Pathophysiology of Hyperthyroidism

Thyrotoxicosis results from the effects of excess thyroid hormone on

peripheral tissues.
Hyperthyroidism, the more specific term, is used to describe a state of
thyrotoxicosis that is due to the overproduction of thyroid hormone by the
thyroid gland.
3 most common cause of hyperthyroidism : Graves disease a.k.a autoimmune
hyperthyroidism), Toxic multinodular goitre & a toxic adenoma
Other causes : multinodular goiter, adenoma, thyroiditis, and exogenous thyroid
hormone.
1.
-

Graves Disease (Diffuse Toxic Goitre)

affects females 7x than males
peak age of onset is btween 20 40 yrs
risk factors : family history of autoimmune disease, HLA-B8 genotype,
smoking, high iodine intake or use of iodine-containing medications (eg
amiodarone).
- Characterised by a triad of features:
a) hyperthyroidism
b) diffuse thyroid enlargement
c) ophtalmopathy
- this autoimmune disease is unique because does not destroy tissue but it
results in hyperfunctioning of the thyroid gland
- Autoantibodies stimulate the TSH receptor via the cAMP pathway just like
TSH and leads to overproduction of thyroid hormone.
- stimulus for Graves disease is unknown but viral illness and stress appear
to play a role
Etiopathogenesis :
1. Genetic factor association
HLA-DR3, CTLA-4 and PTPN22
2. Other factors
emotional stress and smoking
3. Autoantibodies
i) TSI : binds to TSH receptor and stimulates increased release of thyroid
hormones
ii) TGI : stimulates proliferation of follicular epithelium
iii) TBII : it inhibits binding of TSH to its own receptor.
Clinical feature : all clinical features of thyrotoxicosis and specific Graves disease
sign&symptoms -> Exopthalmos

2. Toxic multinodular goitre a.k.a Plummer disease

2nd most common cause, affect at 60 yrs of age
commonly found in areas of iodine deficiency
a portion of thyroid gland develop automaticity and begins to secrete
thyroid hormone in the absence of TSH signal.
- This automaticity is the result of a somatic mutation in the TSH receptor
signaling pathway, causing the continuous activation of the TSH-receptor
pathway
- T4 and T3 levels are elevated, and TSH level is suppressed
Clinical feature : only the core symptom of thyrotoxicosis, no opthalmopathy
-

3. Toxic adenoma
- develops slowly in the fourth to sixth decades of life
- a benign neoplasm, nodules secrete thyroid hormones independently
because this tissue contains mutated TSH receptors
- rarely cause symptoms before reaching 3cm in diameter.
- Same like toxic multinodular goitre, caused by somatic mutations of the
TSH-receptor signaling pathway which leads to increased automaticity of
the thyroid tissue, but difference is that, the automaticity develops in an
otherwise normal thyroid gland.
Clinical Features of Thyrotoxicosis
General
Anxiety
Diaphoresis
Fatigue
Hair loss
Heat intolerance
Insomnia
Irritability
Weight loss
Cardiovascular
Arrhythmias
Sinus tachycardia
Systolic hypertension
Dermatologic
Pretibial myxedema
Thin skin
Onycholysis
Gastrointestinal
Frequent bowel movements
Hematologic
Anemia, normocytic

Pulmonary
Pleural effusions
Musculoskeletal
Muscle aches
Osteoporosis
Weakness
Neurologic
Brisk reflexes
Fine tremor
Ophthalmologic
Lid lag
Thyroid stare
Reproductive
Menstrual
irregularities

The rate of metabolism increases with excess thyroid hormone as the result of
increases in the rates of both the synthesis and the degradation of biologic molecules,
including protein, lipids, and carbohydrates. During the thyrotoxic state, the rate of
degradation increases more than the rate of synthesis, resulting in a net catabolic effect.
The consequences include weight loss and muscle weakness despite increased appetite
and adequate caloric intake.
Cardiovascular manifestations are among the first clinical consequences of the
thyrotoxic state. Excess sympathetic nervous system (SNS) stimulation together
withincreased peripheral oxygen demand secondary to the increased metabolic rate leads
to increased cardiac output. This increase in cardiac output is initially due to an increase
in heart rate and contractility but later results from an increase in stroke volume. Total
peripheral resistance decreases in order to supply more oxygen to peripheral tissues. The
increase in cardiac output with a concurrent decrease in total peripheral resistance leads
to the wide pulse pressure characteristic of the thyrotoxic patient.
The SNS is stimulated by unknown mechanisms in the thyrotoxic state, but it is
believed that thyroid hormone likely plays a permissive role in the SNS, insofar as there
are no signs of direct upregulation of the SNS, and levels of epinephrine, norepinephrine,
and their metabolites remain unchanged. This increased sympathetic tone in the
thyrotoxic state leads to increases in heart rate, respiratory rate, the thyroid stare, and
lagging of the upper eyelid. Stimulation of the SNS results in nervousness, irritability,
hyperactivity, and fatigue; psychosis has also been observed in the thyrotoxic state.
Symptoms of thyrotoxicosis can also be attributed to altered tissue growth and maturation
including integumentary effects such as smooth skin, onycholysis, and osteoporosis.