Systemic Pathology

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Systemic Pathology

• The Endocrine System

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Normal Structure Function

• Endocrine vs Exocrine glands
• Paracrine glands (diffuse endocrine)
• Autocrine effects
• Hormones
• Secondary messenger molecules (e.g. cAMP)

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• Pituitary
• Essential control functions over endocrine system
• Adenohypophysis (75)
• Neurohypophysis (25)
• Adrenal Medulla
• chromaffin cells sympathetic nerves
• catecholamines
• Adrenal Cortex
• 3 histological zones
• Mineralcorticoids glucocorticoids sex steroids
• Thyroid
• Thyroxine (T4) tri-iodothyronine (T3)
• Calcitonin
• Parathyroid
• Parathyroid hormone (PTH) ? calcium homeostasis

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Endocrine Pathology

• Major disorders include
• Hyperfunction
• Hypofunction
• Tumours
• Benign
• malignant
• Considerations
• Interdependency of endocrine system
• Multiple endocrine neoplasia (MEN) syndromes
• A hormone may have diverse clinical effects

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Pituitary
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Hormone Secreting Cells of Adenohypophysis

• Corticotroph
• Basophilic
• Adrenocorticotrophic hormone (ACTH)
• Thyrotroph
• Basophilic
• Thyroid-stimulating hormone (TSH)
• Gonadotroph
• Basophilic
• Follicle-stimulating hormone (FSH)
• Luteinising hormone (LH)
• Somatotroph
• Eosinophilic
• Growth hormone
• Lactoroph
• Eosinophilic

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Hypopituitarism75 loss of parenchyma

• Aetiology
• Congenital (rare)
• Hypothalamic adenomas (prevent delivery of
  releasing factors)
• Non-secretory adenomas metastatic carcinoma
• Ischaemic necrosis
• Post-partum ? outgrows blood supply ? Sheehan
  syndrome
• Sickle cell anaemia
• Shock DIC
• Increased intra-cranial pressure
• Iatrogenic ablation (e.g. radiation surgery)
• Autoimmunity
• Granulomatous disease (e.g. TB sarcoidosis)
• Empty sella syndrome ? aracnoidmater CSF
  herniate into sella tuncica ? compression

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Clinical Features

• Depends on specific hormones lacking
• Hypofunction of adrenal cortex (?ACTH)
• Hypofunction of thyroid (?TSH)
• Hypofunction of gonads (?gonadotropin) ?
  amenorrhoea infertility impotence
• Dwarfism (?GH in children)
• Lack of pasrt-partum lactation (?prolactin)
• Pallor (?MSH)

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Hyperpituitarism

• Aetiology
• Adenoma of anterior lobe
• Hyperplasia of anterior lobe
• Carcinoma of anterior lobe
• Secretion of non-pituitary tumours
• Hypothalamic disorders

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Pituitary Anenomas

• Usually single cell type ? predominant hormone
• May contain 1 cell type that secretes more than
  1 hormone
• May contain more than 1 cell type
• Mostly isoloted lesions ? MEN
• Classified according to hormones produced by
  neoplastic cells

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Morphology

• Well circumscribed soft lesions
• Smaller tumours confined to stella tunica
• Larger lesions ? extend ? through sella diaphram
  ? compress optic chiasma
• 30 non-capsulated
• Foci of haemorrhage necrosis common in larger
  lesions
• Microadenoma lt 1cm macroadenoma gt 1cm

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The circumscribed mass lesion present here in the
sella turcica is a pituitary adenoma. Though
pituitary adenomas are benign, they can produce
problems either from a mass effect (usually
visual problems from pressing on the optic chiasm
and/or headaches) or from production of hormones
such as prolactin or ACTH.
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This is a microadenoma of the anterior pituitary.
Such microadenomas may appear in 1 to 5 of
adults. These microadenomas rarely have a
significant hormonal output that leads to
clinical disease.
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The microscopic appearance of the pituitary
adenoma is shown here. Note the monotonous
appearance of these small round cells.
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A craniopharyngioma is seen here at medium and
high power. It is derived from remnants of
Rathke's pouch and forms an expanding mass
arising in the sella turcica that erodes bone and
infiltrates into surrounding structures. They
are difficult to eradicate, even though they are
composed of histologically appearing squamoid and
columnar epithelium lining cystic spaces filled
with oily fluid.
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Classification

• Prolactinoma
• Most common
• ?chromophobe cells ? ?prolactin
• N.B. other conditions that increase prolactin
• Growth hormone secreting adenoma
• Before closure of epiphyses ? gigantism
• After closure of epiphyses ? acromegaly
• Corticotroph cell adenoma
• Hypercotisolism ? Cushings disease
• Nelsons syndrome ? development of adenoma after
  removal of adrenals
• Other (rare)

