Pathogenesis of diseases of the Pituitary,
Pineal,Thyroid and Parathyroid glands
Trinity Medical School Dublin
Dr. B. Loftus
Endocrine System
• Highly integrated group of organs that
maintains metabolic equilibrium
• Hormones act on distant target cellsconcept of feedback inhibition
• Endocrine disease may be due to
underproduction or overproduction of
hormones, or mass lesions
Pituitary Gland
anterior
posterior
Pituitary Gland- microscopic
adenohypophysis
neurohypophysis
Adenohypophysis
acidophils
basophils
chromophobes
Adenohypophysis:cell types
• Acidophils secrete growth hormone (GH) and
prolactin (PRL)
• Basophils secrete corticotrophin (ACTH), thyroid
stimulation hormone (TSH), and the
gonadotrophins follicle stimulating hormone
(FSH) and luteinizing hormone (LH).
• Chromophobes have few cytoplasmic granules
but may have secretory activity
Cell population of the anterior
pituitary
• Somatotroph (GH)
50%
(acidophils)
• Lactotroph (PRL)
20%
(acidophils)
• Corticotroph (ACTH)
20%
(basophils)
• Thyrotroph/Gonadotroph
(basophils) (TSH/FSH/LH)
10%
Prolactin stain pituitary
Neurohypophysis
• Resembles neural tissue with glial cells,
nerve fibres, nerve endings and intra-axonal
neurosecretory granules
• ADH (antidiuretic hormone, vasopressin)
and oxytocin made in the hypothalmus are
transported into the intra-axonal
neurosecretory granules where they are
released
Neurohypophysis
Control of Anterior Pituitary
Function
The Neuroendocrine Axis
• Cerebral cortical effects on hypothalamic
nuclei
• Hypothalamic releasing and releaseinhibiting factors
• Ambient levels of target-organ hormone
product
Causes of Pituitary Hypofunction
• Infarction:
• Compression:
• Infection:
Post-partum (Sheehans syn.)
DIC
Sickle cell anaemia
Temporal arteritis
DM/hypovolaemia
Cav. sinus thrombosis
Non-functional tumour
Craniopharyngioma
Teratoma
TB meningitis
Symptoms and Signs of Pituitary
Hypofunction
• Acute (adult):
apoplexy
failure of lactation
secondary amenorrhoea
• Chronic (adult):
myxedema
hypoadrenalism
hair loss/depigmentation
hypothermia
hypoglycaemia
• Chronic (childhood): proportional dwarfism
Frolich’s syndrome
Microadenoma Anterior Pituitary
•1-5% of
adults
•Rarely
have
significant
hormonal
output
Pituitary Adenoma
Pituitary Adenoma
Pituitary Macroadenoma
Piuitary macroadenoma- MRI
Pituitary Adenoma-autopsy
Effects of Pituitary Tumour
• Hormone overproduction (e.g.TSH) with
normal production of other hormones
• Hormone overproduction with reduced
production of other hormones
• Pressure atrophy of gland with
panhypopituitarism (non-functioning)
• Space-occupying lesion in the skull
Clinically Significant Pituitary
Tumours
•
•
•
•
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•
•
Lactotroph
Somatotroph
Corticotroph
Mixed somato/lacto
Gonadotroph
Thyrotroph
Non-functional
32.0%
21.0%
13.0%
6.0%
1.0%
0.5%
26.5%
Syndromes of Common
Functional Pituitary Adenomas
• Lactotroph (PRL)
• Somatotroph (GH)
• Corticotroph (ACTH)
Galactorrhoea
Amenorrhoea
Acromegaly
Gigantism
Cushing’s disease
Acromegaly: clinical features
• Median age 30+. Equal male/female incidence.
Characterised by acral enlargement, increased soft
tissue mass, arthritis and osteoporosis. Diabetes
develops in 30%. Serum GH elevated.
• Possible compressive effects of tumour include visual
field defects (bitemporal hemianopia), hypogonadism
and amenorrhoea.
