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ظظظ/

-2

-Dana Alrafaiah

-Amani Nofal

- MousaAlabbadi

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• You don’t need to go back to slide from 34-77 to any info. Only check the

clinical picture .

From the last lecture, adenomas can be functional or non- functional

The old literature: nonfunctioning adenomas are more common but

recent studies are finding more gonadotroph adenomas and old

nonfunctional ones are now mostly FSH/LH containing adenomas.

For exam purposes, the answer depends on old literature.

Thyroid gland

Revision:

Thyroid gland is composed of a right lobe, a left lobe and an isthmus in-

between with 4 parathyroid glands located on its posterior aspect.

Feedback inhibition loop:

Increased serum levels of T3 and T4 will have negative feedback effect

on both the pituitary gland and the hypothalamus; it will inhibit the

release of TSH from the anterior pituitary and TRH from the

hypothalamus.

Thyroid disorders

Thyroid diseases are very common, and like other endocrine glands

there’s hyper and hypofunction- hyperthyroidism and hypothyroidism.

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Inflammation “Thyroiditis” also occurs leading to the destruction of the

gland and has types that are autoimmune(majority) and others.

Enlargements are mostly Euthyroid; not associated with hyper or

hypothyroidism (T3 and T4 levels are normal). An example is Diffuse and

Multinodular Goiter “MNG” which is the most common disease of the

thyroid gland and will be further discussed as we proceed.

Neoplasms of the thyroid are relatively common. Recall that there are

functional adenomas and non-functional adenomas, when discussing the

thyroid gland the nonfunctional adenomas are the most common type.

This is at least according to older literature from 10-15 years ago,

recently more sensitive tests that depend on transcriptional factors and

other molecules say gonadotrophic adenomas are more common now.

HYPERTHYRODISIM/THYROTOXICOSIS

Endocrine pathology is associated with biochemical changes that can be

observed in the serum. Hyperthyroidism is hyper function of the thyroid

gland leading to increased T3 and T4 levels and decreased TSH( negative

feedback inhibition) . TSH serum levels is the most sensitive test that

indicates hyperthyroidism. Hyperthyroidism with increased levels of TSH

is an indication of a TSH producing pituitary adenoma.(In this case only )

Signs and symptoms:

Palpitations, tachycardia,nervousness, impaired fertility, weight loss

despite eating a lot, heat intolerance (the opposite happens in

hypothyroidism) and other signs and symptoms all over the body; GI

tract, mood swings and the menstrual cycle etc.

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(

High TSH)

After a complete thyroidectomy, Hormone

Replacement Therapy (HRT) should be administered

to maintain normal thyroid function in its absence. A

dose of 30 or 50 mg of thyroxin is given and

monitored to make sure no abnormalities occur.

However, if the levels increase abnormally leading to

hyperthyroidism we call this condition factitious

thyrotoxicosis.

NOTE: at this level hyperthyroidism and thyrotoxicosis will be used

interchangeably (some claim that hyperthyroidism is a subtype of

thyrotoxicosis which is a clinical syndrome, however for simplification

purposes they represent the same thing for us)

Within the gland itself

Most common causes of

hyperthyroidism.

Normal

thyroid

gland

(problem is

not within

the gland

itself)

A dermoid/teratoma found in

the ovaries of 18-19 yrs old

females. A cross section of the

tumour shows different types of

normal tissue such as bone, hair,

teeth etc. if thyroid tissue is also

present then we call this

teratomastrumaovarii, it

produces T3 and T4 and increase

their levels in the blood. 95% of

such teratomas are benign. (rare

but can occur)

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This diagram illustrates the needed work up to diagnose a patient with suspected hyperthyroidism.

EXAMPLE: a man comes to the clinic, he is often agitated, has

tachycardia, eats a lot but doesn’t gain any weight. You suspect

hyperthyroidism. What is the first test that you should conduct?