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Clinical Features

• Systemic effects of secreted hormone
• Prolactinoma ? decreased labido impotence
  galactorrhoea amenorrhoea infertility
• GH ? abnormal glucose tolerance muscle weakness
  Ht osteoporosis arthritis CHF
• ACTH ? Cushings syndrome hyperpigmentation
• Local mass effects
• Bone erosion
• Optic chiasm (bilateral haemianopsia)
• Increased intracranial pressure
• Compression of pituitary ? hypopituitism

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Systemic Features of Acromegaly
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Hormones of Neurohypophysis

• Anti-Diuretic Hormone
• Controls plasma osmolarity body water content
• Release stimulated by
• Increased plasma oncotic pressure hypovolaemia
• Left atrial distention
• Exercise
• Emotional states
• Oxytocin
• Stimulates uterine smooth muscle contraction
• Ejection of milk during lactation

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Diabetes Insipidus

• Aetiology
• Head trauma
• Neoplasms
• Pit or hypothalamic inflammation
• Surgery
• Idiopathic
• Clinical Features
• Polyuria
• Increased serum sodium osmolarity
• Increased thirst

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Syndrome of Inappropriate ADH Secretion

• Aetiology
• Ectopic ADH secretion (e.g. malignant carcinomas)
• Non-neoplastic disease of lung
• Local hypothalamus injury
• Clinical Features
• Excess water reabsorption
• Hyponatraemia
• Cerebral oedema
• Neurologic dysfunction
• Total body water increased
• Normal blood volume
• No peripheral oedema

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Adrenal Medulla
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PheochromocytomaNeoplasm of chromaffin cells
(paraganglioma)

• Epidemiology
• Mostly sporadic 10 familial
• Can become malignant
• Morphology
• Small circumscribed lesion or large
  haemorrhagic
• Usually unilateral s/t bilateral
• May have capsular or vascular invasion
• Clinical
• Secondary hypertension
• Paroxysmal episodes of Ht
• Chronic sustained Ht ? risk ? CHF MI renal
  damage sudden death
• Tachycardia palpitations
• Headaches sweating tremor
• Sense of apprehension

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This large adrenal neoplasm has been sectioned in
half. Note the grey-tan color of the tumor
compared to the yellow cortex stretched around it
and a small remnant of remaining adrenal at the
lower right. This patient had episodic
hypertension. This is a tumor arising in the
adrenal medulla--a pheochromocytoma.
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There is some residual adrenal cortical tissue at
the lower center right, with the darker cells of
pheochromocytoma seen above and to the left.
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Adrenal Cortex
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Steroid Hormones

• Glucocorticoids
• CHO, lipid fat metabolism
• Increases blood glucose levels gluconeogenesis
• Increases protein breakdown
• Inhibits protein synthesis
• Mineralcorticoids
• Elecrolyte fluid balance
• Increases sodium water retention
• Regulated by renin andiotensin
• Sex Steroids
• Low synthesis in adrenals compared to gonads
• Virilising hormones may be secreted

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Conditions Affecting Adrenal Cortex

• Adrenocortical Hyperfunction
• Cushings syndrome
• Increased glucocorticoid levels
• Hyperaldosterone
• Excessive water retention ? Ht
• Adrenogenital syndromes
• Excess androgens (testosterone) in peripheral
  tissue
• Dehydroepiandrosterone
• Androstentendione
• Adrenocortical Insufficiency
• Acute Adrenocortical Insufficiency
• Chronic Adrenocortical Insuffeciency (Addisons)

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Cushings SyndromeHypercortisolism

• Constellation of bodily responses to excess
  glucocorticoids
• Most common in adult woman
• May occur with excess androgen production ?
  virilization
• Aetiology Pathogenesis
• Exogenous
• Administration of glucocorticoids (Cushings
  syndrome)
• Endogenous
• Hypothalamic or pituitary dx ? ?ACTH ? Cushings
  dx
• Adrenocortical hyperplasia or neoplasia
• Ectopic ACTH secretion (e.g. oat cell ca)

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Morphology

• Exogenous glucocorticoids
• Bilateral atrophy of adrenal cortex
• Due to suppression of endogenous ACTH
• Endogenous glucocorticoids
• Bilateral adrenal hyperplasia
• Adrenal cortices thickened yellow
• Histologically ? cortex depleted of lipids
  (secretions discharged)
• May show nodularity
• Pituitary
• Crooke hyaline change
• Homogenous basophil material
• replaces normal granular cytoplasm of cells
• ACTH secreting adenoma of hyperplasia (Cushings
  dx)

