Download ENDOCRINE PATHOLOGY: PITUITARY AND THYROID

ENDOCRINE PATHOLOGY: PITUITARY AND THYROID
Trinity Medical School Undergraduate Lecture.
Dr. B. Loftus, Adelaide and Meath Hospital.
Background
Endocrine function refers to the transmission of a message by a chemical substance which
acts on specific receptors. Chemical messengers which are endocrine include amines,
polypeptides, organic acids and steroids.
There are several mechanisms of chemically mediated cell to cell communication.
1. The classical endocrine pathway (e.g. insulin, ACTH, parathyroid hormone) involves
hormone production by a cell which is then released into the circulation and acts on a distant
target cell.
2. Other mechanisms are paracrine whereby chemical modulators do not enter the circulation
but travel a short distance between the secretory cell and the target cell.
3. Neuroendocrine function involves neurones discharging their secretory products directly
into the circulation (hypothalmic and posterior pituitary neurones).
4. The production of chemical substances by certain cells to regulate some of their own
activities is referred to as autocrine.
The endocrine system refers to a highly integrated group of organs that maintains metabolic
equilibrium. Within the various endocrine organs many endocrine cells can secrete and store
more than one hormone. Hormones themselves are capable of conveying different messages
and evoking different responses. Endocrine disease may be due to underproduction or
overproduction of hormones or to mass lesions within endocrine glands.
PITUITARY GLAND
The pituitary gland is also known as the hypophysis and is composed of two anatomically
distinct lobes. The anterior lobe (adenohypophysis) is derived from an upward evagination
of pharyngeal epithelium know as Rathke’s pouch.
The posterior pituitary lobe (neurohypophysis) is a downward projection of neural tissue
from the hypothalamus and is normally joined to the anterior lobe. A rudimentary
intermediate lobe is known as the pars intermedia.
The cells of the anterior pituitary lobe produce growth hormone (GH) which stimulates the
growth of many cells and tissues. Growth hormone is produced by acidophilic cells.
Prolactin (PRL) is also produced by acidophils; it is essential to lactation and also has other
metabolic activities.
FSH (follicle stimulating hormone) is produced by the basophilic cells and stimulates the
formation of Graffian follicles in the ovary.
Luteinizing hormone (LH) is produced by the basophils and together these cells are known
as gonadotroph basophils. LH induces ovulation and formation of corpora lutea in the ovary.
ACTH (adrenocorticotrophic hormone) is created by a subset of basophils and it controls
adrenal secretion of cortisol and other hormones.
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Thyroid stimulation hormone (TSH) is produced by pale basophilic cells and controls the
growth and function of the thyroid.
Melanocyte stimulating hormone (MSH) is part of the ACTH molecule prohormone and
increases skin pigmentation.
There are two posterior lobe hormones, vasopressin (also known as antidiuretic hormone
or ADH) which has the function of promoting water resorbtion from the distal renal tubular
fluid and conserving it for the body.
The other hormone is oxytocin which stimulates uterine muscle contractions during and after
childbirth.
Damage to the posterior pituitary lobe or stalk results in a disorder called diabetes insipidus.
Both ADH and oxytocin are made in the hypothalamus and are transported into intraaxonal
neurosecretory granules in the posterior pituitary from where they are released into the
circulation.
CONTROL OF ANTERIOR PITUITARY FUNCTION
Control of anterior pituitary function is via the neuroendocrine axis. This is an integrated
system both anatomically and functionally. Various neurone groups in the hypothalamus
secrete factors that stimulate the anterior pituitary lobe, and are as follows:
1. Growth hormone releasing factor (GRF),
2. Gonadotrophin releasing hormone (GNRH)
3. Thyrotrophin releasing hormone (TRH)
4. Corticotrophin releasing factor (CRF)
5. Melanotrophic releasing hormone (MRF)
There are three inhibitory hormones produced by the hypothalmus and these are
1. Prolacatin inhibitory factor (PIF)
2. Growth hormone inhibitory factory (GHIF)
3. A melanotrophin inhibitory factor (MIF)
These hormones are polypeptides and are stored in and released from neuronal endocrine
granules. These granules can be demonstrated by electron microscopy and
immunohistochemistry with corresponding antibodies. The hormones are secreted into the
hypothalamic portal capillary network, flow down the pituitary stalk to the second portal
capillary network of the anterior pituitary lobe, and then exert their functions. Hypothalamic
releasing and inhibiting factors are produced by the hypothalmic nuclei in response to
cerebrocortical influences. A negative feedback also exists whereby ambient levels of target
organ hormone product inhibit their release.
