Hormones pdf - د. هدف

Prof. Dr. Hedef Dhafir El-Yassin

2014

Lecture 5

Biochemistry and Disorder of Hormones of the

Thyroid Gland

Objectives:

1. to list the hormones synthesized by the thyroid gland and state their functions

2. to describe synthesis , regulation, and metabolism of thyroid hormones

3. to state the effects of increased and decreased concentrations of thyroid hormones

on TSH concentrations.

4. to understand the disorders of the thyroid and the associated diseases such as :

a. Hashimoto disease

b. Graves disease

c. Secondary hypothyroidism

d. Thyroid antibodies

Case (1): A 19- year-old patient visited the physician office complaining of weight loss,
nervousness, sleeplessness, heart palpitations and irregular menstrual cycle.
Her physical examination showed she had a noticeable tremor in her hands, underweight,
her BP was 160/85, she had a wide

–eyed stare and her lower neck was full. The

physician suspected thyrotoxicosis or increased circulating levels of thyroid hormones.
However, it was unclear from the available information why her thyroid hormone levels
were elevated. Lab tests were performed to determine the etiology of her condition:
Total T4

increased

Free T4

increased

TSH

decreased (undetectable)

1. The physician considered the following possible causes of thyrotoxicosis, based on his

understanding of the hypothalamic-anterior pituitary-thyroid axis:

a.  Increased secretion of TRH from the hypothalamus
b.  Increased secretion of TSH from anterior pituitary
c.  Primary hyperactivity of the thyroid gland (e.g. Graves disease)
d.  Ingestion of exogenous thyroid hormones.

Using the laboratory findings and your knowledge of the regulation of thyroid
hormone secretion, include or exclude each of the four potential causes of the
patient's thyrotoxicosis.

2. The physician performed a radioactive I

uptake test to measure the activity of the

patient's thyroid gland. When her thyroid was scanned for radioactivity, I

was

increased uniformly throughout the gland. How did this additional information help
refine the diagnosis? Which potential cause of thyrotoxicosis discussed in the above
question was ruled out by this result?

Prof. Dr. Hedef Dhafir El-Yassin

2014

Thyroid Hormones



The thyroid gland secretes thyroxine and smaller amounts of triiodothyronine (T3),

which stimulate oxidative respiration in most cells in the body and, in so doing,

help set the body’s basal metabolic rate.



In children, these thyroid hormones also promote growth and stimulate

maturation of the central nervous system.

o Children with underactive thyroid glands are therefore stunted in their growth

and suffer severe mental retardation, a condition called cretinism. This differs

from pituitary dwarfism, which results from inadequate GH and is not

associated with abnormal intellectual development.



People who are hypothyroid (whose secretion of thyroxine is too low) can take

thyroxine orally, as pills. Only thyroxine and the steroid hormones (as in

contraceptive pills), can be taken orally because they are nonpolar and can pass

through the plasma membranes of intestinal epithelial cells without being digested.



The thyroid gland also secretes calcitonin, a peptide hormone that plays a role in

maintaining proper levels of calcium (Ca++) in the blood. When the blood Ca++

concentration rises too high, calcitonin stimulates the uptake of Ca++ into bones,

thus lowering its level in the blood.

1. Thyroxin (T4) and triiodotyonine T3

Biochemistry of Thyroid Hormones

Thyroid hormones are derivatives of the amino acid tyrosine bound covalently to iodine.

The two principal thyroid hormones are:



thyroxine (T

or L-3,5,3',5'-tetraiodothyronine)



triiodotyronine (T

or L-3,5,3'-triiodothyronine).

Thyroid hormones are basically two tyrosines linked together with the critical

addition of iodine at three or four positions on the aromatic rings. The number and

position of the iodines is important. Several other iodinated molecules are generated that

have little or no biological activity; so called "reverse T

Prof. Dr. Hedef Dhafir El-Yassin

2014

A large majority of the thyroid hormone secreted from the thyroid gland is T

, but T

is the considerably more active hormone.

Although some T

is also secreted, the bulk of the

is derived by deiodination of T

in peripheral

tissues, especially liver and kidney. Deiodination of

also yields reverse T

, a molecule with no known

metabolic activity.

Thyroid hormones are poorly soluble in water, and

more than 99% of the T

and T

circulating in blood

is bound to carrier proteins. The principle carrier of

thyroid hormones is thyroxine-binding globulin, a

glycoprotein synthesized in the liver. Another

carrier is albumin.