• Tumours often display synthetic infidelity and may
cause galactorrhoea, hyperpigmentation,
hyperthyroidism, virilisation or adrenal hyperplasia
• The condition of gigantism develops if epiphyses are
unfused
Acromegaly
Coarse
facial
features
Big
hands
Secondary Abnormalities of the
Pituitary
• “Feedback” tumours due to adrenal, thyroid
or gonadal failure (Nelson-Salassa
syndrome)
• “Crooke’s hyaline change” in corticotrophs
due to high plasma cortisol
Suprasellar Craniopharyngioma
Craniopharyngioma
Empty Sella Syndrome
• The pituitary undergoes pressure atrophy
due to a suprasellar mass compressing the
gland in the sella turcica.
• The pituitary becomes completely flattened,
and clinical hypopituitarism accompanies
this.
“Empty Sella”
Diabetes Insipidus
• Failure of ADH release from posterior pituitary
due to destruction of hypothalamic-pituitary axons
• Causes polyuria of up to 10L daily of low specific
gravity urine with concomitant hypovolaemia and
hypernatraemia
• Urine specific gravity does not alter with fluid
deprivation but increases with parenteral ADH
Cushing Disease/Syndrome
• Cushing disease: overproduction of adrenal
cortical glucocorticoids secondary to
overstimulation by ACTH
• Cushing syndrome: similar to Cushing
disease, but is caused by adrenal cortical
adenoma, adrenal cortical hyperplasia or
adrenal cortical carcinoma
Cushing Disease
•Moon
face
•Plethora
Advanced Cushing Disease
•Truncal obesity
•Buffalo hump
•Wasting of extremities
musclature
PINEAL GLAND
• Pinecone shaped, minute, 180mg, at base of
brain
• Stroma and pineocytes (photosensory and
neuroendocrine)
• TUMOURS:
– Germinomas, teratomas (sequestered germ
cells)
– Pinealomas (pineoblastoma, pineocytoma)
Normal Thyroid in Situ
Normal Thyroid
colloid
Thyroid Hormone Synthesis
I-
I2
+ tyrosine
Mono-iodotyrosine
Di-iodotyrosine
Triiodothyronine (T3)
Thyroxine (T4)
Normal Thyroid
Follicular
epithelium
Thyroid Hormone Secretion
• T3 (triiodothyronine) and T4 (thyroxine)
are secreted into the rich vascular supply
of the interstitium
• The “C” cells of the interstitium secrete
calcitonin which lowers serum calcium
but has minimal functionality
Metabolic Effects of Thyroid Hormone
1. Uncouples oxidative phosphorylation
a. less effective ATP synthesis
b. greater heat release
2. Increases cardiac output, blood volume and
systolic blood pressure
3. Increases gastrointestinal motility
4. Increases O2 consumption by muscle, leading
to increased muscular activity with weakness
Thyroid Gland Development
• Downward migration of epithelium from
foramen caecum of tongue along the
thyroglossal duct
• Thyroglossal duct cysts develop from
remnants of this path
Thyroglossal Duct Cyst
Thyroglossal Duct Cyst
Types of Thyroiditis
• Lymphocytic (focal) :immunologic basis?
• Hashimoto (struma lymphomatosa):
antithyroid microsomal antibodies
• Atrophic (primary myxedema):
antithyroid microsomal antibodies
• Granulomatous (de Quervain’s):mumps
or adenoviral antibodies
• Invasive fibrous (Riedel’s): unknown but
associated with fibromatosis
Hashimoto Thyroiditis
• Middle aged females. Diffuse rubbery goitre; initially
painless, later atrophy
• 50% hypothyroid at presentation, many euthyroid,
minority hyperthyroid
• All become hypothyroid eventually
• Strong assn. with other autoimmune disease including
SLE, RA, pernicious anaemia, Sjogren’s syndrome
• Antibodies to TSH and thyroid peroxidases
• Lymphocytic infiltration, Hurthle cell change, follicle
destruction, replacement fibrosis
Hashimoto Thyroiditispathogenesis
Abnormal T cell activation and B cell
stimulation to secrete a variety of
autoantibodies.