The posterior pituitary hormones are produced in the hypothalamus by neurones whose axons
extend into the posterior pituitary lobe. The hormones are stored at the end of the axons in
the posterior pituitary and are released into the general circulation upon the arrival of an
action potential.
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PITUITARY HYPOFUNCTION
In adults hypofunction can be caused by any process that will destroy pituitary tissue.
Pituitary infarction can be caused by post partum or peripartum haemorrhage (also known as
Sheehan’s syndrome), DIC, sickle cell anaemia, temporal arteritis, hypovolaemia, or
cavernous sinus thrombosis.
Hypofunction may also be caused by compression from a tumour (functioning or
nonfunctioning) and also by infection, for example tuberculosis. Pituitary hypofunction is
also known as Simmond’s disease.
Patients may present acutely with apoplexy, failure of lactation and secondary amenorrhoea.
Pituitary hypofuction may also present more chronically (e.g. in the case of Sheehan’s
syndrome up to 2 years after the event) with deceased thyroid or gonadal activity,
hypoadrenalism, hypothermia, hypoglycemia.
Chronic pituitary hypofunction in childhood may present with proportional dwarfism. Other
syndromes include Frohlich’s syndrome in which boys of pubertal age develop a girdle of
obesity and fail to develop either primary or secondary sex characteristics. Again, any
process that will destroy enough anterior lobe tissue may be responsible including tumours
infarctions, inflammations and cysts.
PITUITARY TUMOURS
Anterior pituitary adenomas are benign neoplasms most common between the ages of 20
and 50 years. Small nonfunctioning adenomas are found incidentally in 25% of adult
autopsies. Microadenomas are <1cm in diameter and are rarely functional (with the
exception of some prolactinomas). Macroadenomas (>1cm) generally do produce symptoms.
Effects of macroadenomas include:
1. hormone overproduction with normal production of other hormones
2. hormone overproduction with reduced production of other hormones
3. pressure atrophy
4. effects of a space occupying lesion.
In a familial disorder known as multiple endocrine neoplasia (MEN) syndrome type 1,
pituitary adenomas, adenomas of the thyroid gland, adrenal cortex, parathyroid gland and
pancreatic islets may coexist.
Most commonly a pituitary adenoma presents as an enlarging space occupying mass without
overt endocrine effects. It may produce lateral visual field defects. Headaches are also
characteristic. Very rarely, macroadenomas are silent until revealed by radiological
investigation.
Pituitary tumours may be classified according to the hormones they produce. The most
important microadenomas are prolactinomas. These produce prolactin and may be a cause of
irregular menstruation and ovulation, and infertility. Elevated blood prolactin levels inhibit
luteinising hormone necessary for ovulation. Treatment by transphenoidal removal or drug
inhibition with bromocriptine may restore fertility.
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Of clinically significant pituitary tumours 32% are lactotroph (PRL), 21% are somatotroph
(growth hormone), 13% are corticotroph (ACTH) and a quarter are nonfunctional. The
remainder are mixed somatotroph/lactotroph, gonadotroph and thyrotroph. Syndromes of
common functional pituitary adenomas include galactorrhoea and amenorrhea with prolactinproducing adenomas; acromegaly and gigantism with growth hormone-producing adenomas
and Cushing’s disease in ACTH-producing adenomas.