Quick quiz: The characteristic features of active form of thyroid hormone are all except:

1. T3 is 4 times active than T4

2. T4 acts as a pro-hormone to T3

3. 80% of T3 is converted in circulation to T4

4. T3 is 10 times active at binding of receptors

Synthesis and Secretion of Thyroid Hormones

The entire synthetic process occurs in three major steps:



Production and accumulation of the raw materials



Fabrication or synthesis of the hormones on a backbone or scaffold of precursor



Release of the free hormones from the scaffold and secretion into blood

Prof. Dr. Hedef Dhafir El-Yassin

2014

Raw materials:



Tyrosines are provided from a large glycoprotein scaffold called thyroglobulin,. A

molecule of thyroglobulin contains 134 tyrosines, although only a handful of these are

actually used to synthesize T

and T



Iodine, or more accurately iodide (I

), is taken up from blood by thyroid epithelial cells,

which have on their outer plasma membrane an "iodine trap". Once inside the cell,

iodide is transported into the lumen of the follicle along with thyroglobulin.

Fabrication of thyroid hormones is conducted by the enzyme thyroid peroxidase,

Thyroid peroxidase catalyzes two sequential reactions:

1. Iodination of tyrosines on thyroglobulin (also known as "organification of iodide").

2. Synthesis of thyroxine or triiodothyronine from two iodotyrosines.

Thyroid hormones are excised from their thyroglobulin scaffold by digestion in

lysosomes of thyroid epithelial cells. Free thyroid hormones apparently diffuse out of

lysosomes, through the basal plasma membrane of the cell, and into blood where they

quickly bind to carrier proteins for transport to target cells.

Quick quiz:

Which of the following statement is true regarding thyroid peroxidase?

1. Free tyrosine in thyroid gland

2. It iodinates tyrosine residues in thyroxin binding globulin

3. It iodinates tyrosine residues in thyroxin binding prealbumn;

4. It iodinates tyrosine residues in thyroglobulin

Prof. Dr. Hedef Dhafir El-Yassin

2014

Control of Thyroid Hormone Synthesis and Secretion

Each of the processes described above appears to be stimulated by thyroid-stimulating

hormone from the anterior pituitary gland. Binding of TSH to its receptors on thyroid

epithelial cells stimulates synthesis of the iodine transporter, thyroid peroxidase and

thyroglobulin. When TSH levels are low, rates

of thyroid hormone synthesis and release

diminish.

The thyroid gland is part of the hypothalamic-

pituitary-thyroid axis, and control of thyroid

hormone secretion is exerted by classical

negative feedback.

Thyroid Hormone Receptors and

Mechanism of Action

Receptors for thyroid hormones are

intracellular DNA-binding proteins that

function as hormone-responsive

transcription factors, very similar

conceptually to the receptors for steroid

hormones.

Metabolic Effects of Thyroid Hormones

Thyroid hormones have profound effects on many physiologic processes, such as

development, growth and metabolism. They stimulate diverse metabolic activities

most tissues, leading to an increase in basal metabolic rate. One consequence of

this activity is to increase body heat production, which seems to result, at least in

part, from increased oxygen consumption and rates of ATP hydrolysis. A few

examples of specific metabolic effects of thyroid hormones include:



Lipid metabolism: Increased thyroid hormone levels stimulate fat

mobilization, leading to increased concentrations of fatty acids in plasma. They

also enhance oxidation of fatty acids in many tissues. Finally, plasma

concentrations of cholesterol and triglycerides are inversely correlated with

thyroid hormone levels - one diagnostic indication of hypothyroidism is

increased blood cholesterol concentration.

Prof. Dr. Hedef Dhafir El-Yassin

2014



Carbohydrate metabolism: Thyroid hormones stimulate almost all aspects of

carbohydrate metabolism, including enhancement of insulin-dependent entry of

glucose into cells and increased gluconeogenesis and glycogenolysis to

generate free glucose.

Other Effects: A few additional, effects of thyroid hormones include:



On muscle: T3 increases glucose uptake by muscle cells it also stimulate

protein synthesis and therefore growth of muscle through its stimulatory

actions on gene expression. Thyroid hormone sensitizes the muscle cell to the

glycogenolytic actions of epinephrine. Glycolysis in muscle is increased by

this action of T



On the pancreas: thyroid hormone increases the sensitivity of the



cells of

the pancreas to those stimuli that normally promote insulin release and is

required for optimal insulin secretion



On Cardiovascular system: Thyroid hormones increases heart rate, cardiac

contractility and cardiac output. They also promote vasodilation, which leads

to enhanced blood flow to many organs.



On Central nervous system: Both decreased and increased concentrations of

thyroid hormones lead to alterations in mental state. Too little thyroid

hormone, and the individual tends to feel mentally sluggish, while too much

induces anxiety and nervousness.



