THE THYROID GLAND

1
THE THYROID GLAND

• HYPERTYROIDISM

2
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

3
THE THYROID GLAND

• T3 and T4 circulate in plasma are almost entirely
  (gt99,9) 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

4
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
• NEGATIVE FEEDBACK

5
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.

6
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
7
AETIOLOGY
PREVALENCE
Females 20/1000
Males 4/1000

• It is important to identify the cause of
  hyperthyroidism in order to prescribe appropriate
  treatment

8
Causes of thyrotoxicosiscommon types

• With low RAIU
• Thyroiditis
• subacute (3)
• silent (painless)
• post-partum
• Iodine-induced thyrotoxicosis
• drugs (e.g. amiodarone)
• radiografic contrast media
• iodine prophylaxis programme

• With high RAIU
• Graves diseases (60-90)
• Multinodular goitre (14)
• Autonomously functioning solitary thyroid nodule
  (5)
• Iodine-induced thyrotoxicosis

9
Causes of thyrotoxicosisuncommon types

• With high RAIU
• Congenital hyperthyroidism
• TSH-induced hyperthyroidism
• TSH-secreting adenoma
• selective pituitary resistance to thyroid hormone
• Trophoblastic tumors

• With low RAIU
• Thyrotoxicosis facticia (0.2)
• Metastatic thyroid carcinoma (0.1)
• Struma ovarii

10
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
thyroid pain tendernees
Graves disease
subacute thyroiditis
11
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

12
GRAVES DISEASEthe 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

13
Graves disease - pathogenesis

• Thyroid antigen-specific T lymphocytes
• Humoral and cell-mediated immune reactions
• Infiltration of the thyroid gland by immune
  effector cells

14
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

15
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.

16
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 immune-competent cells?).

17
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).

18
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

19
Graves disease - clinical findings

• THYROID GLAND
• Symmetrically enlarged
• Firm
• Thrills and bruits
• Goiter is absent in 3 of causes

20
Graves disease clinical findings

• LOCALIZED MYXEDEMA
• Pretibial region
• Raised, light colored or yellow-reddish lesion
  with orange peel apperance
• Sometimes pruritus

21
Graves disease clinical findings

• THYROID ACROPATHY
• Swelling and soft tissues of hands feet
• Clubbing of fingers and toes

22
True ophtalmopathy is specific of Graves disease

• Soft tissue involvement
• Lacrimation ? Redness
• Burning sensation ? Photophobia
• Gritty sensation
• Proptosis (exophtalmos) and lagophthalmos
• keratitis
• Extra-ocular muscle dysfunction
• diplopia
• Optic neuropathy
• blidness

23
Cardiovascular system

• Tachycardia
• Palpitations
• Blood pressure
• systolic? diastolic?
• THYROCARDIAC SYNDROME
• Premature heart beats
• Atrial fibrillation
• Heart failure and/or angina

24
Alimentary system

• Increased appetite
• but weight loss
• Increased frequency of bowel movements and
  diarrhea
• Rarely ?liver dysfunction

25
Nervous system

• Nervousness
• Anxiety
• Emotional instability

• Hyperactivity
• Insomnia
• Fine tremors

Muscles

• Muscular weakness
• In most severe cases ?muscular atrophy

26
Skeletal system
osteoporosis
Increased loss of bone
Thyrotoxicosis
Metabolism

• Increased oxygen consumption
• Diabetes mellitus may be exacerbated
• Serum cholesterol ? plasma triglycerides?

27
GRAVES DISEASE DIAGNOSTIC PROCEDURES

• Labolatory investigation
• ?
• important particularly in the absence of goitre
  and eye disease

• Imaging studies
• ?
• Important particularly in diagnostic of Graves
  ophtalmophathy
• ?
• Computed tommography
• Magnetic resonance

28
LABORATORY INVESTIGNATION

• Hyperthyroidism
• Serum concentrations of
• TSH undetectable or ?
• FT4 ?
• FT3 ?
• T3-toxicosis
• TSH undetectable or ?
• FT3 ?
• FT4 ?

• Graves disease
• TRAb ? ?
• TPO ?
• ATG ?