Pituitary adenomas that secrete growth hormone produce acromegaly in adults and
gigantism if the epiphyses are unfused. Once full adult height has been achieved only some
bones will respond to excess growth hormone. In particular, these are the bones of the hands,
feet, mandible and maxilla. The affected person therefore develops course facial features
with overgrowth of the mandible and maxilla and enlarged hands and feet. Increased soft
tissue mass, arthritis and osteoporosis may also develop. Diabetes mellitus will develop in
30%, as growth hormone has an anti-insulin effect. Compressive effects of the tumour
include visual field effects (bitemporal hemianopia), hypogonaism and amenorrhea.
Occasionally galactorrhoea, hyperpigmentation, hyperthyroidism, virilisation or adrenal
hyperplasia may develop due to synthetic infidelity and production of other hormones.
Basophil pituitary adenoma is the classic cause of Cushing’s disease. Excessive ACTH
secretion causes hypersecretion of cortisol and cortisone by the adrenal cortex. This brings
on the changes seen in Cushing’s syndrome. The major clinical aspects of Cushing’s
syndrome include emotional disturbance, an enlarged sella turcica, moon facies, osteoporosis,
cardiac hypertrophy with hypertension, a buffalo hump, obesity, thin wrinkled skin,
abdominal striae, amenorrhea, muscle weakness, purpura and skin ulcers due to poor wound
healing.
Secondary pituitary abnormalities include feedback tumour, for example due to adrenal,
thyroid or gonadal failure (also known as Nelson’s syndrome). In the case of an ACTH
secreting feedback tumour, this may develop several years after bilateral subtotal
adrenalectomy for Cushing’s syndrome. These pituitary tumours are due to lack of feedback
control by the target organ.
In both animals and humans who are exposed to high levels of corticosteroids, whether
administered therapeutically or endogenously produced by adrenocortical hyperfunction, the
corticotrophic basophils of the pituitary gland undergo vacuolar degeneration with loss of
basophilic granules and a microscopic change known as Crooke’s hyaline change. This is
another secondary abnormality of the pituitary.
Tumours of the posterior pituitary lobe are uncommon.
Occasionally, minute remnants of Rathke’s pouch persist (between the anterior and posterior
pituitary) and are composed of nests of squamous epithelial cells. The latter may be the
source of craniopharyngioma, a benign tumour arising in this region.
Craniopharyngiomas compress adjacent structures. Crainopharyngiomas are slow growing
and patients may survive for prolonged periods. They consist of anastomosing cords of
epithelial cells with glandular spaces. Keratin pearls and calcification may also occur.
Diabetes insipidus or other types of hypopituitarism may develop. ADH deficiency due to
defective secretion by the neurohypophysis results in impairment of water reabsorption in the
distal renal tubule. This results in the production of inappropriately dilute urine and the
clinical syndrome of diabetes insipidus, with polypuria and polydipsia. Typically polyuria of
up to 10 litres daily of low specific gravity urine is produced with a concomitant
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hypovolemia and hypernatremia. Urine specific gravity does not alter with fluid deprivation
but if ADH is administered parenterally, urine specific gravity will increase.
THYROID GLAND
The thyroid is located anterior to the thyroid cartilage just below the larynx in the neck. It
consists of right and left lobes joined by an isthmus. The weight of the normal thyroid is
between 10 and 30 grams.
The normal thyroid gland is impalpable. The thyroid is derived embryologically from a
downward migration of epithelium from the foramen caecum of the tongue along the
thyroglossal duct. Remnants of this migrational path are known as thyroglossal duct cysts.
Microscopically the thyroid parenchyma consists of many follicles with a rich vascular
stroma which contains scattered ‘C’ cells and minimal collagenous septae. The follicles are
lined by cuboidal epithelium and filled with a pink colloid material, which is stored
thyroglobulin. Under thyroid stimulating hormone (TSH) secretion by the pituitary,
thyroglobulin in the follicles is processed to thyroxine (T4), and a small amount of
triiodothyronine (T3), which are then released into the blood stream. T3 and T4 are produced
by the follicular epithelium and TSH stimulation causes the follicular epithelium to become
more columnar. Trace amount of iodine in the diet are needed to form thyroid hormones.