On Reproductive system: Normal reproductive behavior and physiology is

dependent on having essentially normal levels of thyroid hormone.

Hypothyroidism in particular is commonly associated with infertility.

Prof. Dr. Hedef Dhafir El-Yassin

2014

Thyroid Disease States

1. Hypothyroidism : a deficiency in thyroid hormone secretion and action

a. Primary: the synthesis of T4 and T3 is impaired due to one or more of

the following:

i. Loss of functional tissue

ii. Infiltrative disease o the thyroid

iii. Defects in the thyroid hormone synthesis

iv. Idiopathic (TSH receptor defect)

v. Thyroditis with auto-antibodies

b. Secondary: (central) occurs as a result of pituitary or hypothalamic

disease that produce a deficiency in TSH, TRH or both.

2. Hyperthyroidism (thyrotoxicosis): a hyper-metabolic condition caused by

excessive production of thyroid hormones. Causes are divided into:

a. Those that are associated with clinically evident hyperthyroidism and

increased production and secretion of thyroid hormones from the gland:

i. . Graves's disease: development of IgG antibody against the

thyroid TSH receptor resulting n overproduction of T4 and T3.

ii. Autonomous production by thyroid nodules

iii. A toxic solitary edema

iv. Excessive TSH secretion (rare)

b. Those that are not

i. Exogenous intake

ii. Iodine ingestion in excess

iii. Thyroid carcinoma

iv. Drug induced thyrotoxicosis with iodine containing medication

Prof. Dr. Hedef Dhafir El-Yassin

2014

Quick quiz:

A patient has a elevated serum T3 and free T4 and a very low serum

TSH. What is the most likely cause of theses results?

1. primary hyperthyroidism

2. secondary hyperthyroidism

3. euthyroid with increase throxine-binding proteins

4. euthyroid sick syndrome

Euthyroid sick syndrome: condition of abnormal thyroid hormone and TSH

concentrations in the severely ill opposing normal thyroid function. Often stimulates

hypothyroidism in euthyroid patients that suffer another illness, such as, DM of liver

cirrhosis.

Conclusions:

1. The thyroid gland is shaped like a shield and secretes hormones that help set the

body’s basal metabolic rate.

2. the thyroid gland secretes Thyroxin (T4) and triiodotyonine T3 which stimulate oxidative

respiration and calcitonin which stimulates the uptake of Ca++ into bones.

3. Thyroid hormones are derivatives of the amino acid tyrosine bound covalently to iodine

4. The thyroid gland is part of the hypothalamic-pituitary-thyroid axis, and control of

thyroid hormone secretion is exerted by classical negative feedback.

5. Thyroid Disease States might be hyper or hypo , and might be primary or secondary

autoimmune or other.

Prof. Dr. Hedef Dhafir El-Yassin

2014

Clinical Correlations

A 48-year-old woman was admitted to the hospital because of weight loss, palpitation,

weakness, and exophthalmos. She stated that a goiter, which had been present for years,

had recently begun to enlarge. She was extremely irritable, could not tolerate heat and

was short of breath. Physical examination revealed bilateral eyelid lag. The thyroid gland

was diffusely enlarged, and a bruit was audible over the right lobe. Her heart was

enlarged, a prominent apical thrust was noted, and there was a soft systolic heart murmur

along the left sternal border. Laboratory examination revealed that the hemoglobin was 1.8

mmol/L and that the hematocrit was 38%. The basal metabolic rate was 145% of normal.

plasma T4 and T3 were grossly elevated, and the

131

I uptake by the thyroid gland was

very high (18% in 4 hr). A diagnosis of hyperthyroidism was made.

Biochemical questions:

1. What are T3 and T4, and how are they related to the thyroid gland?

2. How are TRH and TSH involved in the regulation of thyroid hormone production and

secretion?

3. What is the mechanism of increased

131

I uptake in hyperthyroidism?

T3 and T4, are the thyroid hormones, triiodothyronine and thyroxine, respectively. Both are

tyrosine derivatives. Although lesser amounts of T3 are released by the thyroid gland, it

has a more potent effect than T4 in producing the hyper metabolic effects of the thyroid

hormones. T4 is converted to T3 in the target cells, and it is likely that T3, actually is the

metabolically active form of the thyroid hormone. In this sense, T4 may be considered as a

prohormone.

TSH is released from-the anterior pituitary and stimulates T3 and T4 production and

release. In turn, TSH release is stimulated by TRH, which is made in the hypothalamus.