TSH levels. (Remember it’s the most sensitive test)

If the TSH levels are elevated, this indicates a pituitary adenoma. You

refer your patient to imaging for an MRI to examine sellaturcica and the

tumor, and find out with it’s a micro or a macro adenoma etc.

If the TSH levels are low, you have to know the reason behind that. This

can be determined by obtaining a radioactive iodine uptake scan; here

we inject the blood with radioactive iodine and let some time pass, then

we measure iodine levels in the blood to see if it has been up taken by

the thyroid gland - high uptake or if the levels are the same- low uptake.

Low uptake indicates a primary thyroid problem (problem within the

gland itself; the gland cannot take iodine from the blood to synthesize its

hormones due to a problem with its cells), such problems include:

thyroiditis, ectopic thyroid hormone, exogenous thyroid hormone.

High uptake poses another question, how is the distribution of the

radioactive iodine? It could be Homogenous or nodular; Homogenous

indicates Graves disease,while nodular distribution can be one of two:

single or multiple areas.Multiple areas indicate Toxic multinodular goiter

(rare but can happen). A single area indicates Toxic adenoma.

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*note: the most common disease of thyroid is multinodular goiter (most cases are

euthyroid ) rarely goiter can be associated with hyperthyroidism (toxic goiter )

NOTE: check your patients eyes when hyperthyroidism is suspected; as

you will find many signs associated with it there, such as exophthalmos,

wide gaze vision etc. (will be further discussed).

NOTE: Another diagnostic scan is PETscan- stands for Positron Emission

Tomography- which is used in staging cancer. This scan uses a

radioactive sugar molecule-fludeoxyglucose (FDG). It measures its

uptake by the body in addition to creating a 3D image that allows us to

examine the region properly; it detects 1 cm nodules which can lead to

diagnosis of papillary thyroid carcinoma. This type of scanning increases

the detection of thyroid cancer and is the cause for the increased

detected incidences in recent years.

HYPOTHYROIDSM

The biochemical formula is increased TSH levels (primary) and decreased

T3 and T4 levels.

Clinical presentation:

In children- Cretinism. Remember that T3 and T4 are needed for mental

growth in addition to physical growth, so in their absence the child

would have impaired CNS and bone growth, mental retardation, short

stature, coarse facial features, protruding tongue and umbilical hernia.

Early detection and treatment of cretinism is extremely vital to prevent

mental retardation (most importantly) in addition to all other

complications. Cretinism is now supposedly gone since in most countries

children are screened early on for thyroid abnormalities and parents

have better awareness about signs and symptoms that indicate

hypothyroidism, all leading to early detection and treatment .

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For treatment of squamous cell

carcinoma of the tongue or

larynx, that leads to damage to

neck causing hypothyroidism

MOST COMMON

Currently the most common

cause of hypothyroidism in non-

iodine deficient areas. (In the

Himalayas and South America

where iodine is deficient,

iodinated salt is sold everywhere

in order to prevent iodine

deficiency, so even in those

areas we find Hashimoto

thyroiditis to be the most

common cause of

hypothyroidism).

Result of end organ

resistance, one of the

mechanisms of

endocrine dysfunction

Lithium based drugs are used in

treatment of psychic illnesses

like mania.

In adults-Myxedema. Here growth is over( no mental or physical

retardation), and complications include: slow physical and mental

activity, cold intolerance(opposite of hyperthyroidism), overweight, low

cardiac output, GI symptoms like constipation, decreased sweating, cool

pale thick skin especially on the chin(opposite of pretibial myxedema).

Causes of hypothyroidism:

For localized tumours in one lobe Ablation is damaged to

thyroid gland

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Notice how the signs and symptoms of hyper and hypothyroidsm are

mostly the opposite of each other and involve all bodily functions.

Clinically speaking it’s not difficult to differentiate the two from each

other.

AUTOIMMUNE TYROID DISEASES

a very common and large group that includes: Hashimoto thyroditis,

Granulomatous thyroditis(de Quervain) and subacute lymphocytic

thyroditis.

