thyroid hormones - lecture 28 FIRST LECTURE FOR EXAM 5

hypothalamus and pituitary

control the normal secretion of thyroid hormones, which in turn control metabolism

thyroid gland

is a butterfly-shaped organ located in the base of your neck

main function is the synthesis and storage of thyroid hormone

Thyroid hormones

circulate throughout the body bound to proteins- thyroid-binding globulin (TBG)

bind to their receptors, expressed in virtually all tissues and affect multiple cellular events

Genomic effects

Effects mediated primarily by the transcriptional regulation of target gene

Nongenomic effects

stimulations of activity of Ca2+ ATPase at the plasma membrane increasing oxygen uptake of the cells and the sarcoplasmic reticulum needed for cellular metabolism

THYROID HORMONE TRANSPORT AND CLEARANCE IN BLOOD

Circulating T4 - 90-95% - t1/2 = 6-8 d

Circulating T3 - 5% (1/100 of T4), t1/2 = 3-4 d

T4 and T3 are bound tightly to TBG - T4 also binds albumin and transthyretin

0.03% T4 free and bioactive compared to 0.3% T3

decrease levels of free hormone/drug

Drugs that increase thyroid binding globulin (TBG) binding: e.g., estrogens and opiates are going to ....

increase levels of free hormone/drug

Drugs that decrease TBG binding: e.g., glucocorticoids, androgens, aspirin and anti-seizure medications are going to ...

Steps in hormone synthesis and secretion

1. Iodide trapping (Iodide is the ion state of iodine)

2. Organification reaction(Iodination of thyroglobulin (Tg))

3. Coupling reaction (conjugation of monoiodotyrosine (MIT) and diiodotyrosine (DIT))

4. Hormone release (T4 and T3)

symptoms of hypothyroidism

Enlarged thyroid - goiter

Fatigue

Weight gain, inability to lose weight

A puffy-looking face

Primary Hypothyroidism

Low free T4, low or sometimes normal T3

High TSH

In utero - severe mental retardation or cretinism

In adults: -

-- Hashimoto disease – autoimmune

-- Causes might also include radioactive iodine therapy or surgery for an overactive thyroid

Secondary Hypothyroidism

Low T4 and T3 and TSH

-- Pituitary failure Thyroid gland functions well, but the pituitary gland doesn't stimulate the thyroid to produce more hormones.

-- The hypothalamus causing secondary hypothyroidism - The brain does not stimulate the gland for more hormone production.

Treatment: levothyroxine (T4)

Myxedema Coma

Rare life-threatening clinical condition in patients with longstanding severe untreated hypothyroidism. Early diagnosis, rapid administration, IV administration of levothyroxine and adequate supportive measures are essential for a successful outcome (e.g., IV hydrocortisone to address adrenal insufficiency, O2 therapy, fluid management to correct dehydration, warm blanket). The prognosis, however, remains poor.

-- Medical emergency - Extreme prolonged hypothyroidism

-- Elderly in winter, Infection, congestive heart failure can precipitate emergency

-- Mortality up to 60%.

•Features: hypothermia, respiratory depression, coma -Test plasma T4/TSH

-- Therapy: supportive care, ventilation, warming, intravenous steroids for

coexisting decreased adrenal reserve, thyroxine therapy with loading dose

Usually, a precipitating event disrupts homeostasis which is maintained in hypothyroid patients by a number of neurovascular adaptations:

-- chronic peripheral vasoconstriction

-- diastolic hypertension

-- diminished blood volume, to preserve a normal body core temperature.

ACT IMMEDIATELY

Hypothyroidism in Pregnancy

1. Pregnancy may exacerbate or unmask disease in patients with

preexisting autoimmune disease or living with iodine deficiency

due to increased estrogens increasing serum Thyroxine- binding globulin (TBG).

2. May increase miscarriage, preterm delivery, produce developmental delay.

Treatment : levothyroxine with regular monitoring with blood tests to ensure dosage is correct.

Levothyroxine (Synthroid)

Thyroid Replacement Therapy

is used to treat an underactive thyroid gland (hypothyroidism).

Used to treat pituitary failures, Hashimoto disease

Adverse effects rare unless excessive doses are taken

Thyroid Hormone Receptor

Nuclear receptor

Function as molecular switches in response to hormone binding

Can activate or repress gene transcription thereby effecting protein expression

Unoccupied thyroid hormone receptors are bound to DNA thyroid hormone response element (TRE)

Binding of the hormone to its receptor leads a confirmational change and modulates transcriptional regulation of target gene

Levothyroxine

Drug-Drug Interactions

Estrogen: Increase thyroxine-binding globulin (TBg) thereby decreasing free T4/T3

Barbiturates: Increases hepatic metabolism of levothyroxine

T4/T3: Increase receptor responsive of anticoagulants and tricyclic antidepressants

Increases receptor expression of vasopressors and sympathomimetics

Contraindications:

Patients with heart disease, diabetes, adrenal insufficiency and treatment for obesity

Hyperthyroidism

excessive thyroid function

Symptoms of Hyperthyroidism

Goiter

Anxiety

Weight loss

Larger eyes

secondary hyperthyroidism

High TSH

High T4 and t3

Increased thyroid hormone release by the thyroid gland in response to elevated TSH levels TSH-secreting pituitary adenomas

Treatment: methimazole, propylthiouracil

Graves disease autoimmune

TSH receptor stimulation by immunoglobulin G

Excessive T3 and T4 production

Protruding eyeballs exophthalmos

Thyroid storm

uncommon but is a crisis or life-threatening condition characterized by an exaggeration of the usual physiologic response seen in hyperthyroidism.