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Clinical Features

• Develops slowly ? exaggerated symptoms of
  glucocorticoids
• Ht weight gain ? early manifestations
• Truncal obesity moon face buffelo hump
• Decreased muscle mass proximal limb weakness
• Hyperglycaemia glucosuria polydipsia
  (gluconeogenesisinhibition of glucose cellular
  uptake)
• Loss of collagen bone reabsorption (protein
  catabolism) ? osteoporosis skin thinning etc
• Increased risk of infections
• Hirsutism menstrual irregularities
• Mood swings depression psychosis
• Skin pigmentation

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Diagnosis

• ? 24 hr free urinary cortisol
• Loss of normal diurnal pattern of cortisol
  secretion
• Aetiology
• Serum ACTH levels
• Dexamethasone suppression test
• Pituitary
• ?ACTH
• ?urinary cortisol with dexamethasone
• Ectopic ACTH
• ?ACTH no dexamethasone response
• Adrenal tumor
• ?ACTH no dexamethasone response

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Hyperaldosteronism

• Primary Hyperaldosteronism
• Autonomous secretion of excess aldosterone
• Usually due to an adenoma (Conns syndrome)
• Affects middle aged females mostly
• May be d.t. zona glomerulosa hyperplasia
• Children young adults most affected
• Retention of H2O/Na ? Hypertension
• K loss ? hypokalaemia
• muscular weakness cardiac arrhythmias
• Metabolic alkalosis ? tetany parasthesiae
• Plasma aldosterone raised with decreased renin

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• Seconday Hyperaldosteronism
• Aet ? ? renal glomerular perfusion ? activation
  of renin-angiotensin system ? increased
  aldosterone
• Aetiology
• Arteriolar nephrosclerosis
• Arterial hypovolaemia oedema
• CHF cirrhosis nephrotic syndrome
• Pregnancy ? increased oestrogen ? increased renin
• Increased plasma renin with raised aldosterone
• Treat underlying cause

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Adrenogenital Syndromesvirilization ? symptoms
of androgen excess

• Congenital adrenal hyperplasia
• (inherited)
• ?
• Defect in enzyme biosynthesis
• ?
• Decreased cortisol production
• ?
• Increased ACTH
• ?
• Adrenal hyperplasia
• ?
• Increased production or cortisol precursor
  steroids
• ?
• Androgen activity

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Clinical Features

• Increased androgens in female
• Masculinization
• Clitoral hypertrophy
• Oligomenorrhoea
• Hirsutism
• Post-puberty acne
• Increased androgens in male
• Enlargment of ext genetalia
• Oligospermia (infertility)

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Acute Adrenocortical Insufficiency

• Aetiology pathogenesis
• Sepsis ? Waterhouse-Friderichsen syndrome
• Neisseria meningitidis (classic)
• Pseudonomas pneumococci H. influenzae (others)
• Unclear pathogenesis ? endotoxin induced vascular
  injury (massive haemorrhage) with associated DIC
• Sudden withdrawal of long term corticosteroid
  treatment
• Inability of atrophic adrenals to produce
  glucocorticoids
• Stress with underlying chronic adrenal
  insufficiency
• Acute adrenal crises on limited physiological
  reserves

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Chronic Adrenocortical InsufficiencyAddisons
Disease

• Aetiology pathogenesis
• Primary ? Addisons disease
• Secondary causes
• Tuberculosis ? caseous necrosis of adrenal cortex
• Autoimmune adrenalitis
• Ass with e.g. pernicious anaemia thyroiditis
  IDDM
• AIDS
• Metastatic disease
• Systemic amyloidosis
• Fungal infections
• Haemochromatosis
• Sarcoidosis

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Morphology

• Primary autoimmune adrenitis
• Irregularly shrunken glands
• TB fungi sarcoidosis
• Granulomas in adrenals
• Metastatic Ca
• Adrenals enlarged
• achitecture obscured
• Secondary hypoadrenalism
• Adrenals small flattened
• Atrophy of corticol cells

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Clinical Features

• Insidious onset
• Progressive weakness fragiability
• Non-specific complaints (anorexia N/V WL)
• Primary adrenal disease
• Hyperpigmentation (increased ACTH)
• Hyperkalaemia hyponatraemia
• Hypotension (volume depletion) dehydration
• Hypoglycaemia
• Sexual dysfunction
• Adrenal crises
• Infections trauma sugery ? intractable
  vomiting abdominl pain hypotension vascular
  collaspe ? death
• Diagnosis
• Low plasma cortisol