NOTE: some do not consider Granulomatous thyroditis atrue immune

disease because it’s not associated with anti-thyroid antibodies.

However, it is still included as some argue that it has an underlying

autoimmune cause.

HASHIMOTO THYRODITIS (CHRONIC LYMPHOCYTIC THYRODITIS)

Most common cause of hypothyroidism in areas with no iodine

deficiency (very important).Initial presentation (phase) includes a

transient increase in T3 and T4 levels (thyrotoxicosis) before it develops

into hypothyroidism. This may lead to misdiagnosis if the patient

presents to the hospital at this stage (gradual hypothyroidism, rarely

initial transient Hashitoxicosis). It is also common in middle aged females

(45-60 years).

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Basic pathogenesis:

Autoimmune destruction of thyroid epithelial follicular cells -which

release T3 and T4- by high anti-thyroid antibodies.

People who have it are at an increased risk of developing papillary

thyroid carcinoma and primary B-cell NH lymphoma (4-6 times more at

risk).

The body’s tolerance towards its own thyroid epithelial cells is

maintained by memory cells that recognize those cells as normal and do

not produce antibodies against them. If this tolerance is disrupted then

antibodies will be produced (can be detected in the serum) and will

attack thyroid cells by antibody-dependent cell-mediated cytotoxicity

(1). CD4+ T cells will react with thyroid antigens and produce cytokines

such as interferon ɣ (IFN-ɣ), which in turn activates macrophages

resulting in thyrocyte injury(2). CD8+ cytotoxic T cells will be activated as

well leading to T-cell-mediated cytotoxicity.

1 3

2

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Histologically: we can observe:

1-lymphoid inflammation: the thyroid gland

is destroyed due to inflammation resulting in

abnormal lymphoid follicles.

2- Atrophy of follicles. And no colloid

3- Hurthle cell change: enlarged thyroid

follicular cells with large cytoplasm that

appear pinkish and eosinophilic due to

increased number of mitochondria.

Under the microscope:

Lymphocytic follicular inflammation

and atrophy+ Hurthle cell change.

SUBACUTE GRANULOMATOUS (DE Quervian) THYROIDITIS

Granulomatous inflammation (thyroiditis), more acute with neck pain

and results in a firm thyroid.

Remember: granulomatous inflammation is associated with chronic

inflammation that includes epithelioidhistocytes, reactive T cells and

plasma cells. It could be necrotizing(TB) or non-necrotizing (sarcidosis).

Some trace de quervian thyroiditis to viral causes; they claim the

presence of coxsackievirus or EPV antibodies in the serum but nothing is

proved yet. De Quervian is also more common in females aged 30-50

years and has an initial transient thyrotoxicosis phase before developing

into hypothyroidism (same as in Hashimoto thyroiditis). This

inflammation is a self-limiting disease that resolves on its own within 6-8

weeks, it is usually diagnosed clinically and patients are not referred to

pathologists.

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OTHER LESS COMMON THYROIDITIS:

1. Subacute lymphocytic thyroiditis: a chronic lymphoid

inflammation with no granulomas or Hurthle cell change.

Common in middle aged women who are post-partum. Like the

previous two inflammation, has an initial transient thyrotoxicosis

then gradual hypothyroidism. It’s an autoimmune disease where

circulating anti-bodies are found. The gland’s size is normal.

2. Riedel thyroditis: specific type of inflammation characterized by

IgG4 mediated destruction of the gland with severe fibrosis to the

point where the thyroid becomes stony-hard.

IgG4 can cause the same destruction in many organs. Fibrosis is

mediated by Transforming Growth Factor-β (TGF-β).

GRAVES DISEASE (TOXIC DIFFUSE GOITER)

Remember: toxic indicates thyrotoxicosis (hyperthyroidism) due to

high homogeneous uptake.