29
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

30
GRAVES DISEASE TREATMENT

• General principles of treatment

RADIOIODINE
Treatments available for Graves disease
SURGICAL
MEDICAL
Most treatment regiments are directed at the
thyroid, but there is a small place for
peripherally acting drugs such as propranolol and
ipodate.
31
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

32
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

33
THIONAMIDES

• Goal
• Permanent remission of hyperthyroidism
• Limitations
• High recurrence rate of hyperthyroidism
• Possible side effects

34
Factors that may influance antithyroid drug
therapyassociated with remission

• Clinical
• Small goitre
• Mild disease
• Rapid responce to antithyroid drugs
• Small maintenance dose
• Female sex
• Low iodine intake

• Laboratory
• Modest elevation of thyroid hormones
• Low urinary iodine excretion
• Low or absent TSH-R9s) antibodies at end of
  therapy
• Normal responce to TRH at end of therapy
• Normal suppression of thyroidal radioiodine
  uptake at end of therapy

35
Factors that may influance antithyroid drug
therapyassociated with relapse

• Clinical
• Large goitre
• Vascular goitre
• Severe disease
• Slow responce to antithyroid drugs
• Large maintenance dose
• Male sex
• High iodine intake

• Laboratory
• Major elevation of thyroid hormones
• High urinary iodine excretion
• Raised TSH-R(s) antibodies at end of therapy
• Absent responce to TRH at end of therapy
• Impaired or absent suppression of thyroidal
  radioiodine uptake at end of therapy

36
THIONAMIDES

• Side effects
• (overall frequency lt5)

• Mild leukopenia (12 25)
• Agranulocytosis (0.1 0.5)
• Aplastic anemia
• Thrombocytopenia
• Cholestasis
• Hepatocellular necrosis
• Lupus-like syndrome
• Nephrotic syndrome

• Nausea
• Vomiting
• Pruritis
• Skin rash
• Urticaria
• Loss of taste

37
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

38
SURGICAL TREATMENT?PARTIAL THYROIDECTOMY

• Mechanism of action
• ?
• removal of tissue responsible for excessive
  thyroid hormone synthesis

39
PARTIAL THYROIDECTOMY

• Goal
• ?
• thyroid ablation, i.e. hypothyroidism
• Contraindications
• ?
• systemic contraindications to surgery

40
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

41
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)

42
RADIOIODINE THERAPY

• Mechanism of action
• ?
• Destruction of thyrocytes by ß-radiation
• Goal
• ?
• thyroid ablation, i.e. hypothyroidism
• Contraindications
• ?
• pregnancy

43
RADIOIODINE THERAPY

• Complcations
• Permanent hypothyroidism
• Transient hypothyroidism
• Thyroiditis
• Sialadenitis
• Thyrotoxic crisis
• Nodule formation
• Possible exacerbation of ophtalmopathy
• (preventable by glucocorticoids)

44
GRAVES DISEASE TREATMENT
Other drugs

• ?-adrenergic antagonists
• (e.g. Propranolol)
• Inorganic iodide

• Potassium perchlorate
• Glucocorticoids

45
GRAVES DISEASE TREATMENT OF OPHTHALMOPATHY

• Mild ophthalmopathy
• Guanethidine or ß-adrenergic eye drops
• (lid retraction)
• Methylcellulose eye drops
• (lacrimation, burning sensation)
• Sunglasses
• (photophobia)
• Nighttime tapering of eyes
• (lagophthalmos)
• Prisms
• (mild diplopia)

46

• 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.

47
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
48
THYROTOXIC STORM - TREATMENT

• The treatmnent of underlying non-thyroidal
  illness
• Correction of dehydration
• Normalisation of body temperature
• Plasmapheresis or peritoneal dialysis

• High doses of thionamide
• Iodide or iodinated contrast agents
• Glucocorticoids
• ß-adrenergic antagonists

49
TOXIC ADENOMA

• An autonomously functioning, benign thyroid
  nodule causing thyrotoxicosis

gt10
Iodine-deficient areas
FREQUECY
Iodine-sufficient areas
10
50
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
51
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

52
TOXIC MULTINODULAR GOITER

• Multiple hyperfunctioning thyroid nodules
• or areas of autonomously functioning thyroid
  follicles
• Commonly found in older patients with
  long-standing multinodular goiter.

53
UNUSUAL FORMS OF THYROTOXICOSIS
TSH-INDUCED HYPERTHYROIDISM

• TSH-secreting pituitary adenoma
• (280 cases so far described)
• TSH ? or ? FT4 ? FT3 ?
• TSH a-subunit ?
• TSH a-subunit / TSHgt1

• Selective pituitary resistence
• TSH ? or ? FT4 ? FT3 ?
• TSH a-subunit ?
• TSH a-subunit / TSHlt1

54
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

55
UNUSUAL FORMS OF THYROTOXICOSIS

• Metastatic thyroid carcinoma
• Follicular thyroid arcinoma
• ?
• Metastases to lung and bone
• ?
• Thyrotoxicosis (rarely)

• Struma ovarii
• Functioning thyroid tissue within an ovarian
  teratoma or dermoid

56
UNUSUAL FORMS OF THYROTOXICOSIS

• Trophoblastic tumors
• High serum and urine concentrations
• of ß-subunit of chorionic gonadotropin
• ?
• stimulation of TSH receptor