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THE THYROID
GLAND
HYPERTYROIDISM
THE THYROID GLAND
The thyroid secretes primarily
Thyroxine / T4 /
T4 is probably not metabolically active until
converted to T3
(T4 = prohormone)
~85% of T3 is produced by monodeiodination
of T4
THE THYROID GLAND

T3 and T4 circulate in plasma are almost
entirely (>99,9%) bound to transport
proteins
(mainly TBG, less TBPA and albumins)

Only free hormones exert its metabolic
action

It is better to measure the concentration
in plasma FT3 or FT4
Patterns of thyroid function test results
in patients with hyperthyroidism
Conventional hyperthyroidism
(95% of cases):
FT4 ; FT3 ; TSH  or undetectable
T3-hyperthyroidism
(5% of cases):
FT4 ↔; FT3 ; TSH  or undetectable
Subclinical hyperthyroidism:
FT4 ↔; FT3↔; TSH  or undetectable
Not-thyroidal illness
(e.g. myocardial infarction or pneumonia):

Decreased peripherial conversion of T4 to T3.



Alterations in the binding proteins.
Alterations in the affinity of binding proteins
for thyroid hormones.
↓TSH levels as a results of the illness itself or
the use of drugs (e.g. dopamine or
corticosteroids).

↑TSH into the hypothyroid range during
convalescence.
THYROTOXICOSIS

Hypermetabolic state caused by thyroid
hormone excess at the tissue level
HYPERTHYROIDISM

Increased thyroid hormones synthesis and
secretion
All patients with hyperthyroidism have thyreotoxicosis
Not all patients with thyreotoxicosis are hyperthyroid
PREVALENCE
Females:
Males:
~20/1000
~4/1000
AETIOLOGY
It is important to identify the cause of
hyperthyroidism in order to prescribe
appropriate treatment
Causes of thyrotoxicosis
common types
With low RAIU
With high RAIU
 Graves diseases (60-90%)
 Multinodular goitre (14%)
 Autonomously
functioning solitary
thyroid nodule (5%)
 Iodine-induced
thyrotoxicosis

 Thyroiditis
 subacute (3%)
 silent (painless)
 post-partum
 Iodine-induced
thyrotoxicosis
drugs (e.g. amiodarone)
 radiografic contrast
media
 iodine prophylaxis
programme
Causes of thyrotoxicosis
uncommon types
With high RAIU
With low RAIU
 Congenital
hyperthyroidism
 TSH-induced
hyperthyroidism
 TSH-secreting adenoma
 selective pituitary
resistance to thyroid
hormone
 Trophoblastic tumors
 Thyrotoxicosis facticia
(0.2%)
 Metastatic thyroid
carcinoma (0.1%)
 Struma ovarii
CLINICAL FEATURES OF
HYPERTHYROIDISM
Most signs and symptoms are common
to all types of thyreotoxicosis;
Some of them are specific to defined
disease
for example:
ophthalmopathy
pretibial myxoedema
thyroid acropathy
Graves’
subacute
disease
thyroiditis
thyroid pain
tendernees
CLINICAL FEATURES OF
HYPERTHYROIDISM
(according to frequency)
SYMPTOMS
Nervousness
 Palptations
 Increased sweating
 Haet intolerance
 Fatigue
 Weight loss
 Dyspnea
 Increased appetite
 Eye symptoms
 Friable hair and nails
Increased bowel movements
 Diarrhoea
 Menstrual disturbances
SIGNS


Tachycardia
 Goitre
 Tremors
 Skin changes
 Hyperkinesis
 Thyroid bruit
 Lid lag and retraction
 Ophthalmopathy
 Atrial fibrillation
 Onycholisis
Localized (pretibial) myxedema
 Vitiligo
 Acropathy


GRAVES’ DISEASE
the most frequent cause of
hyperthyroidism
Graves’ disease is an autoimmune
thyroid disease, characterized by diffuse
thyroid enlargement, ophtalmopathy and
less frequently dermopathy (pretibial
myxedema) and acropathy.
It can occur at any age
(unusual before puberty and most commonly
affects the 30-50- years-old age group)
the female/ male ratio  ~7 : 1
Graves’ disease - pathogenesis
Thyroid antigen-specific T
lymphocytes
Humoral and cell-mediated immune
reactions
Infiltration of the thyroid gland by
immune effector cells
Graves’ disease - pathogenesis
Genetic and environmental factors