This disease was described by Robert Graves in 1835. It is the most

common cause of endogenous hyperthyroidism and includes the

triad of: thyrotoxicosis(with its associated signs and symptoms),

opthalmopathy (eye signs, like exopthalmos) and dermopathy(skin,

like pretibial myxedema).

*The doctor said this picture is not important*

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Histologically:

Observe that the follicles are surrounded by a

white columnar cells that resorb the colloid , the

colloid is pale with scalloped margin

Exopthalmos

AUTOANTIBODIES OF GRAVES DISEASE:

Normally T3 and T4 are released upon stimulation of the thyroid

gland by TSH, which is released from the anterior pituitary. Thyroid

hormones release is regulated; when their levels increase in the

blood there’s feedback inhibition on the release of TSH to prevent

further secretion of T3 and T4.

In Graves this mechanism is lost; there are antibodies that bind to

TSH receptor on the thyroid continuously stimulating it and resulting

in overproduction of T3 and T4 withno response to the feedback

inhibition on the pituitary gland that would normally occur due to

these increased levels.

**autoimmune ,HLA-DR3 and CTLA-4 / women 20-40 years

** sometimes TSH- binding inhibitor Ig , may cause hypothyroidism.

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Pretibial Myxedema:

subcutaneous deposition of fat

tissue on the shin.

DIFFUSE AND MULTINODULAR GOITER

This is a very common disease and it is the most common disease of the

thyroid gland. It is usually euthyroid; the goiter is not associated with

hyper or hypothyroidism, however there are rare cases in which we have

goitrous hypothyroidism.

The underlying pathogenesis in not yet understood; some claim there’s

hormonal imbalance with continuous stimulation and inhibition of the

gland causing it to enlarge and shrink throught the years, leading to

hyperplasia, hypertrophy and elevated TSH levels.

This disease is more common in females, and can be endemic-more

prevalent in certain geographical regions or sporadic. It starts initially

diffused then becomes multinodular, however it usually is detected in

the nodular phase. The goiter will enlarge and cause pressure on the

surrounding tissue leading to difficulty in swallowing, breathing, pain

and spontaneous hemorrhage(mass and cosmetic effect). In certain rare

cases, one or two of the nodules will release T3 and T4 increasing their

levels and leading to toxic MNG also known as “Plummer syndrome”.

Clinical features:

Middle aged female with

multiple masses.

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Note the fibrosis along with the nodules. Under the microscope: variable size follicles.

THYROID NEOPLASMS

Benign neoplasms are much more common the malignant ones. Most of

those benign neoplasms are non-functional adenomas as was

mentioned before. However, risk of malignancy increases with:

- Solitary nodules more than multiple nodules.

- Male nodules more than female nodules.

- Ages younger than 20 and older than 70 years old.

- Family history and previous history of radiation.

- Cold nodules much more than hot nodules.

What is cold/hot nodule?

Thyroid gland after resection: note the right and

left lobe, the isthmus and the nodules.

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In iodine uptake scan, a cold nodule has no iodine uptake(inactive),

while a hot nodule uptakes iodine and has zero(less than 1%) chance of

becoming malignant.

NOTE: MNG is more common than benign neoplasms.

FINE NEEDLE ASPIRATION

Routine initial tool for evaluating thyroid neoplasms. Simple, cost

effective, very accurate and is now well-standardized. If the mass is

palpable then the procedure can be carried out normally, however if it is

not the case is referred to a radiologist who conduct it under the

guidance of ultrasounds. After the sample is obtained it is put on a slide,

stained and examined under the microscope for features of follicular

carcinoma for example. Recent recommendations suggest that ALL FNA

procedures should be done under ultrasound’s guidance.

FOLLICULAR ADENOMAS

NOTE: the word follicle could be associated with adenoma or

carcinomas. However, the word adenoma-in the context of thyroid

neoplasms- indicates only follicular adenomas as there’s no such thing as

papillary adenomas only papillary carcinomas.

