HY-ROAD Section 3 -> THYROID GLAND

Endocrine Lecture 3 - Exam 1

Gross Anatomy of the Thyroid Gland

The thyroid gland is located anterior and lateral to the trachea, just below the

thyroid cartilage (Adam's apple).

• It consists of two (sometimes three) lobes (one on each side of the trachea).

• The lobes are connected by a bridge of thyroid tissue called the isthmus, which is located just below the cricoid cartilage.

• The thyroid gland is barely palpable.

• The thyroid gland weighs 10 to 20 grams in normal adults.

Microanatomy of the Thyroid Gland

Microscopically, the thyroid is composed of

spherical follicles, each composed of a single

layer of follicular cells surrounding a lumen

filled with colloid

TGB

thyroglobulin (some people call it TG)

C cells (parafollicular cells)

secrete calcitonin

There are two types of thyroid hormone

1. triiodothyronine (T3 )

2. thyroxine (T4 )

Thyroid Hormone Structure

Thyroid hormones are derivatives of the amino acid tyrosine. A majority of

the thyroid hormone secreted by the thyroid gland is T 4 (approx. 95%). Most of

the T 4 released by the thyroid gland, however, is converted to T 3 by target

tissues. T 3 is about 4‐5 times more potent than T4 .

Thyroid hormones are unique in that they contain …

60‐65% of the trace element

iodine (I). Adequate iodide (I‐) intake is necessary for normal thyroid hormone

synthesis as thyroid hormones are the only substances in the body that have iodine

in their structure.

How much iodine should one eat?

The minimum dietary requirement

of iodide for adults is about 75‐150 micrograms/day (normal US daily intake is 500).

What’s the difference between primary, secondary and tertiary hypothyroidism?

• Primary is thyroid

• Secondary Pituitary

• Tertiary is making to little hormones in the hypothalamus

What’s the difference between primary, secondary and tertiary hyperthyroidism?

Thyroid Hormone Synthesis 8 Steps (3 catagories)

GATHER UP THE INGREDIENTS

1) Follicular cells synthesize TGB (with its numerous tyrosine) and dump into the colloid

2) Iodine trapping via the Na+ /I‐ pump (active transport)

.

MIX & BAKE THE INGREDIENTS

3) Oxidation of I‐ to I2

4) Organification of I2 , i.e., add the iodine to the tyrosine on TGB to make MIT and DIT

5) Coupling and colloid storage

• MIT + DIT = T3

• DIT + DIT = T 4

The mixing and baking steps (3‐ 5) require THYROID PEROXIDASE

Thyroid Hormone Synthesis (GATHER UP THE INGREDIENTS)

1) Follicular cells synthesize TGB (with its numerous tyrosine) and dump into the colloid

2) Iodine trapping via the Na+ /I‐ pump (active transport)

Thyroid Hormone Synthesis (MIX & BAKE THE INGREDIENTS)

3) Oxidation of I‐ to I2

4) Organification of I2 , i.e., add the iodine to the tyrosine on TGB to make MIT and DIT

5) Coupling and colloid storage

• MIT + DIT = T3

• DIT + DIT = T 4

The mixing and baking steps (3‐ 5) require THYROID PEROXIDASE

Thyroid Hormone Synthesis (RELEASE THE FINISHED PRODUCT)

6) Transport from colloid to follicular cells

7) Cleavage of T 3 , T 4 , DIT and MIT (via lysosomal fusion) & release of T 3 and T4 to the blood

.

8) Deiodination of residual MIT & DIT (via thyroid deiodinase) and recycling of I‐ and tyrosine

Enlarged Theroid is ….

Goiter

How long can people go without Iodine/no T3/T4

Estimated that individuals can store

1‐2 month supply of T 3/T 4

TSH Actions

Stimulates TGB synthesis

Stimulates Na+ /I‐ pump

activity

Activates thyroid peroxidase

Stimulates growth of thyroid

follicles (hypertrophy and

hyperplasia of thyroid

follicular cells and increased

thyroidal blood flow)  If

TSH levels are extremely

high, this can manifest in a

patient as _______

Thyroid Hormone Transport

Thyroid hormones are transported in blood bound to carrier

proteins. Although only approx. 0.04% of T3 and T4 are "free", it is

the free fraction that is responsible for hormonal activity.

There are three major thyroid hormone transport proteins:

thyroxine‐binding globulin (TBG) [Don’t confuse with TGB]

• thyroxine‐binding pre‐albumin (TBPA)

• albumin

The total amount of thyroid hormones bound to these plasma

proteins provides a substantial reservoir of T3 and T4 in the blood

Congenital Hypothyroidism

• Either no thiroid

• Have a thrioid that jsut does not work

.