Production of IgG antibodies
(thyroid-stimulating immunoglobulins TSI
or TSH-receptor antibodies TRAb)

Stimulation thyroid hormone production and
goitre formation
Graves’ disease - pathogenesis
Genetic factors:
The familial predisposition.
The frequent finding of circulating autoantibodies
in relatives of Graves’ patients.
The high concordance rate in monozygotic twins.
The positive association with haplotypes HLA-B8
and DR3 (Caucasians), HLA-B35 (Japonese
population), and HLA-Bw46 (Chinese population).
Female sex hormones.
Graves’ disease - pathogenesis
Environmental factors:
Iodine

Immune-stimulant effect
(in areas of iodine defficiency thyroid autoimmune
diseases are rare).
Cigarettes
(assotiation with Graves’ ophtalmopathy influence on immunecompetent cells?).
Graves’ disease - pathogenesis
Environmental factors:
Escherichia coli and Yersinia enterocolitica
(antibodies to these microbial antigens

cross-reaction with the TSH-receptor

hyperthyroidism.
Stress
(relationship between the onset of hyperthyroidism
and a major life event).
Graves’ disease - pathogenesis
Ophtalmopathy and dermopathy:
 Pathogenesis is less well understood.
 Immunologically mediated but TRAb is not implicated.
Proliferation of fibroblasts (adipocytes?) within the orbit

Increased interstitial fluid content
Chronic inflammatory cel infiltrate

Swelling of the extra-ocular muscles
Rise in retrobulbar pressure
Graves’ disease - clinical findings
THYROID GLAND:

Symmetrically enlarged


Firm
Thrills and bruits
Goiter is absent in 3% of causes
Graves’ disease –
clinical findings
LOCALIZED MYXEDEMA:


Pretibial region
Raised, light colored or yellow-reddish
lesion with orange peel apperance

Sometimes pruritus
Graves’ disease –
clinical findings
THYROID ACROPATHY:

Swelling and soft tissues of hands feet

Clubbing of fingers and toes
True ophtalmopathy is
specific of Graves’ disease
 Soft tissue involvement:
 Lacrimation
 Burning sensation
 Redness

Photophobia
 Gritty sensation
 Proptosis (exophtalmos) and lagophthalmos
 keratitis
 Extra-ocular muscle dysfunction
 diplopia
 Optic neuropathy
 blidness
Cardiovascular system
Tachycardia
Palpitations
Blood pressure:
systolic
diastolic
THYROCARDIAC SYNDROME
Premature heart beats
Atrial fibrillation
Heart failure and/or angina
Alimentary system
Increased appetite
but weight loss
Increased frequency of bowel
movements and diarrhea
Rarely liver dysfunction
Nervous system
Nervousness
Hyperactivity
Anxiety
Insomnia
Emotional instability
Fine tremors
Muscles
Muscular weakness
In most severe cases muscular atrophy
Skeletal system
Thyrotoxicosis
Increased
loss of bone
osteoporosis
Metabolism
Increased oxygen consumption
Diabetes mellitus may be exacerbated
Serum cholesterol 
plasma triglycerides
GRAVES’ DISEASE –
DIAGNOSTIC PROCEDURES
Labolatory investigation
Imaging studies


important particularly in
the absence of goitre
and eye disease
Important particularly in
diagnostic of Graves’
ophtalmophathy

Computed tommography
Magnetic resonance
LABORATORY INVESTIGNATION
Hyperthyroidism

Serum concentrations of:

TSH: undetectable or 
 FT4: 
 FT3: 
T3-toxicosis:
TSH: undetectable or 
FT3: 
FT4: ↔
Graves’ disease:
 TRAb  
 TPO 
 ATG 
Imaging studies
24-hour thyroidal radioactive iodine uptake:
 increased
 thyroid scan diffuse, homogenous goitre
Thyroid ultrasound:
 enlarged gland
 hypoechoic pattern
 increased blood flow
Computed tomography and magnetic
resonance
GRAVES’ DISEASE –
TREATMENT
General principles of treatment
RADIOIODINE
MEDICAL
Treatments available
for Graves’ disease
SURGICAL
Most treatment regiments are directed at the thyroid, but there is
a small place for peripherally acting drugs such as propranolol
and ipodate.
GRAVES’ DISEASE –
TREATMENT
Indications for medical treatment