Most common adenomas are follicular adenomas. The underlying

pathogenesis is driver mutations in TSH stimulation and less commonly

RAS mutations, leading to autonomous adenoma.

Follicular adenomas come solitary, they are well-circumscribed within an

intact thick capsules that has no infiltrations in it or vascular invasion.

Bland cells or Hurthle cells may be present and in that case it is called

Hurthle cell adenoma. Occasional atypia can be seen as well.

The aforementioned intact capsule is the main feature through which

we distinguish between follicular adenomas and follicular

carcinomas(carcinomas have both capsular and vascular invasion).

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Normal compressed resected

lobe.

Capsule (note that there’s no

infiltration).

Tumor tissue

Hurthle cell adenoma

Remember Hurthle cells are large cells with

pinkish cytoplasm due to increased

number of mitochondria

Note: some people claim that hurthle cell

carcinoma is more dangerous than

follicular carcinoma.

THYROID MALIGNANCIES

Common but not aggressive, they generally have good prognosis even in

the presence of lymph node metastasis. They’re more common in

females and risk factors include: ionizing radiation (Chernobyl 1986) and

iodine deficiency.

Primary malignancies of the thyroid gland:

1- Papillary carcinoma: represent 75-85% of thyroid malignancies.

Metastasizes to cervical lymph nodes. Treatment of this

carcinoma includes total thyroidectomy and lymph node

dissection on right and left side of the neck.(note: remember

there’s no papillary adenoma).

2- Follicular carcinoma: 5-15% of all malignancies. Metastasizes

through the hematogenous route to the bones and the lungs.

3- Anaplastic carcinoma: one of the most aggressive human cancers,

patients live up to only one year after diagnosis. <5%

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4- Medullary carcinoma: not very common(5%), tumor arises in

parafollicular cells that produce calcitonin. May be a part of

Multiple EndocrineNeoplasia syndrome type2 (MEN2).

5- Lymphomas: remember patients with Hashimoto thyroiditis have

an increased risk of developing Papillary Thyroid Carcinoma(PTC)

and B-cell non Hodgkin lymphoma.

In recent years studies began on what is the underlying genetic

abnormalities resulting in malignancies, it was found that RET/PTC and

BRAF are linked to papillary carcinoma while RAS is linked to follicular

and anaplastic carcinomas. This can help in determining the best

candidates for thyroidectomies and aids in avoiding unnecessary

surgeries which will reduce costs and possible complications.

PAPILLARY THYROID CARINOMA

The most common thyroid carcinoma, relatively inactive (indolent). Has

good prognosis with 95% 10 years survival case, even in the presence of

lymph node metastasis(50% of PTC have lymphoid metastasis at the

time of presentation, which is why when thyroidectomy is preformed,

lymph node dissection is automatically done in the same surgery).

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Orphan Annie eye nuclei

Can be uni and multifocal- the two lobes and the isthmus all have

nodules.

Preoperative diagnosis by FNA is accurate because since there’s no

papillary adenoma, once papillary features are detected that

automatically indicates papillary carcinoma. There are 15 papillary

features such as: papillae, psammomabodies(calcification),

pseudonuclear inclusions and nuclear features (which are of great

importance in diagnosis): nuclear grooves and Orphan Annie eye nuclei.

Resected thyroid: firm and

calcified

This section shows well-formed

papillae lined by empty appearing

nuclei or “Orphan Annie eye”

Orphan Annie eye

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Nuclear groove

Inclusions

Calcifications

Vascular invasion Capsular invasion

Notice the “mushrooming” of the

tumor tissue into the capsule and how

it pierces it.

FOLLICULAR CARCINOMA(macro follicles that lack papillary nuclear features).

Solitary cold nodule that upon evaluation exposes capsular and vascular

invasion; these two characteristics differentiates it from follicular

adenoma. Common in women aged 40-60 years old and in iodine

deficient regions. Metastasizes through the hematogenous route to the

bones, lungs and liver. It doesn’t metastasize to the lymph nodes which

is why when follicular carcinoma is removed no lymph node dissection is

carried out. 50% of patients die within 10 years.

