-       Stroke: 5^th leading cause of death and the primary of long-term adult disability in the US

-       Hypothyroidism can cause hypertension, hypercholesterolemia, cardiac dysfunction, hypo/hypercoagulability which increases risk of stroke

-       Low T3 level following acute ischemic stroke (AIS) are associated with greater stroke severity and mortality, and poorer functional outcomes

-       Non-thyroidal illness syndrome (NTIS): poorer short-term prognosis and higher mortality rates at 12 months compared to non-NTIS patients

-       No significant difference between males and females in TSH, free T4 (fT4) or free T3 (fT3) levels

-       Patients with low levels of fT3 had increased disability at baseline indicated by higher pre-stroke mRS scores

-       There was no association between hospital mortality and fT3 or fT4

-       Patients who were alive at discharge had significantly higher fT3 levels than patients who either died in hospital or went to hospice

-       Patient who died at 3 months had lower TSH values than those who were alive at 3 months

-       Patients with a favourable composite outcome at 3 months had higher TSH levels than those with a poor composite outcome, no association between outcome and fT4

-       Patients with the highest fT3 levels were the most likely to be independent

-       Higher the initial fT3, the better the outcome

-       Patients with small vessel disease had higher fT3 values than those with large vessel or cardioembolic stroke aetiology

-       Low TSH and fT3 were associated with poor function at 3 months, and that low TSH and fT3 were associated with higher rates of death in the hospital

- Most common thyroid condition
- more common in women 

- Iodine deficiency and autoimmune diseases (Hashimoto thyroiditis) accounts for most of primary cases of hypothyroidism 

- Iodine deficiency affects 1/3 of the world population due to living in iodine-deficient areas – iodine deficiency affects the neurological development of foetuses and children.

Global variation in epidemiology of hypothyroidism 
-Overall prevalence is 4.6% 

-More common in white and Hispanic individuals. Lower in afro-caribbean descent. 

-Prevalence in china has increased by 13.48%

Hypothyroidism in pregnancy 
-Control of thyroid status is essential for obstetric and offspring outcome.

-Subclinical hypothyroidism before 20weeks of gestation = higher risk of miscarriage and isolated hypothyroxinaemia. 

Congenital hypothyroidism
-Most common treatable causes of mental retardation 

-Birth screening programmes have reported an increase in prevalence. 

-Increases can be associated with changes in ethnicity of the populations or lowering the TSH cut-off

Drug induced hypothyroidism
-Lithium, amiodarone, tyrosine kinase inhibitors can cause hypothyroidism 

-Amiodarone induced hypothyroidism is more common than amiodarone induced thyrotoxicosis in iodine sufficient areas.  

-Immune checkpoint inhibitors – used for managing advanced cancer – reactivate the immune system against cancer cells but can induce autoimmune adverse effects that have a majority for the hypothalamic pituitary thyroid axis.

- Pts taking immune checkpoint inhibitors can develop primary or secondary hypothyroidism. 

 
Iodine – induced hypothyroidism 

-Underlying mechanism is not understood 

-Failure of the thyroid adaptive mechanisms to an acute iodide load (the wolff-chaikoff effect)

-Common source of excess iodine supplementation, diet, iodinated contrast agents and medications. 

Effects of iodine fortification 
-Mandated in over 120 countries 

-Requires regular monitoring to ensure that fortification programmes meet changing demands given the adverse outcomes

-There is an increase in the frequency of thyroid autoimmunity post iodization programmes thought to be caused by iodization of thyro-globulin which enhances immunogenicity

-Iodization increases the risk of thyrotoxicosis secondary to excessive iodization – meaning increased sodium intake. In some areas, increased cases of toxic nodular goitres were observed post iodization.

 

 

 

 

-       Located in the anterior neck, on the trachea just inferior to the larynx 

-       Blood supply comes from superior and inferior thyroid arteries 

-       Epithelial cells (follicle cells) in the follicles produce thyroglobulin 

o   Thyroid hormone is derived from iodinated thyroglobulin 

-       Central cavity stores colloid, which consists of thyroglobulin molecules attached with iodine atoms 

-       Two amine hormones: thyroxine (T₃) and triiodothyronine (T₄)

-       Affects virtually every cell in the body 

-       Binds to intracellular receptors in a cell nucleus and turns on transcription genes concerned with glucose oxidation 

-       TH increases basal metabolic rate and body heat production 

-       Plays an important role in maintaining blood pressure 

-       Secretion of TH from anterior pituitary binds to receptors on follicle cells to synthesize thyroid hormone

1.     Thyroglobulin is synthesized and discharged into the follicle lumen

2.     Iodide is trapped 

3.     Iodide is oxidized into iodine

4.     Iodine is attached to tyrosine

5.     Iodinated tyrosine’s link together to form T₃ and T₄

6.     Endocytosis of thyroglobulin and combined with lysosome

7.     T₃ and T₄ cleaved and sent into the bloodstream 

-       Both overactivity and underactivity of the thyroid can cause metabolic disturbances

o   Problems such as myxoedema, endemic goitre, cretinism, Grave’s disease 

·      2002 United States National Health and Nutrition Examination Survey (NHANES III):

o   Overt hyperthyroidism detected in 0.5% of general population

o   0.7% of the general population had subclinical hyperthyroidism, with an overall prevalence of 1.3%.

o   Studies from several other countries, including Sweden, Denmark, Norway, and Japan have all reported comparable incidence and prevalence rates. 