Patient preference
 Small goitre
 Mild disease
 Other diseases
 Children
 Pregnancy
Ophtalmopathy
 Preoperative
 Pre-radioiodine
 Thyrotoxic crisis
 Relapse after
thyroidectomy

ANTITHYROID DRUGS
THIONAMIDES:
Methimazole, Carbimazole, Propylthiouracil
Mechanism of actions:
Inhibition of thyroid hormone synthesis
and secretion
PTUinhibition of peripheral conversion
of T4 to T3
THIONAMIDES
Goal:
 Permanent remission of
hyperthyroidism
Limitations:
 High recurrence rate of
hyperthyroidism
 Possible side effects
Factors that may influance antithyroid drug therapy
associated with remission
Laboratory
 Modest elevation of
 Small goitre
thyroid hormones
 Mild disease
 Low urinary iodine
excretion
 Rapid responce to
 Low or absent TSH-R9s)
antithyroid drugs
antibodies at end of
Small maintenance dose
therapy
 Female sex
 Normal responce to TRH at
end of therapy
 Low iodine intake
 Normal suppression of
thyroidal radioiodine
uptake at end of therapy
Clinical

Factors that may influance antithyroid drug therapy
associated with relapse
Laboratory
 Major elevation of thyroid
 Large goitre
hormones
 Vascular goitre
 High urinary iodine
excretion
 Severe disease
 Raised TSH-R(s)
 Slow responce to
antibodies at end of
antithyroid drugs
therapy
Large maintenance dose  Absent responce to TRH at
end of therapy
 Male sex
 Impaired or absent
 High iodine intake
suppression of thyroidal
radioiodine uptake at end
of therapy
Clinical

THIONAMIDES
Side effects
(overall frequency <5%)
Nausea
 Vomiting
 Pruritis
 Skin rash
 Urticaria
 Loss of taste

Mild leukopenia (12 – 25%)
Agranulocytosis (0.1 – 0.5%)
 Aplastic anemia
 Thrombocytopenia
 Cholestasis
 Hepatocellular necrosis
 Lupus-like syndrome
 Nephrotic syndrome


GRAVES’ DISEASE –
TREATMENT
Indications for surgical treatment
Experienced thyroid
surgeon avaliable
 Patient preference
 Adults up to 40
years
 Severe disease

Nodular goitre
 Large goitre
Relapse after drug
treatment


SURGICAL TREATMENT

PARTIAL THYROIDECTOMY
Mechanism of action

removal of tissue responsible for
excessive thyroid hormone synthesis
PARTIAL THYROIDECTOMY
Goal

thyroid ablation, i.e. hypothyroidism
Contraindications

systemic contraindications to surgery
PARTIAL THYROIDECTOMY
- COMPLICATIONS
EARLY
 Recurrent laryngeal nerve
palsy
 Superior laryngeal nerve
palsy
 Haemorrhage
 Hypoparathyroidism
 Pneumothorax
 Thyroid crisis
 Damage to thoracic drug
 Damage to carotic artery
 Damage to jugular vein

LATE
 Cheloid scar
 Tethered scar
 Hypothyroidism
 Recurrence of
hyperthyroidism
Recurrent upper pole
nodules
GRAVES’ DISEASE –
TREATMENT
Indications for radioiodine therapy
Patient preference
 Poor-compliance
with antithyroid
drugs
 Patients over 40
years
 Recurrence after
thyroidectomy


Severe uncontrolled
disease
 Large goitre
 Unco-operative
patients
 Presence of other
disease(s)
RADIOIODINE THERAPY
Mechanism of action

Destruction of thyrocytes by β-radiation
Goal

thyroid ablation, i.e. hypothyroidism
Contraindications

pregnancy
RADIOIODINE THERAPY
Complcations
 Permanent hypothyroidism
 Transient hypothyroidism
 Thyroiditis
 Sialadenitis
 Thyrotoxic crisis
 Nodule formation
 Possible exacerbation of ophtalmopathy
(preventable by glucocorticoids)
GRAVES’ DISEASE –
TREATMENT
Other drugs