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This pinkish material is amyloid

which is protein deposition

produced by cancer cells.

ANAPLASTIC CARCINOMA

This type is rare, representing less than 5% of all thyroid malignancies. It

is extremely aggressive and infiltrates the surrounding it can enlarge to

the point where it suffocates the patient. It has a mortality rate of 100%.

The cells are undifferentiated and can be easily distinguished using FNA.

Occurs in 25% of people with previous history of a well-differentiated

carcinoma-papillary or follicular carcinoma. >than 65 years .

MEDULLARY CARINOMA

Arises from C-cells or parafollicular cells which are neuroendocrine cells

of the thyroid gland that release calcitonin, which in turn leads to

decreased calcium serum levels and hypocalcemia. It can be a part of

Multiple Endocrine Neoplasia syndrome type 2(MEN2)a &b, and can be

sporadic(70%) and in this case patients are of older-ages 50-60 yrs or

familial(30%) and patients here are of younger ages.

RET receptor tyrosine kinase mutations on chromosome 11 result in

medullary carcinoma ( as what doctor said in record sec.4 (1:07: 28). If a

person is diagnosed with this type of carcinoma his/her entire family

should be tested for this mutation, and those who appear to be positive

have to undergo a prophylactic thyroidectomy even if no medullary

carcinoma is present, because future risk remains high.

Medullary carcinoma ismulticentric and contains amyloid. It is also a

great mimicker; underthe microscope it can look like any tumor

(plasmatic, spindle etc), so usually when you examine a tumor that

doesn’t look strictly papillary or follicular you always think of medullary

carcinoma.

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Sometimes you can’t tell

whether the cells are C-cells or

follicular cells, so we stain using

Immunohisto chemistry (IHC),

the brown colour indicates

calcitonin which conforms that

this is medullary carcinoma.

Diagnosis of medullary carcinoma: amyloid deposition and calcitonin.

Parathyroid gland

Chief cells produce PTH, the gland is controlled by free calcium levels in

the blood more than by tropic hormones. Like other endocrine glands

there’s hypo/hyper functions and tumors, but tumors here rarely have a

mass effects because the parathyroid glands themselves are very small,

so even a 1 cm mass is considered massive, meaning the gland doesn’t

enlarge to the point where it can have a mass effect.

Functions of the parathyroid glands:

- Reabsorption of Ca from renaltubules.

- Excretion of PO4 into urine.

- Vitamin D conversion to active form.

- Stimulates osteoclast activity on bone resorption.

The end result is increased calcium levels in the blood.

HYPERPARATHYROIDISM

It can be primary, secondary and tertiary. Complications include:

Osteitisfibrosacystica, Brown tumor of bone, nephrolithiasis,

nephrocalcinosis and metastatic calcifications.

Primary HPT is due to adenomas in 85-95% of the cases, hyperplasia in

5-10% and carcinoma in 1% of the cases. Mutations in Cyclin D1 gene on

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chromosome 1 or MEN1 mutations can be the underlying genetic

abnormalities leading to HPT. ( go to slide 73)

When calcium and PTH levels are elevated we carry out an uptake scan

to see which of the 4 parathyroid glands is actively causing this, we

suspect parathyroid gland abnormalities because it is known that

parathyroid adenoma is one of the most common causes of

hypercalcemia and hyperparathyroidism. Once the abnormal gland is

identified, it is resected, and samples of the serum before and after the

resection are obtained and compared to make sure the correct gland has

been removed (PTH will be more sensitive that calcium).

CAUSES OF Hypercalcemia.

Due to chronic renal

failure and

continuous

stimulation of the

gland

Rare

Cancer metastasizes to the

bone, causing bone

destruction and the release of

calcium into the blood

Rare

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*Focus on primary and secondary HPT as tertiary HPT is more difficult to dignose*

HYPOPARATHYROIDSIM