When the plasma T3 and T4 concentrations are elevated, TRH production and release are

inhibited. This leads to decreased T3 and T4 release from the thyroid gland.

T3 and T4 contain iodine atoms attached to their phenolic rings. Thyroglobulin, the protein

precursor of these hormones that is contained in the thyroid cells, has many iodinated

tyrosine residues. The iodine is obtained from iodide ions in the blood plasma, and the

thyroid-cells have the capacity to take up and concentrate iodide ions.

Prof. Dr. Hedef Dhafir El-Yassin

2014

In hyperthyroidism the thyroid gland is rnore active than normal. It synthesizes more

thyroglobulin, T3, and T4 and takes up much larger amounts of iodine than in the euthyroid

(normal) state. Therefore, when

131

I is administered to a hyperthyroid patient, a larger

fraction of the dose is concentrated within the thyroid gland than in a euthyroid subject.

This is useful clinically in two ways.

1. Small quantities of

131

I can be administered as a diagnostic test of thyroid function.

After administration, the radiation emanating from the thyroid grand can be

measured at various times by placing a scanning device over the neck. Greater

than normal uptakes occur in hyper thyroidism, and less than normal uptakes occur

if the thyroid gland is hypo functioning (hypothyroidism).

2. The enhanced iodine uptake can be used to treat hyper thyroidism. If larger

amounts of

131

I are administered, enough

131

I will concentrate in the thyroid to

provide intense but localized radiation to the glandular cells. This will destroy many

of the T3- and T4- producing cell, reducing the excessive function of the thyroid and

correcting the hyperthyroidism.

As compared with the thyroid, other tissues take up very little iodine. Consequently, most

of the

131

I that is not taken up by the thyroid is rapidly excreted in the urine, and there is

comparatively little radiation exposure in other tissues. In some respects this is a safer

form of treatment than surgical removal of a large portion of he hyperactive grand. It is not

without some danger, however, for

131

I treatment can lean in some cases to either

hypothyroidism or even thyroid cancer.

Prof. Dr. Hedef Dhafir El-Yassin

2014

Answers to case (1):

The physician considered the following possible causes of

thyrotoxicosis, based on his understanding of the hypothalamic-anterior
pituitary-thyroid axis:
a.  Increased secretion of TRH from the hypothalamus
b.  Increased secretion of TSH from anterior pituitary
c.  Primary hyperactivity of the thyroid gland (e.g. Graves disease)
d.  Ingestion of exogenous thyroid hormones.
Using the laboratory findings and your knowledge of the regulation of thyroid
hormone secretion, include or exclude each of the four potential causes of
the patient's thyrotoxicosis.
A1

(a) Theoretically, but rarely, a hypothalamic tumor can secrete increased levels of

TRH. As a result, secretion of TSH by the anterior pituitary is increased, leading
to increased secretion of thyroid hormones from the thyroid gland. However, this
diagnosis was ruled out by the decreased (undetectable) levels of TSH in the
blood. If the primary defect was in the hypothalamus, TSH levels would have
been increased, not decreased.

(b) By similar reasoning, anterior pituitary can secrete too much TSH(e.g from a

pituitary adenoma), driving increased secretion of thyroid hormones. However,
this diagnosis was also ruled out by findings of undetectable levels of TSH in the
blood.

(c) If there was primary hyperactivity in the thyroid land itself, either because the

thyroid gland was secreting its hormones autonomously or because a substance
with TSH-like action was driving the thyroid gland, then the lab. Data were
consistent levels of both free T4 (the primary secretory product of the gland) and
total T4 (which includes both free and protein bound forms in plasma) would be
increase. Importantly, TSH levels would be decreased because of negative
feedback inhibition of thyroid hormones on the anterior pituitary gland

(d) If the patent had ingested synthetic thyroid hormone, her levels of T4 and total

T4 have been increase and her TSH level would have been decrease.

(e) The physician is left with the question of whether the patent ha hyperactive

thyroid or ingesting exogenous thyroid hormone for weight control. So he
applied the radioactive I

scan.

The physician performed a radioactive I

uptake test to measure the

activity of the patient's thyroid gland. When her thyroid was scanned for
radioactivity, I

was increased uniformly throughout the gland. How did this

additional information help refine the diagnosis? Which potential cause of
thyrotoxicosis discussed in the above question was ruled out by this results?
I

uptake was increased throughout the gland, suggesting uniform hyperactivity. If

the patent was ingesting exogenous thyroid hormones, her thyroid gland would not
have shown increased functional activity, I

uptake would have been decreased

because the high levels of thyroid hormone would have suppressed thyroid gland
activity.