* High fever

* Tachycardia

* Nausea/vomiting

* Irregular heartbeat

* Acute heart failure

* Confusion/disorientation

Usually precipitated by concurrent medical problems (infections, stress, surgery, trauma, heart disease, diabetic ketoacidosis).

Treatment:

- antipyretics,

- large dose (200-400 mg) propylthiouracil (PTU) because of additional action of blocking peripheral T4 conversion

- b-blockers (propranalol) to counteract effects on SNS and heart

methimazole, (Tapazole) - antithyroid drug

Used to treat hyperthyroidism (overactive thyroid) and it is also used before thyroid surgery or radioactive iodine treatment

Prevents the thyroid gland from producing too much thyroid hormone. Inhibits the actions of thyroid peroxidase inhibiting organfication.

Using ____________ during pregnancy could harm the unborn baby. Methimazole can pass into breast milk and may harm a nursing baby. You should not breast-feed while using this medicine

propylthiouracil (PTU), (Propacil) - antithyroid drugs

Drug of choice in the treatment of thyroid storm;

Inhibits actions of thyroid peroxidase thereby inhibiting iodine organification and partially inhibits the peripheral deiodination of T4 to T3

There is positive evidence of human fetal risk during pregnancy.

perchlorate - Ionic Inhibitor - antithyroid drugs

2nd line treatment, used in wwii

limited use, low dose may be considered as a second-line treatment

Inhibits the sodium-iodide symporter (NIS). Blocks the entrance of iodide into the thyroid and inhibits the organification of iodine

Iodine - SSKI (potassium iodide saturated solution) - antithyroid drugs

Reduces the synthesis and secretion of thyroid hormones

Autoregulatory phenomenon inhibits organification (Wollf-Chaikoff effect)

Protects the thyroid from radioactive iodine fallout

131 I radioactive Iodine - antithyroid drugs

Destroys hyper-functioning thyroid tissue

Effective for permanent treatment of Graves disease and toxic goiter

Permanent cure to hyperthyroidism, results in permanent hypothyroidism and lifelong requirement for levothyroxine replacement

Euthyroid Sick Syndrome

Levels of T3 and/or T4 are abnormal, but the thyroid gland does not appear to be dysfunctional

A state of adaptation or dysregulation of thyrotropic feedback control

Caused by increased circulating cytokines and other inflammation mediators

Starvation, sepsis, surgery, myocardial infarction, bone marrow transplantation

Mediators Inhibit the thyroid axis at multiple levels, including the pituitary, the thyroid , transport proteins, peripheral tissues

Treatment: Primary goal is to treat underlying medical condition (e.g., infection or malnutrition. Use of thyroid hormone is controversial will depend on attending physician

KNOW THIS

KNOW THIS

Secondary Hypothyroidism

Pituitary Failure

what does low T4 and low TSH mean

Primary hypothyroidism

Hashimoto's thyroiditis

what does low T4 and high TSH mean

Primary Hyperthyroidism

Grave's disease (autonomous secretion of target gland hormone)

what does high T4 and low TSH mean

Secondary Hyperthyroidism

Pituitary tumor

what does high T4 and high TSH mean

Goiter

Excessive Thyroid Function or Lack of Iodine

Treatment: depends on the underlying cause

levothyroxine if caused by underactive thyroid

methimazole or propylthiouracil (PTU) if overactive thyroid

Corticosteroid medication if goiter is caused by inflammation

Amiodarone

is a class III antiarrhythmic agent commonly used to treat Afib

Amiodarone-induced hypothyroidism (AIH)

Amiodarone-induced Thyrotoxicosis (AIT)

Intrinsic drug effects of amiodarone

Amiodarone-induced hypothyroidism (AIH)

- inhibits thyroxine (T4) conversion to T3 and rT3 thus decreasing triiodothyronine (T3) production

- (and particularly the metabolite desethylamiodarone) blocks T3-receptor binding to nuclear receptors and decreases expression of some thyroid hormone-related genes

- may have a direct toxic effect on thyroid follicular cells, which results in a destructive thyroiditis

Effects due to iodine of amiodarone

Amiodarone-induced hypothyroidism (AIH)

- contains a large proportion of iodine: When intrathyroidal iodine concentrations reach a critical high level, iodine transport and thyroid hormone synthesis are transiently inhibited until intrathyroidal iodine stores return to normal levels (the Wolff-Chaikoff effect).

- contains two iodine atoms. It is estimated that amiodarone metabolism in the liver releases approximately 3 mg of inorganic iodine into the systemic circulation per 100 mg of amiodarone ingested. The average iodine content in a typical American diet is approximately 0.3 mg/day. Thus, 6 mg of iodine associated with a 200 mg dose of amiodarone markedly increases the daily iodine load

Treatment: Levothyroxine

Amiodarone-induced Thyrotoxicosis (AIT)

manifests with clinical signs indistinguishable from spontaneous hyperthyroidism

Treatment:

Mild AIT may spontaneously resolve in about 20% of the cases.

Type 1 AIT should be treated with high doses of methimazole (20-60 mg/day) or propylthiouracil (400-600 mg/day) to block the synthesis of thyroid hormones. The response to methimazole or propylthiouracil is often modest due to the high iodine levels in patients taking amiodarone. In selected patients, potassium perchlorate can also be used to increase sensitivity of the gland to methimazole or propylthiouracil by blocking iodine uptake in the thyroid.

Type 2 AIT can be treated with prednisone, starting with an initial dose of 0.5-0.7 mg/kg body weight per day and the treatment is generally continued for three months. Methimazole and propylthiouracil are generally not useful in Type 2 AIT.