Incidence  1 in 3000 to 5000 newborns

Untreated  Growth retardation and delayed cognitive development

Three screening approaches are generally used:

Primary screening for low free T 4 with follow up (secondary) screening for high TSH if the free T 4 value is below a certain concentration

• Primary screening for high TSH

• Primary screening for both low free T 4 and high TSH

How can the lab tell if a baby needs theriod treatment?

Blood for screening is collected onto filter paper cards after heel prick, usually two to five days after birth.

In the adult, thyroid hormones’ effects

on the CNS mainly consist of maintaining a level of alertness, concentration and focus

Thyroid hormone & growth

Thyroid hormone is required for growth to adult stature.

• Thyroid hormones act synergistically with growth hormone and somatomedins to promote bone formation.

• Thyroid hormones promote ossification and fusion of bone plates and bone maturation.

• In hypothyroidism, bone age is less than chronologic age.

• Mainly important in pre puberty (After puberty growth hormone takes over)

Thyroid Hormones on BMR

Thyroid Hormones on Metabolism

Thyroid Hormones on Cardiovascular

Thyroid Hormones on intestinal motility

Thyroid hormones stimulate intestinal motility

Causes of Hypothyroidism (4)

Hashimoto’s (chronic autoimmune)

thyroiditis (P) [the most common

cause]

• Iodine deficiency (P)

• Thyroidectomy (P)

• Lack of TSH (S

Clinical Manifestations of Hypothyroidism

Hypothyroidism → Soft tissue damage process

Synthetic thyroid hormone (T4)

Levothyroxine (T4 ) [Levothroid, Levoxyl, Synthroid, Unithroid]

.

By far and away, the most popular preparation used clinically

Synthetic thyroid hormone (T3)

Liothyronine (T3 ) [Cytomel]

• Typically only given to patient in which they cannot naturally produce this (typically converted from T4)

Typical Dosing of Levothyroxine

The average replacement dose of T 4 in adults is approx. 1.6‐1.8 mcg/kg

body weight per day (approx. 112 mcg/day in a 70‐kg adult)

Dosing of Levothyroxine in the Elderly

In older patients, those with heart problems, and those with long‐

standing hypothyroidism  they should be started on a lower dose (as

little as 12.5‐25 mcg/day), as moving from a hypothyroid to a euthyroid

state can cause excessive stress on the cardiovascular system; the dose

can be increased, if necessary, by 12.5‐25 mcg/day every 4‐6 weeks

Levothyroxine for weight loss

This can lead to what is known as FACTITIOUS

HYPERTHYROIDISM

Levothyroxine Negative Side Effects (7)

General  fatigue, increased appetite, weight loss, heat intolerance, fever, excessive sweating

• Central nervous system  hyperactivity, nervousness, anxiety, irritability, insomnia

• Musculoskeletal  tremors, muscle weakness

• Cardiovascular/Respiratory  palpitations, tachycardia, arrhythmias, increased blood pressure, angina, myocardial infarction, dyspnea

• Gastrointestinal  diarrhea, abdominal cramps

• Endocrine  decreased bone mineral density

• Reproductive  menstrual irregularities, impaired fertility

Myxedema

Myxedema describes the skin and soft

tissue changes that occur in

hypothyroidism (especially when severe)

What causes the Skin Swelling in Myxedema

The deposition of GLYCOSAMINOGLYCANS

occurs most notably in the dermis of the

skin, which results in swelling of the

affected areas.

Myxedema Coma

Myxedema coma is defined as severe hypothyroidism (with all the

skin and soft tissue swelling) PLUS DECREASED MENTAL STATUS

(mental slowness, confusion, apathy, depression) and

HYPOTHERMIA. However, hypotension, bradycardia, hypoglycemia,

hyponatremia, and hypoventilation are often present as well.

.

It is a medical emergency with a high mortality rate (30‐40%);

fortunately, it is a rare presentation of hypothyroidism

Myxedema Coma Management:

• Supportive measures  correction of hypothermia, administration

of electrolytes and glucose, mechanical ventilation if necessary

• IV T 4

Potential oral findings in hypothyroidism include:

macroglossia (which would be a sign of ______)

• micrognathia (pediatric)

• dysguesia

• enamel hypoplasia in both dentitions (being less intense

in the permanent dentition)

• delayed eruption in children

• poor periodontal health

• delayed wound healing

• thick lips (which would be a sign of ________)

• burning mouth syndrome

Clinical Manifestations of Hyperthyroidism

Causes

• Graves’ disease (P) [the most common cause]

• Toxic nodular goiter (P)

• Hyperfunctioning thyroid adenoma (P)

• Acute (destructive) thyroiditis (P)

• Jod‐Basedow syndrome (iodine‐induced

thyrotoxicosis)

• TSH‐secreting adenoma (S)

Symptoms of Hyperthyroidism (3)

More Symptoms of Hyperthyroidism (2)

Graves’ Disease Photo

Graves’ Disease Cause

TSH Actions (Graves’ Disease)

Graves’ disease occurs

when autoantibodies

known as TSIs (thyroid

stimulating

immunoglobulins)

.