The follicular epithelium adds or subtracts colloid depending on the degree of stimulation
from TSH.
The ‘C’ cells in the interstitium between the follicles produce calcitonin, which in humans
has minimal functionality.
Thyroid hormone synthesis involves numerous enzymatic pathways. Iodine is trapped,
coupled with tyrosine, and results in the formation of monoiodothyronine, and
diiodothyronine. Eventually the active thyroid hormones triiodothyronine (T3) and thyroxine
(T4) are formed. T3 is also converted directly to T4. Dietary iodine is essential to this
process.
There are numerous metabolic functions of thyroid hormone of which the most important are
as follows:
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T3 and T4 uncouple oxidative phosphorylation resulting in a. less effective ATP
synthesis and b. greater heat release.
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Increase in cardiac output, blood volume, and systolic blood pressure.
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Increased gastrointestinal motility.
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Increased oxygen consumption by muscle, leading to increased muscular activity with
weakness.
THYROID DISEASE- THYROIDITIS
Among the diseases of the thyroid, thyroiditis is relatively common. There are several
clinico-pathologic type of thyroiditis.
1.
Lymphocytic, (focal) which may have an immunologic basis.
2.
Hashimoto thyroiditis (struma lymphomatosa) in which patients develop antithyroid
microsomal antibodies.
3.
Atrophic thyroiditis (primary myxodema); these patients also have antithyroid
microsomal antibodies.
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4.
5.
Granulomatous (deQuervain’s) in which patients may have antibodies to adenovirus
or mumps virus.
Riedel’s thyroiditis (also known as woody thyroiditis or invasive fibrous thyroiditis).
The cause of this is unknown but it may be associated with fibromatosis.
HASHIMOTO THYROIDITIS
This disease occurs in middle aged females and often presents with a diffuse rubbery goitre
(enlargement of the thyroid). At presentation approximately 50% of the patients will be
hypothyroid but many will be also euthyroid (normal thyroid function) and a small minority
will present with symptoms of hyperthyroidism. Eventually all patients become hypothyroid.
There is a very strong association with other autoimmune disease and patients have
anticytoplasmic antibodies. It is thought that abnormal T cell activation and B cell
stimulation results in the production of variety autoantibodies to TSH and thyroid peroxidases
(antimicrosomal), with lymphocytic infiltration, Hurthle cell change, follicle destruction and
replacement fibrosis of the thyroid gland. Initially the enlargement is painless, later on in the
disease, the gland atrophies. Hurthle cells are follicular epithelial cells which have abundant
granular and pink cytoplasm. Hashimoto thyroiditis is the most common cause of
hypothyroidism in adults apart from surgery. Microsomal antibodies can be detected in the
serum and in the tissue. Patients may have other autoimmune conditions including Grave’s
disease, SLE, rheumatoid arthritis, pernicious anaemia and Sjogren’s syndrome.
DeQuervain’s thyroiditis is a subacute granulomatous thyroiditis. This is a self-limited
disease lasting for weeks to months. The patients present with painful enlargement of the
thyroid gland. On microscopy there are numerous foreign body giant cells and inflammatory
cells with active destruction of follicles.
SIMPLE GOITRE
Simple goitre refers to diffuse enlargement of the thyroid gland without nodularity.
Patients are euthyroid (normal thyroid function).
The aetiology includes an absolute or relative lack of iodine which may be endemic or
nonendemic.
Nonendemic causes include inherited enzyme defects and excess dietary goitrogens.
Inherited enzyme defects (also known as dyshormogenesis) include defects of iodine
trapping, organification, coupling and deiodination. Dietary goitrogens suppress the
synthesis of T3 and T4. These include foods such as cassava, brassica, turnip, cabbage, kale
and sprouts.
Treatment with thiourea also causes simple goitre. Simple goitre is also associated with
increased physiologic demand on thyroid function such as that occurring during puberty,
pregnancy and stress.