Antibodies to TSH and thyroid peroxidases
(antimicrosomal)
Hashimoto’s Thyroiditis
Hashimoto’s Thyroiditis
Lymphoid
follicle
Hurthle
cells
Hashimoto’s Thyroiditis
Hurthle
Cells
Anti-microsomal antibody
Anti-thyroglobulin antibody
De Quervain’s Thyroiditis
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•
•
•
Subacute granulomatous thyroiditis
Self-limited disease, weeks to months
Painful enlargement of thyroid
Microscopy shows numerous foreignbody giant cells and destruction of
follicles
De Quervain’s Thyroiditis
Primary
Hypothyroidism
Low T4, low BMR:
• Slow mentation,bradycardia,constipation,
muscle weakness, coarse and scanty hair,
menorrhagia, cold sensitivity
• Increased tissue mucopolysaccharide: nonpitting oedema, hoarseness, cardiomegaly
• Hypercholesterolemia: accelerated
atherosclerosis
• Commonest cause is autoantibodies to TSH
Hypothyroidism in infants
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•
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•
Cretinism
goitre in endemic cretinism
pale cold skin with myxedema
mental retardation
stunted growth
protruding tongue, round face
Patient with Myxedema
Aetiology of Simple Goitre (euthyroid,
enlargement without nodularity)
• Absolute or relative lack of iodine: endemic goitre
• Inherited enzyme defects (dyshormogenesis): iodine
trapping, organification, coupling, deiodination
• Excess dietary goitrogens :cassava, brassica, turnip,
cabbage, kale, sprouts- these suppress the synthesis
of T3 and T4
• Treatment with thiourea
• Increased physiologic demand on function, e.g.
puberty, pregnancy, stress
Colloid Cysts
• Appear as “cold” nodules on scanning, do
not take up radioactive iodine
• Usually an incidental finding
Colloid Cysts
Multinodular Goitre
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•
•
•
•
•
Also known as colloid goitre
End result of long-standing ‘simple’ goitre
The gland is enlarged and weighs over 30g
Majority of patients are euthyroid
Presents as swelling in the neck
Commonest cause of enlarged thyroid
Multinodular Goitre
Multinodular Goitre
Multinodular Goitre
Clinical features of Primary
Hyperthyroidism
• SYMPTOMS
Weight loss
Nervousness
Heat intolerance
Palpitation
Diarrhoea
Amenorrhoea
• SIGNS
Tachycardia
Warm, moist palms
Lid-lag
Diffuse Goitre +/- bruit
Tremor
High T4, low TSH
Causes of Hyperthyroidism
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•
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•
Grave’s Disease (diffuse hyperplasia)
Ingested exogenous hormone
Hyperfunctional adenoma
Hyperfunctional multinodular goitre
Thyroiditis
Features unique to Grave’s
Hyperthyroidism
•
•
•
•
Exophthalmos
Lymphoid hyperplasia
Pretibial Myxedema
Pathogenesis is autoantibodies that bind and
activate TSH receptors on follicular cells
• Strong association with other autoimmune
diseases e.g. PA and myasthenia gravis
Thyroid Storm
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•
•
•
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•
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Severe hyperthyroid symptoms
Hyperpyrexia
Dehydration
Hypertension
Tachycardia, arrthymias
Shock
May be fatal
Grave’s Disease
Grave’s Disease
Hyperplasia
Thyroid Adenoma
• Uncommon benign tumours of thyroid follicular
epithelium which occur at any age but with female
preponderance (6F:1M)
• Solitary
• Encapsulated
• Uniform internal pattern
• Expansile growth compresses surrounding thyroid
• Usually non- or hypofunctional (cold nodule);
rarely hyperfunctional
Follicular Adenoma
Follicular Adenoma
Follicular Adenoma
Thyroid Carcinoma
• Accounts for 0.4% of all deaths from
malignancy but forms a higher proportion of
those under 30 years (up to 15%)
• More frequent in females (3:1)
• Types of cancer in descending order of
incidence are:
Papillary, Follicular, Medullary, Anaplastic
Papillary Thyroid Cancer
• Over 80% of all thyroid malignancies
• Up to 10% radiation-induced
• Unencapsulated tumour with papillary structures and
focal calcifications (psammoma bodies)
• Uniform age distribution (6 months to 104 years)
• Early rapid spread to cervical lymph nodes- 60% have
metastases at presentation but long survival common- 25
years or more
• Only 5% have spread outside the head and neck at
autopsy
Papillary Carcinoma
Papillary Carcinoma
Papillary Carcinoma
Papillary Carcinoma
Psammoma Bodies
Follicular Thyroid Cancer
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•
•
•
•
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About 10% of thyroid Cancers
Peak incidence 5th to 6th decade
Female preponderance, but less than PTC
Blood borne metastases to lung and bone
5 yr. Survival 30%
Follicular/solid growth pattern, often
encapsulated- invasion of capsule and blood
vessels distinguishes it from follicular
adenoma
Follicular Carcinoma
Medullary Thyroid Cancer
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•
•
•
•
•
•
Rare. Less than 5% of thyroid malignancies
Familial (under 30) or sporadic (over 30)
Equal male:female incidence
Solid C-cell tumour with amyloid stroma
Like PTC shows early spread to nodes
10 year survival 42%
Secretes calcitonin(+/- 5HT, ACTH, Pge) which
lowers serum calcium
Medullary Carcinoma
Amyloid in Medullary Carcinoma
Amyloid fluorescence
Anaplastic carcinoma
Anaplastic Carcinoma
Parathyroid and Adrenal
Glands,Endocrine Pancreas
Trinity Medical School
Dr. B. Loftus
Normal Parathyroid Gland
• Parenchyma consists of chief cells that
secrete parathyroid hormone
(parathormone, PTH) under the influence of
decreasing serum calcium.