DON’T

DESTROY THE THYROID

GLAND, but instead BIND

TO TSH RECEPTORS AND

CONSTANTLY STIMULATE

THE THYROID

Acute (Destructive) Thyroiditis

First things first: Acute (destructive) thyroiditis is NOT the same as Hashimoto’s

thyroiditis

In acute thyroiditis, here is an initial presentation of hyperthyroidism which is followed by a hypothyroid phase and then recovery of thyroid function

In Hashimoto’s thyroiditis

In Hashimoto’s thyroiditis, there is no

recovery of thyroid function

Treatment of Hyperthyroidism

Graves’ disease may be treated with:

• anti‐thyroid drugs (i.e., thionamides)

• radioactive iodine (RAI) therapy

• surgery (thyroidectomy)

Ancillary medications may also be used to treat specific

symptoms as well.

Thionamide Drugs

Methimazole and propylthiouracil (PTU) inhibit thyroid peroxidase‐ catalyzed steps in the synthetic process

.

In addition, PTU inhibits the conversion of T4 to T3 in peripheral tissues

Thionamide Drugs

Although the inhibition of thyroid hormones synthesis occurs promptly, thyroid hormone levels may not become normal for several weeks (typically 4‐8) because thyroid hormone already stored in the colloid of thyroid follicles continues to be released into the circulation.

.

Once thyroid hormone stores are depleted, doses can be gradually tapered at monthly intervals to achieve the desired steady‐state thyroid hormone level.

Why do patients with Graves Disease take a Thionamide Drugs? (2)

In patients with Graves disease, a thionamide

drug can be used in:

1) An attempt to induce remission (may take 1‐2 years)

2) As a means to control symptoms before surgery or RAI

treatment.

Side Effects of Thionamide Drugs (3 Minor)

Relatively minor side effects of thionamides include

1. Skin rash

2. Gastric intolerance

3. Arthralgia.

Side Effects of Thionamide Drugs (2 Serious)

Serious side effects associated with thionamides include:

1. Agranulocytosis (granulocyte count < 250 l; normal: 2500‐6000)

2. Liver failure (much higher incidence with PTU)

Frequency of side effects in Thionamide Drugs

Agranulocytosis occurs in less than 0.5% of patients, generally within the first 3

months of taking thionamides, but may occur at any time.

.

• To detect this complication as early as possible, patients are instructed to have a CBC done immediately if they develop unexplained fever, malaise, sore throat, mouth sores or flu‐like symptoms, and not to resume the medication until a normal white blood cell count is reported.

• Prior to initiating thionamides, many clinicians obtain baseline blood tests, including a complete blood count (white count with differential) and a liver profile

Radioactive Iodine (RAI) Therapy

A single dose of radioiodine will cure the majority of patients with Graves’ disease within 6 weeks to 3 months

• a second dose may be given after this time if necessary (10‐15% of patients typically need a second dose).

.

Radioiodine is administered orally as sodium 131 I in solution or capsule.

• The radioiodine is rapidly incorporated into the thyroid, and its beta‐emissions result in extensive local tissue damage (tissue penetration of 2 mm).

Who should not receive Radioactive Iodine (RAI) Therapy

No woman of child‐bearing age should be treated with radioiodine without a careful inquiry about or testing for pregnancy.

.

Fetal thyroid tissue is present by 10 to 12 weeks and would be destroyed by the radioiodine, resulting in cretinism

Does Radioactive Iodine (RAI) Therapy help hypothyroidism?

In the past, it was controversial whether radioiodine should be given in a sufficient dose to induce hypothyroidism or a lower dose in an attempt to achieve a euthyroid state.

However, due to the high failure rate associated with lower doses designed to leave a patient euthyroid, most experts advocate radioiodine doses that result in hypothyroidism.

There is no evidence that radioactive iodine treatment of hyperthyroidism causes cancer of the thyroid gland or other parts of the body

Post‐Treatment Precautions of RAI Therapy

Patients who receive RAI therapy have the potential to expose their home and household contacts via saliva, urine, or radiation emitting from their body. They should be instructed to avoid the following during the restricted period:

.

1) Sharing cups or utensils

2) Sleeping in the same bed with another adult, pregnant woman, infant, or child

3) Sexual contact

4) Close contact with children and pregnant women

Thyroidectomy

The use of surgery as definitive therapy for hyperthyroidism varies with the cause of the disease and the characteristics of the patient.

