TRH is released which stimulates pituitary

Pituitary releases TSH which stimulates thyroid

Thyroid produces T3 and T4 which have a negative feedback loop on TRH and TSH

Mutations are HLA-DR3 or HLA-B8 which leads to hyperactivation of plasma cells which produce TSH-R antibodies, which can bind to TSH receptors and also fibroblasts and adipose tissue, increasing fibrous tissue and adipose tissue

TSH receptor antibodies which attack thyroid follicle cells leading to diffuse hyperactivity

TSH receptor clicks with TSH antibodies, stimulating the TSH receptor like TSH would, leading to high T4 and T3 without the high TSH response, TSH can actually be quite low due to negative feedback low through HPA axis

Leads to goiter formation, firm and rubbery gland

Diagnosed with TPO-antibodies

Treatment is levothyroxine

Phases

1. Destroyment of follicles

   -> Releases thyroid hormones

   -> Hyperthyroidism

2. Destroyed follicles

   -> No more / less TH production

   -> Hypothyroidism

3. Regeneration

   -> Euthyroidism

More common in women

Incidence rises with age

Causes atrophy and fibrosis because of infiltration in thyroid

Comorbid with other autoimmune disorders

No goiter, instead has no thyroid because it's atrophic

• Normal Physiological Conditions (Adolescence, Pregnancy, Lactation) –Ie: Conditions requiring ↑Metabolism

• Iodine Deficiency – Most Common

• Pathogenesis:

  • Note: Hyperplasia → NOT Neoplastic – (Due to ↑ TSH Stimulation)

• Morphology:

  • Goitre is Mild, Diffuse & Symmetrical

• Clinical Features:

  • Most Pts are Euthyroid

• Ix:

  • ↑↑TSH

  • Normal T3/T4 (Unless Severe -↓T3/T4)

• Complications:

  • Mechanical (Dysphagia, Airway Obstruction)

  • Endocrine (Toxic Nodule→Hyperthyroidism)

Non-functional nodules

-> They can be malignant!!

2 Lateral lobes connected by the isthmus

Attached to thyroid cartilage at upper hand of trachea which moves during swallow movement

Often palpable in healthy women as very squishy

4 Parathyroid glands are located at the posterior corners of the thyroid gland

Surrounding

Surrounded structures may be affected because of goitre or thyroidectomy, such as recurrent laryngeal nerve that may be affected or damaged resulting in a hoarse voice, branch of vagus nerve or parathyroid glands

C cells

Secrete calcitonin

Follicular cells

Secrete thyroid hormone

-> Brain, bones, heart, intestine

-> Absence causes thyroid hyperplasia, high T4

Beta

-> Liver, pituitary, hypothalamus, kidneys

-> Absence causes poor growth, hypothermia

1. Active Transport of iodide into follicular cell via sodium-iodide symporter (NIS)

2. Thyroglobulin (Tg) is formed in follicular ribosomes and placed into secretory vesicles

3. Exocytosis of thyroglobulin into the follicle lumen, where it is stored as colloid

4. Iodination of the thyroglobulin → iodide is made reactive by thyroid peroxidase, then binds to benzene ring on tyrosine residues of thyroglobulin, forming monoiodotyrosine (MIT), then diiodotyrosin (DIT)

5. Coupling of MIT and DIT gives rise to T3 and coupling of DIT and DIT gives rise to T4

6. Endocytosis of iodinated thyroglobulin back into the follicular cell, where it undergoes proteolysis in lysosomes to cleave iodinated residues; Free T3 or T4 is released and thyroglobulin is recycled

• T3 and T4 are fat soluble and are mostly carried by plasma proteins (thyronine binding globulin and albumin)

  • less than 1% of T3 and T4 is unbound free hormone

• In the peripheries, T4 is deionated to T3

• In the liver and kidney T3 and T4 are deactivated by removing iodine

  
  

  TPO = Thyroid peroxidase

  --> catalyzes iodide oxidation to form iodine atoms which are added onto tyrosine residues on thyroglobulin for the production of thyroxine or triiodothyronine

Formation of MIT and DIT

When thyroid gland is producing an inadequate amount of T3 and T4, it stimulates the hypothalamus and pituitary to increase TRH and TSH which triggers them to undergo proliferation and follicles grow

Painful

→ Infectious → De Quarvain’s

Painless

→ Autoimmune

→ Iodine deficiency (strong!!!)