COLLOID CYSTS
Colloid cysts are focal nodular lesions within the thyroid gland and on scanning appear as
cold nodules. This means that they do not take up radioactive iodine and are nonfunctional.
MULTINODULAR GOITRE
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Multinodular or colloid goitre refers to nodular enlargement of the thyroid gland where the
gland is well over the normal weight of 30 grams and the patient is euthyroid but has a
swelling in the neck. Multinodular goitre is the commonest cause of an enlarged thyroid. It
is thought to be the result of long standing simple goitre.
THYROID ADENOMA
Adenomas of the thyroid gland are uncommon benign tumours of thyroid follicular
epithelium which may occur at any age but have a female preponderance of 6 to 1. They are
solitary, encapsulated and have a uniform microscopic pattern. Expansile growth of these
tumours may compress surrounding thyroid tissue. They are almost always nonfunctional or
hypofunctional (cold nodules) but very rarely may be hypofunctional and produce
thyrotoxicosis.
THYROID CARCINOMA
This accounts for 0.4% of all deaths from malignancy but forms a higher proportion of those
under 30 years (up to 15%). Thyroid cancer is more common in females (3 to 1) and the
types of cancer in descending order of incidence are papillary carcinoma, follicular
carcinoma, medullary carcinoma and anaplastic carcinoma.
PAPILLARY THYROID CANCINOMA
Over 80% of all thyroid malignancies are papillary carcinoma. Up to 10% are radiation
induced. These are unencapsulated tumours with papillary structures and focal calcifications
known as psammoma bodies. There is a uniform age distribution, and they have been
reported in patients as young as 6 months and as old as 104 years. Papillary carcinoma has a
particular propensity for lymphatic spread and there is frequently early rapid spread to
cervical lymph nodes. Approximately 60% will have cervical lymph node metastasis at
presentation; however, this is compatible with long survival of up to 25 years or greater. At
autopsy only 5% of patients will have spread outside the head and neck. The tumour is
common in middle age females. It may be multifocal within the thyroid due to the propensity
to invade lymphatics. Microscopically there is a papillary architecture and the tumour cells
have optically clear nuclei (also known as ‘orphan Annie’ nuclei !)
Laminated
calcifications known as psammoma bodies are frequent. Papillary thyroid carcinoma may
present as cervical lymph nodes metastasis where the primary tumour is in apparent.
FOLLICULAR THYROID CANCER
This represents about 10% of thyroid cancers and the peak incidence is in the 5th and 6th
decade. There is a female preponderance but this is less prominent than in papillary thyroid
carcinoma (PTC). The tumour is characterised by blood borne metastases to lung and bone.
The 5 year survival of follicular thyroid carcinoma is approximately 30%. There is a
follicular or solid growth pattern, tumours are often encapsulated and invasion of the tumour
capsule and blood vessels distinguishes it from follicular adenoma. Vascular invasion is
indicative of malignancy.
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MEDULLARY CARCINOMA
This is a rare tumour and represents <5% of thyroid malignancies. It may be familial in
patients under 30 or sporadic in those over 30 years. There is an equal male to female
incidence. It is a solid tumour of ‘C’cells (interstitial calcitonin-producing cells) and there is
abundant amyloid containing stroma. Like papillary thyroid carcinoma it shows early spread
to cervical lymph nodes. The 10 year survival is approximately 42%. The tumour secretes
calcitonin which may lower the serum calcium and can be measured in the serum. It may
also secrete 5HT, ACTH or prostaglandins.
ANAPLASTIC CARCINOMA
Anaplastic carcinomas are rare tumours of the thyroid and are undifferentiated and high
grade. They are clinically obvious and rapidly lethal. They present as fast growing hard neck
masses and usually develop in older patients. They may develop in a pre-existent goitre.
Microscopically the commonest pattern is of a bizarre cellular proliferation of spindle and
giant cells.
B. Loftus AMNCH.
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