• There are also variable numbers of oxyphil
cells in small nodules which have pink
cytoplasm
Parathyroid Glands
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•
•
Normal number 4 (but can be 2 or 6)
Normal combined weight 120 mg
Normal maximum dimension 6mm
Derived from epithelium and 3rd and 4th
branchial clefts
Normal Parathyroid
Actions of Parathormone PTH
• Kidney: a.increased Ca resorbtion by tubule
b.decreased phosphate resorbtion
c. stimulate 1,25-OH2D3 synthesis by the kidney,
thus promoting Ca absorbtion from the gut
• Bone: increased calcium and phosphate resorbtion
by osteoclasts
• Bowel: increased calcium and phosphate
absorbtion by enterocytes
Net effect:raises serum calcium, lowers serum
phosphate
Normal mineral metabolism
Ca2+ reabsorption
PO43– excretion
Ca2+
Kidneys
PTH
Calcitriol
Normal Ca2+
Parathyroid
glands
Ca2+
Bone
PO43–
Release
Brown EM. In: The Parathyroids – Basic and Clinical Concepts 2nd ed. 2001. Bilezikian JP et al. (eds)
PTH, parathyroid hormone
Causes and Types of
Hyperparathyroidism
• Primary: found in 1:1000 adults. Usually
female, 30+. Adenoma 70%, hyperplasia
30%.
• Secondary: less common. Chronic renal
disease, Vit D deficiency, malabsorbtion,
ectopic hormone production
• Tertiary: rare. Autonomous adenoma
developing in secondary hyperplasia.
Parathyroid Hyperplasia
Parathyroid Hyperplasia
Parathyroid Hyperplasia
Clear cell Hyperplasia
Parathyroid Adenoma
Dystrophic Calcification
Parathyroid Carcinoma
Features of Hyperparathyroidism
• Malaise, constipation, muscle weakness,
neuropsychiatric disorders
• renal colic due to stones (60%)
• bone pain due to generalised Ca loss
• peptic ulcer (10%)
• acute pancreatitis
• nephrocalcinosis
• raised serum calcium and PTH
• raised urinary PO4 and serum alk phos
• raised urinary hydroxyproline
Osteitis Fibrosa Cystica
• Classic localised bone lesion of hyperparathyroidism.
Bone is lysed by osteoclasts driven by elevated PTH.
Marrow replace by highly vascularised fibrous tissue.
Stress on weakened bone causes haemorrhage and cyst
formation.
• Old term for this lesion was “brown tumour”. Colour
due to massive haemosiderin deposition
• Typically found in jaw and long bones and may cause
pathological fractures
• Can be distinguished from other giant cell tumours of
bone by estimation of serum Ca.
Causes and features of
Hypoparathyroidism
• Injury or removal: surgery, birth trauma,
autoimmune destruction
• Receptor defect: X-linked dominant
receptor deficiency- so-called
pseudohypoparathyroidism
• Clinical features: tetany, low Ca, high PO4,
low urine PO4