GIT dysfunction

Low thyroid hormones leads to decreased smooth muscle contraction and thus decreased GIT motility

→ Constipation

Integumentary dysfunction

→ Especially in primary hypothyroidism

→ Dry skin

→ Brittle hair and nails

Increased TSH leads to overactivation of fibroblasts and make

→ Glycose amino glycans (GAGs)

→ Lead to increased water retention in soft tissues

→ Pre tibial myxoedema

→ Non-pitting oedema

→ Periorbital oedema

→ Capral tunnel region so can develop carpal tunnel syndrome since nerve is compressed

Metabolic dysfunction

Low thyroid hormone inhibits Na+K+ pump which leads to less metabolic activity

Leads to

1. Low catabolism

→ Can’t break down fats or macronutrients easily

→ Weight gain

2. Decreased heat production

→ Low body temperature

→ Cold intolerance

3. Increased ADH

→ Because hypothyroidism stimulates posterior pituitary gland

→ Hyponatraemia

Cardiovascular system

Thyroid hormones work on B1 receptors

Low thyroid hormones leads to low B1 receptor sensitivity, leading to smaller response to NE

→ Lower heart rate and contractility

→ Bradycardia

→ Increase in vasoconstriction

→ Increase in blood pressure

→ Specifically diastolic BP

Reproductive dysfunction

Thyroid levels affect prolactin levels

Low thyroid hormones → High production of prolactin

High prolactin

→ Alterations in progesterone and oestrogen

→ Menstrual dysfunction

→ Heavy bleeding

→ No menses

→ Infertility

→ Reduced libido

Hepatic system

LDL receptors are stimulated by thyroid hormones

Less thyroid hormones means less uptake of LDL into liver

High LDL in blood

→ Hyperlipidaemia

Neurological dysfunction

Decreased neuronal activity

→ Lethargy

→ Fatigue

→ Depression

→ Delayed deep tendon reflexes

In acute or chronic illness, TSH is lower

Average diagnosis is 60 years old

Stressors could be

→ Infection

→ Sepsis

→ Surgery

→ Hypothermia

→ Non-compliance with meds

Effect

→ Shut down of Na+/K+ pumps

→ Heat production reduces significantly

→ Hypothermia

→ Shuts down AV node

→ Severe bradycardia

→ Intense vasoconstriction

→ Acute hearth failure

→ Altered mental status

→ Encephalopathy

→ Coma

→ Pretibial myxoedema

Can cause goiter because of increased TSH

IgG4 systemic disease which is present in other systemic diseases

→ Autoimmune pancreatitis

→ Aortitis

→ Fibrosis of retroperitoneum

Mechanism

Activates fibroblasts which release fibrous tissue, leading to increased fibrosis of thyroid gland with consequential compression of nearby structures

→ Recurrent laryngeal nerve → Hoarseness

→ Trachea → Dyspnoea / stridor

→ Oesophagus → Oesophageal dysphagia

De Quervain’s thyroiditis is transient

Clinical features

• !!! Increased erythrocyte sedimentation rate (ESR)

• Low grade fever

• Muscle aches

• Headaches

• Stiff / painful joints

• Runny nose / congestion

• Painful thyroid

• Possible goiter

When very high dose of Iodine

→ TPO senses this and is inhibited

→ Decreased synthesis of thyroid hormone

When?

→ Patients who take Amiodarone (atrial fibrillation medication)

→ Radioiodine therapy

Small goiter can lead to swelling

Goiter can be associated with lymph nodes

Can use needle aspiration if maybe malignant

Goiter is hyperplasia, not neoplasia

Diagnosis: look at

1. Is it pathological

2. Does it compress other structures

3. Thyroid status

4. Cosmetic concern

Rapid enlargmene, lymph node and pain : maybe malignancy

Presents with high TSH and low T4 & T3

Includes:

1. Autoimmune

   1. Hashimoto's

   2. Postpartum thyroiditis

   3. Riedel's

2. Infectious

   1. DeQuervain's thyroiditis

3. Iatrogenic

   1. Thyroidectomy

   2. Wolff-Chaikroff effect

• Precipitated by Infection (sepsis) / Trauma / Surgery / Massive iodine load in TA, TM and Grave’s / Non-compliance with ATD

  • In a Hyperthyroid Patient

Pathogenesis:

• Pre-existing Hyperthyroidism → ↑Sympathetic Sensitivity
  • + Precipitant → ↑Catecholamine Levels → Sympathetic Symptoms

  
  

SEVERE Clinical Features → 50% mortality

→ Hyperthermia (>41.5 C)

→ Seizure (more rare)

→ Agitated delirium (more common) + coma (more severe)

→ Profound tachycardia + arrhythmias

→ Afib / SVT

→ Profound increased contractility

→ Profound vasodilation and dropped SVR (hypotension)

→ High output/congestive cardiac failure

→ Profound increase in cardiac output which will never be sufficient for the amount of energy needed because of hyperactivity

→ Vomiting/Diarrhoea

Differentials:

→ Sepsis

→ Phaeochromocytoma

→ MalignantHyperthermia

Lab Findings:

• ↑↑↑T3/T4

• ↓↓↓TSH

• (Leukocytosis, Hypercalcaemia,↑LFTs)

Treatment:
→ Treat Precipitating/Causing Factor, PLUS (image):

→ Especially in Grave’s

→ Pituitary microadenoma

→ Also seen in secondary hypothyroidism

Cardiovascular dysfunction

→ T3 and T4 binds to B receptors and increases and increases activity of myocardium cells

→ Tachycardia, SVT, afib

→ Increase in contractility, increased cardiac output and causes systolic hypertension

→ T3 and T4 can trigger vasodilation and drops systemic vascular resistance

Metabolic dysfunction

→ High T3 and T4 hyperactivates Na+/K+ ATPases

→ We deplete ATP because of this

→ Increase in catabolic state

→ Leading to weight loss and increase in hunger

→ Increase in body temperature and heat intolerance

Neurological dysfunction

→ T3 and T4 act on neurons in CNS and causes hyperactivity of neurons

→ Causes irritability, hyperactive behaviour, insomnia, anxiety

→ Causes hyperactive deep tendon reflexes, tremor

→ Can cause seizures

Reproductive dysfunction

→ T4 and T3 increases TBG synthesis in liver

→ TBG soaks up oestrogen, progesterone and testosterone

→ Reduces those, leading to reduced libido, infertility and menstrual abnormalities

Integumentary system

! Graves only

→ Increased TSH-receptor antibodies which can also act on

→ Fibroblasts → Increases glycose amino glycans which causes water retention, primarily in extremities, causing pre-tibial myxoedema (non-pitting)

→ Adipose → Increase in adipose tissue formation, combination of this and water retention causes swelling behind the eye causing Grave’s ophthalmopathy

Gastrointestinal dysfunction

→ T3 and T4 increases GIT motility

→ Causes diarrhoea

If mother has Graves:

Causes fetal hypothyroidism, you take carbimazole to combat this, but then again the mother needs drugs to maintain euthyroidism

Together 90% of thyroid carcinoma’s (70% P and 20% F)

Young people

Spread

Local

Lung/bone secondaries possible

Prognosis

Good especially in young, smaller primary tumour size and no metasteses

Treatment

Surgical

→ Total or near-total thyroidectomy

→ Neck dissection needed if local nodal spread or involvement of other structures

Radioactive ablation

→ Most tumours take up iodine

→ Can localize residual diseases using low doses

→ Can treat residual diseases using high dose

Suppressive doses of levothyroxine

→ To minimize risk of recurrence

Monitoring

Serum Tg is used as tumour marker, but this measurement is insensitive when TSH is low, so levothyroxine should be stopped…. but this has negative effect so we use recombinant TSH to stimulate Tg without stopping thyroxine treatment

When Tg is detected, recurrence is suspected and whole body iodine scanning is required

5% Of thyroid cancers

Often familial

Neuroendocrine tumour of calcitonin-producing C cells

Spread

Local and metastases

Treatment

People with MEN2 mutations are advised to have a prophylactic thyroidectomy as early as 5 years of age to prevent development (includes wide lymph node clearance)

Responds poorly to treatment

Prognosis

Poor, indolent (slow progression)

100% mortality, no treatment!

Prevalence

<5% Of thyroid cancers

Aggressive and very rapidly growing

Presentation of patient is usually metastesized

Spread

Locally invasive

Prognosis

Very poor

Treatment

Does not respond to radioactive iodine

2% Of thyroid cancers

Variable behaviour

Spread

Unknown?

Treatment & prognosis

Sometimes responsive to radiotherapy