·      Prevalence and incidence of thyroid dysfunction difficult to compare across countries owing to differences in diagnostic thresholds, assay sensitivities, population selection and fluxes in iodine nutrition and population dynamics.

·      Prevalence of overt hyperthyroidism is roughly similar in Europe and the United States (0.7% versus 0.5%)26,27. 

·      In Australia, slightly lower prevalence of 0.3% was reported in 2016 for both overt and subclinical hyperthyroidism, while a 5-year incidence of hyperthyroidism was estimated at 0.5% in 2010.

·      In general incidence of hyperthyroidism corresponds to population iodine nutrition, with higher rates of hyperthyroidism occurring in iodine-deficient countries.

·      Primary:

o   Increased stimulation, secondary to TSH receptor antibodies (Graves disease) and excess human chorionic gonadotropin secretion (hyperemesis gravidarum and trophoblastic tumours, such as choriocarcinoma or hydatidiform mole)

o   Autonomous thyroid function: toxic multinodular goitre, solitary toxic nodule and familial non-autoimmune hyperthyroidism 

o   Excess release of stored thyroid hormone: autoimmune (silent or post-partum thyroiditis), infective (viral (De Quervain thyroiditis)), bacterial or fungal) pharmacological (amiodarone IFN-α) or radiation - Exposure to excess iodine known as the Jod–Basedow effect (from excess iodine intake including radiographic contrast) 

·      Secondary (central): 

o   Inappropriate TSH secretion (TSH secreting pituitary adenoma or pituitary resistance to thyroid hormone) 

·      Extra-thyroidal:

o   Excess intake of thyroid hormone (iatrogenic or factitious)

o   Ectopic thyroid hormone secretion (struma ovarii and functional thyroid cancer metastases)

·      Graves disease is characterized by hyperthyroidism and diffuse goitre; ophthalmopathy, pretibial myxedema and thyroid achropachy can also be observed

·      Pathogenesis remains incompletely understood, but the central pathogenic event is the unregulated stimulation of the TSH receptor by autoreactive TSH receptor antibodies. 

·      More common in females.

·      Toxic nodular goitre is the most frequent cause of thyrotoxicosis in elderly individuals, especially those in iodine-deficient areas

·      Solitary toxic nodules are more common in women than in men, and some studies have reported a male:female ratio of 1:5.

·      Thyroiditis is characterized by a self-limiting course of thyrotoxicosis, followed by hypothyroidism and then return to normal thyroid function

·      The condition is slightly more common in females than males (female:male ratio of 1.5:1) and permanent hypothyroidism occurs in 10–20% of cases overall. 

·      Acute painful thyroiditis often presents following a respiratory tract infection61, while painless thyroiditis can occur post-partum in up to 9% of otherwise healthy women

Drug-induced hyperthyroidism. 

·      Iodine-rich compound amiodarone widely prescribed as an anti-arrhythmic agent.

·      Amiodarone-induced thyrotoxicosis is more common in iodine-deficient areas and appears to be more common in men with a male:female ratio of up to 3:1. 

·      The reported regional prevalence of amiodarone-induced thyrotoxicosis is highly variable, ranging from 1% to 38% with more detailed reported rates of 3% in North America and 5.8% in Japan 

·      Other drugs that cause thyrotoxicosis include IFN-α, lithium, tyrosine kinase inhibitors, highly active antiretroviral therapies, immune checkpoint mediators and the humanized monoclonal antibodies used in the treatment of multiple sclerosis.

·      Although these drugs can cause transient thyrotoxicosis through destructive thyroiditis, immune-modifying agents such as IFN-α, highly active antiretroviral therapies and alemtuzumab can also induce Graves disease through less well-defined immune reactivation mechanisms.

·      More common in women.

·      Often progresses to more overt disease.

·      Globally, the greatest risk factor for subclinical hyperthyroidism, aside from levothyroxine use, is iodine deficiency. 

·      Iodine-induced hyperthyroidism, also known as the Jod–Basedow phenomenon.

·      More common in older persons with longstanding nodular goitre and in regions of chronic iodine deficiency, undergoing iodine supplementation.

·      In addition to iodine supplementation, radiographic contrast agents can cause iodine-induced hyperthyroidism. 

·      Thyrotoxicosis in pregnancy has an estimated incidence of 0.2% for overt thyrotoxicosis and 2.5% for subclinical thyrotoxicosis

·      Greatest risk of hyperthyroidism in the first trimester.

·      Graves disease is the most common cause of thyrotoxicosis in pregnancy, although other causes, such as toxic nodules and goitres, can occur during gestation. 

·      Occurrence of hyperthyroidism in pregnancy may be overestimated, due to inclusion of cases of gestational thyrotoxicosis,

·      Management of thyrotoxicosis in pregnancy is complex, has to address risk of maternal hyperthyroidism with that of fetal harm from transplacental transfer of maternal antibodies and thionamide drugs.

Treatment

·      A substantial global variation exists in the treatment of hyperthyroidism. 

·      Choice of antithyroid drugs, radioiodine or surgery might have a modest impact on the epidemiology of hypothyroidism given that radioiodine and surgery ultimately result in permanent hypothyroidism.