Β-adrenergic
antagonists
(e.g. Propranolol)

Inorganic iodide

Potassium
perchlorate

Glucocorticoids
GRAVES’ DISEASE –
TREATMENT OF OPHTHALMOPATHY
Mild ophthalmopathy
 Guanethidine or β-adrenergic eye drops
(lid retraction)
 Methylcellulose eye drops
(lacrimation, burning sensation)
 Sunglasses
(photophobia)
 Nighttime tapering of eyes
(lagophthalmos)
 Prisms
(mild diplopia)
Severe ophthalmopathy
 High-dose glucocorticoids
(active ophthalmopathy)
 Orbital radiotherapy
(active ophthalmopathy)
 Orbital decompresion
(active or inactive ophthalmopathy)
 Rehabilitative surgery: eye muscles, eyelids
(to be performed at least 6 months after rendering
ophthalmopathy stable and inactive with other
treatments)
 Immunosuppressive drugs, somatostatin analogues,
intravenous immunoglobulins, plasmapheresis.
THYROTOXIC STORM
RARE BUT VERY SERIOUS COMPLICATION
OF HYPERTHYROIDISM
 Severe manifestations of hypermetabolic
(fever, profound sweating, dehydration,
restlessness, insomnia)
 In patients with not diagnosed or
inadeguately treated hyperthyroidism
INFECTIONS
SURGERY
THYROTOXIC STORM
TRAUMAS
THYROTOXIC STORM TREATMENT
 High doses of
thionamide
 Iodide or iodinated
contrast agents
 Glucocorticoids
 β-adrenergic
antagonists
 The treatmnent of
underlying nonthyroidal illness
 Correction of
dehydration
 Normalisation of body
temperature
 Plasmapheresis or
peritoneal dialysis
TOXIC ADENOMA
An autonomously functioning, benign
thyroid nodule causing thyrotoxicosis
>10%
Iodine-deficient
areas
FREQUECY
Iodine-sufficient
areas
≤10%
TOXIC ADENOMA
Solitary nodule
in:
otherwise normal
thyroid gland
goiter
Pathogenesis:
Somatic mutations in the gene encoding the TSH receptor

constitutive activation of TSH receptor
TOXIC ADENOMA
 Smptoms and signs of thyrotoxicosis
 Ophthalmopathy, localized myxedema and
acropachy are absent
Thyroid scan

Prevalent tracer uptake in the nodule
(„hot nodule”)
Treatment
Radioiodine or surgery
Antithyroid drugs only for preparation of definitive
treatment
TOXIC MULTINODULAR GOITER
Multiple hyperfunctioning thyroid
nodules
or areas of autonomously functioning
thyroid follicles
Commonly found in older patients with
long-standing multinodular goiter.
UNUSUAL FORMS OF THYROTOXICOSIS
TSH-INDUCED HYPERTHYROIDISM
TSH-secreting
Selective pituitary
resistence
pituitary adenoma
(280 cases so far described)

TSH  or ↔; FT4 ;
FT3 



TSH α-subunit 
TSH α-subunit / TSH>1
TSH  or ↔; FT4 ;
FT3 


TSH α-subunit ↔
TSH α-subunit / TSH<1
UNUSUAL FORMS OF THYROTOXICOSIS
Thyrotoxicosis factitia

Clinical and biochemical
picture is typical of
thyrotoxicosis



Goiter is absent
RAIU is very low/suppressed
Serum thyroglobulin – very
low or undetectable
Congenital hyperthyroidism

Germline mutations of the
TSH-R gene

Constitutional activation in all
thyroid follicular cells
UNUSUAL FORMS OF THYROTOXICOSIS
Metastatic thyroid
carcinoma
Struma ovarii

Follicular thyroid arcinoma

Metastases to lung and bone

Thyrotoxicosis (rarely)
Functioning thyroid tissue
within an ovarian
teratoma or dermoid
UNUSUAL FORMS OF THYROTOXICOSIS
Trophoblastic tumors
High serum and urine concentrations
of β-subunit of chorionic gonadotropin

stimulation of TSH receptor