boy was born by vaginal delivery at 38 weeks and 3 days gestational age. Amniotic fluid was
clear and maternal infectious risk factors were not found. The pregnancy was complicated by
gestational diabetes treated with diet therapy and autoimmune hypothyroidism (with anti-thyroid
peroxidase antibodies positivity) in replacement therapy.
• The infant’s parents were from Egypt and were consanguineous. There was a family history of three
paternal uncles who underwent surgery for cervical mass during childhood. Fetal ultrasound at 33
weeks of gestational age was normal, without mass in the fetal neck.
• Birth weight was adequate for gestational age (3250 g). Length and head circumference were 51
cm and 34 cm, respectively. The first and fifth minute Apgar scores were 10–10.
• On first clinical examination, a remarkable cervical swelling was observed (Figure 1A). No signs of
respiratory distress or other clinical malformations were seen.
31. Figure 1. Clinical aspect of the neck mass at birth (Panel A) and at three months follow-up (Panel B).
Ultrasound showed an enlargement of the thyroid gland (antero–posterior diameter of the right lobe
was 2.5 cm and the left one was 2.2 cm, Figure 2), with a normal echogenic pattern and increased
blood flow with central vascularization.
32. • Figure 2. Thyroid ultrasound
at birth in which the
enlargement of the gland was
detected (cursor 1 isthmus,
0.8 cm; cursor 2 antero–
posterior diameter of the right
lobe, 2.5 cm; cursor 3 antero–
posterior diameter of the left
lobe, 2.2 cm).
33. • The endocrinological profile showed increased TSH levels (TSH > 100 mIU/L, nv 1–6.5)
with low levels of thyroid hormones (FT3 6.6 pmol/L nv 4.1–8.1; FT4 6.4 pmol/L vn 10.3–
19.9), TG < 0.04 ng/mL (nv < 78).
• The laboratory assessment of autoantibodies against thyroglobulin (Tg), thyroid
peroxidase (TPO) and thyroid-stimulating hormone receptor (TSH-R) was negative.
Urinary iodine level was in the normal range. Radiological assessment of the knee
showed the ossification nucleus of femoral epiphysis (diameter 3.9 mm) but the absence
of the tibial one. Hearing screening results were normal.
• Immediately after the diagnosis was made, oral levo-thyroxine was started at a dosage of
8 ug/kg per day. The infant’s growth was regular, with effective suction during
breastfeeding. Objective neurological assessments were normal.
• Immediately after the diagnosis was made, oral levo-thyroxine was started at a dosage of
8 ug/kg per day. The infant’s growth was regular, with effective suction during
breastfeeding. Objective neurological assessments were always within the normal range.
34. • Genetic analysis via the next generation sequencing of causative genes associated with
congenital hypothyroidism (DUOX2, DUOXA2, FOXE1, GLIS3, IYD, NKX2-1, NKX2-5,
JAG1, PAX8, SLC5A5, SLC26A4, TG, TPO, TSHR), was performed using DNA extracted
from a blood sample.
• Two mutations were detected: c.7813 C > T (p.Arg2605Stop) homozygous mutation in the
exon 45 of TG gene (NM_003235, Chr8(GRCh37):g.134128911C > T) and c.1682 G > A
(p.Gly561Asp), heterozygous mutation in the exon 15 of SLC26A4 gene
(NM_000441Chr7(GRCh37):g.107340595G > A). Sanger sequencing of parents’ DNA
samples revealed that the first mutation (c.7813 C > T) was inherited from both parents,
while the second one (c.1682 G > A) was inherited from the mother.
• At the beginning of the second month of life, thyroid ultrasound showed a drastic
reduction in the antero–posterior diameters of the lobes (1.3 cm), with a normal echogenic
pattern.
• During follow-up, TSH and hormone levels were monitored and dosage was adjusted
according to weight and hormone levels. The infant’s growth status and neurological
development were regular. A progressive decrease in the size of the goiter was observed
(Figure 1B).
35. • Treatment
• Without early hormone replacement therapy a number of adverse sequelae may occur.
• • Neurodevelopmental delay and mental retardation.
• • Poor motor coordination.
• • Hypotonia.
• • Ataxia.
• • Poor growth and short stature.
• The earlier the treatment with oral thyroid hormone replacement therapy is initiated the better the
prognosis: levothyroxine (initial dose 10–15micrograms/kg/day).
• Monitoring therapy
• Monitor serum TSH and T4 levels:
• • Every 1–2mths 1st year; every 2–3mths age 1–2yrs; every 4–6mths age >2yrs.
• • Maintain T4 level in upper half of normal range; TSH in lower end of normal range.
36. • Transient hyperthyrotropinaemia
• This is uncommon and is usually detected at the time of
neonatal thyroid screening. It is characterized by slightly
elevated serum TSH level in presence of otherwise normal
serum T4 levels. It is probably due the transplacental
transmission of maternal thyroid antibodies to the child in utero.
Presumed cases do not need treatment, but must be monitored.
• TSH levels that remain persistently elevated after a few months
or low T4 levels should be treated with oral levothyroxine.
37. • Acquired hypothyroidism
• A relatively common condition with an estimated prevalence of 0.1–0.2% in the population. The
incidence in girls is 5–10 times greater than boys.
• Aetiology
• Acquired hypothyroidism may be due to a primary thyroid problem or indirectly to a central disorder
of hypothalamic–pituitary function.
• Primary hypothyroidism (raised TSH; low T4/T3)
• • Autoimmune (Hashimoto’s or chronic lymphocytic thyroiditis).
• • Iodine defi ciency: most common cause worldwide.
• • Subacute thyroiditis.
• • Drugs (e.g. amiodarone, lithium).
• • Post-irradiation thyroid (e.g. bone marrow transplant—total body irradiation).
• • Post-ablative (radioiodine therapy or surgery).
38. • Central hypothyroidism (low serum TSH and low T4)
• Hypothyroidism due to either pituitary or hypothalamic
dysfunction.
• • Intracranial tumours/masses.
• • Post-cranial radiotherapy/surgery.
• • Developmental pituitary defects (genetic, e.g. PROP-1, Pit-1
genes):
• isolated TSH defi ciency; multiple pituitary hormone defi
ciencies.
39. • Clinical features
• The symptoms and signs of acquired hypothyroidism are usually insidious and can be
extremely diffi cult to diagnose clinically. A high index of suspicion is needed.
• • Goitre: primary hypothyroidism.
• • Increased weight gain/obesity.
• • Decreased growth velocity/delayed puberty.
• • Delayed skeletal maturation (bone age).
• • Fatigue: mental slowness; deteriorating school performance.
• • Constipation: cold intolerance; bradycardia.
• • Dry skin: coarse hair.
• • Pseudo-puberty: girls—isolated breast development; boys—isolated testicular
enlargement.
• • Slipped upper (capital) femoral epiphysis: hip pain/limp.
40. Diagnosis
• Diagnosis is dependent on biochemical confi rmation of hypothyroid state.
• • Thyroid function tests: high TSH/low T4/low T3.
• • Thyroid antibody screen. Raised antibody titres:
• • antithyroid peroxidase;
• • anti-thyroglobulin;
• • TSH receptor (blocking type).
• Treatment
• • Oral Levothyroxine (25–200 micrograms/day).
• • Monitor thyroid function test every 4–6mths during childhood.
• • Monitor growth and neurodevelopment.