Pathogenesis of diseases of the Pituitary, Pineal,Thyroid and Parathyroid glands

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 cells-concept of feedback inhibition

• Endocrine disease may be due to underproduction or overproduction of hormones, or mass lesions

Pituitary Gland

anterior

posterior

Pituitary Gland- microscopic

neurohypophysis

adenohypophysis

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 10% (basophils) (TSH/FSH/LH)

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 release-inhibiting factors

• Ambient levels of target-organ hormone product

Causes of Pituitary Hypofunction

• Infarction: Post-partum (Sheehans syn.)DICSickle cell anaemiaTemporal arteritisDM/hypovolaemiaCav. sinus thrombosis

• Compression:Non-functional tumourCraniopharyngiomaTeratoma

• Infection: TB meningitis

Symptoms and Signs of Pituitary Hypofunction

• Acute (adult): apoplexyfailure of lactationsecondary amenorrhoea

• Chronic (adult): myxedemahypoadrenalismhair loss/depigmentationhypothermia

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 overproductionHormone overproduction (e.g.TSH) with normal production of other hormones

• Hormone overproductionHormone overproduction with reduced production of other hormones

• Pressure atrophyPressure atrophy of gland with panhypopituitarism (non-functioning)

• Space-occupying lesionSpace-occupying lesion in the skull

Clinically Significant Pituitary Tumours

• Lactotroph 32.0%

• Somatotroph 21.0%

• Corticotroph 13.0%

• Mixed somato/lacto 6.0%

• Gonadotroph 1.0%

• Thyrotroph 0.5%

• Non-functional 26.5%

Syndromes of Common Functional Pituitary Adenomas

• Lactotroph (PRL) Galactorrhoea

Amenorrhoea

• Somatotroph (GH) Acromegaly

Gigantism

• Corticotroph (ACTH) 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

Coarse facial features

Big hands

Acromegaly

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 SynthesisI- 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 Thyroiditis-pathogenesis

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

• Subacute granulomatous thyroiditis

• Self-limited disease, weeks to months

• Painful enlargement of thyroid

• Microscopy shows numerous foreign-body 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: non-pitting oedema, hoarseness, cardiomegaly

• Hypercholesterolemia: accelerated atherosclerosis

• Commonest cause is autoantibodies to TSH

Hypothyroidism in infants

• 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

• 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

• 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

• 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

• 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

• 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

• 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 Ca2+

Ca2+

PO43–

ReleaseBone

Kidneys

Ca2+ reabsorptionPO4

3– excretion

PTH

Normal mineral metabolism

Brown EM. In: The Parathyroids – Basic and Clinical Concepts 2nd ed. 2001. Bilezikian JP et al. (eds)PTH, parathyroid hormone

Ca2+

Parathyroidglands

Calcitriol

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