Subtotal or total thyroidectomy is appropriate for patients with:

• very large or and/or obstructive goiters (as in some cases of Graves' disease)

• those who allergic to thionamides

• those who are unable to or refuse to receive RAI therapy.

Thyroidectomy complications include (4)

1) Transient vocal cord paralysis ‐ 3%

2) Prolonged post‐operative hypocalcemia – 3%

3) Permanent hypoparathyroidism – 1%

4) Recurrent hyperthyroidism – 2%

Beta‐blockers

Beta‐blockers are often started in most patients soon after the diagnosis of hyperthyroidism is made (assuming no contraindications to their use).

.

Beta‐blockers decrease the adrenergic manifestations (e.g. – tachycardia, palpitations, tremulousness, anxiety etc.) of hyperthyroidism.

.

Due to their relatively rapid onset of action, they can be used to alleviate symptoms until a thionamide takes effect or the patient is scheduled for surgery or RAI therapy.

Iodine Salts / Solutions

These salts/solutions also became “famous” during the age of nuclear reactor accidents, as they can block radioactive iodine uptake due to accidental exposure.

Why it is important for Treatment of Graves’ Ophthalmopathy

Reducing thyroid hormone secretion does not necessarily improve the pathology of Graves' ophthalmopathy, although it does decrease eyelid retraction and stare.

• Patients with Graves' ophthalmopathy should be treated according to the severity of their eye disease.

Treatment of Graves’ Ophthalmopathy (Mild)

For these patients only local measures are required, including

• Eye shades, artificial tears (saline eye drops),

• Avoiding sleeping on the face

• Raising the head of the bed

Treatment of Graves’ Ophthalmopathy (Severe)

The patient with red eyes and increasing diplopia & proptosis ‐‐‐ A trial of oral glucocorticoid therapy (prednisone, 30 mg/day for four weeks) can be initiated in patients with progressive ophthalmopathy.

• Higher doses may be required if this dose is ineffective. Local measures should also be used.

Thyroid Storm

Thyroid storm is a rare, life‐threatening condition causes by severe

clinical manifestations of hyperthyroidism (basically, exaggeration of

the usual symptoms of hyperthyroidism)

• Often precipitated by an acute event such as surgery, trauma,

  infection or parturition

• More likely to occur in a patient who has or has had Graves disease.

Thyroid Storm Symptoms (6)

1. Resting tachycardia (>140 bpm) or cardiac arrhythmia (A‐fib)

2. Hypotension/shock

3. Hyperpyrexia (104‐106 o F)

4. Agitation/anxiety/delirium/psychosis/stupor/coma

5. Severe nausea/vomiting/diarrhea/abdominal pain

6. Lab: elevated T3 & T4, low TSH

Potential oral findings in hyperthyroidism include (3)

1) Accelerated dental eruption in children

2) Increased susceptibility to dental caries & periodontal disease burning mouth syndrome

3) Plus, hyperthyroidism can exacerbate the patient’s response to dental pain and anxiety

First signs of Thyroid Cancer

Thyroid Cancer Types (5)

1. PAPILLARY

2. FOLLICULAR

3. HURTHLE CELL

4. MEDULLARY

5. ANAPLASTIC

PAPILLARY

• Arises from follicular cells, slow‐growing, treatable with good prognosis

• Cancer cells look and act similar to normal follicular cells

• Most common form of thyroid cancer, females affected 3X more than males

• Often spreads to lymph nodes

• (80%)

FOLLICULAR

• Arises from follicular cells, slow‐growing but more aggressive than papillary

• Cancer cells look and act similar to normal follicular cells

• 2nd most common thyroid cancer, females affected 3X more than males

• Associated with low dietary iodine

• Does not spread to lymph, but rather through the blood to lungs, liver, bone and/or brain
  
  

• (10%)

HURTHLE CELL

Arises from follicular cells, spreads through the blood, fairly aggressive,

lower cure rate than papillary and follicular thyroid cancer

• (3‐4%)

MEDULLARY

Arises from C‐cells, hence tumor secretes large amount of calcitonin

25% cases are inherited (familial medullary thyroid carcinoma)

Fairly aggressive, will spread through lymph nodes

Females and males are equally affected

• (4‐5%)

ANAPLASTIC

Rare (accounts for 1‐2% of thyroid cancer), but extremely aggressive

as it spreads to nearby structures (trachea, lungs, esophagus)

.

Cancer cells look much different compared to normal follicular cells

Very poor prognosis

Treatment for thyroid cancer

• thyroidectomy (partial or total)

• radiation therapy

• radioactive iodine therapy

• chemotherapy

• various types of immunotherapies and target therapies

(typically medications)

Radiation therapy and chemotherapy can lead to oral

health concerns such as ____________________