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This is a caseating granuloma of tuberculosis in
the adrenal gland. Tuberculosis used to be the
most common cause of chronic adrenal
insufficiency. Now, idiopathic (presumably
autoimmune) Addison's disease is much more often
the cause for chronic adrenal insufficiency.
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The pair of adrenals in the center are normal.
Those at the top come from a patient with
adrenal atrophy (with either Addison's disease or
long-term corticosteroid therapy). The adrenals
at the bottom represent bilateral cortical
hyperplasia. This could be due to a pituitary
adenoma secreting ACTH (Cushing's disease), or
Cushing's syndrome from ectopic ACTH production,
or idiopathic adrenal hyperplasia.
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Thyroid
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The follicles are irregularly enlarged, with
flattened epithelium, consistent with inactivity,
in this microscopic appearance at low power of a
multinodular goiter. The earlier phase of a
diffuse (non-toxic) goiter leading up to this
point may have resulted from either "endemic"
goiter (seen in parts of the world where dietary
deficiency of iodine may occur) or the uncommon
"nonendemic" or sporadic goiter. Inborn errors
of thyroid hormone biosynthesis leading to goiter
are extremely uncommon.
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Hyperthyroidism(Thyrotoxicosis)

• Aetiology
• Graves dx (diffuse thyroid hyperplasia)
• Exogenous thyroid hormone ingestion
• Hyperfunctional multinodular goitre
• Hyperfunctional adenoma of thyroid
• Thyroiditis
• TSH secreting pit adenomas
• Ectopic thyroid

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Clinical Features

• Hypermobility of GIT
• Nervousness irratibility
• Tremor
• Tachycardia palpations ? CHF
• Wide staring gaze (sympathetic overstimulation)
• Proptosis (Graves dx only)
• Skin ? warm, flushed, soft
• Excessive sweating
• Heat intolerance
• Weight loss with increased appetite

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• Thyroid Storm
• Abrupt onset of severe hyperthyroidism
• Underlying Graves disease ? acute increase of
  catecholamines
• May be precipitated by stress
• Medical emergency ? arrhythmias ? death
• Diagnosis
• Clinical features
• Lab tests
• ?free T4 or T3 levels
• ?TSH (-ve feedback)
• ?TSH ? ant. pit. Adenoma
• Radioactive iodine uptake
• Diffuse uptake of whole gland ? Graves disease
• Uptake of solitary nodule ? toxic adenoma
• Decreased uptake ? thyroiditis

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HypothyroidismMyxoedema

• ?T4 or T3 levels
• ? decreased metabolic rate
• ? mucopolysaccharide accumulation in dermal CT
  (myxoedema)
• Aetiology Pathogenesis
• Primary (idiopathic)
• Ablation of thyroid
• Hashimotos thyroiditis ? autoimmune destruction

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Clinical Features

• Cretinism
• Children infants
• Dietary insufficiency of Iodine
• May be inbon error of metabolism (rare)
• Impaired skeletal CNS development
• Myxoedema
• Adults older children
• Generalised apathy listless mental sluggishness
• Cold intolerance
• Often obese
• Mucopolysaccharide accumulation in skin ?
  non-pitting oedema enlarged tongue
• Decreased bowel motility
• Pericardial effusions cardiomegaly
• Diagnosis
• ? T4 or T3
• ? TSH (primary lesion) normal TSH (hypothalamic
  pituitary)

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Simple Goitre(Enlargement of the thyroid gland
without hyperthyroidism)

• Parenchymatous goitre
• Hyperplasia of thyroid epithelium with loss of
  stored colloid
• Less active areas appear later ? compresses by
  hyperplastic areas
• Multinodular goitre
• Tracts of fibrosis separating hyperplastic less
  active areas
• Multiple nodules may be palpated
• 1 large nodule ? suspicion of neoplasia
• Colloid
• No epithelial hyperplasia
• Follicles accumulate large volumes of colloid ?
  coalesce ? colloid-filled cysts
• Areas of haemorrhage, fibrosis dystrophic
  calcification
• May be diffuse or multinodular
• Rapid enlargement d.t. haemorrhage ? tracheal
  compression stridor

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This diffusely enlarged thyroid gland is somewhat
nodular. This patient was euthyroid. This
represents the most common cause for an enlarged
thyroid gland and the most common disease of the
thyroid--a nodular goiter.
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The follicles are irregularly enlarged, with
flattened epithelium, consistent with inactivity,
in this microscopic appearance at low power of a
multinodular goiter. The earlier phase of a
diffuse (non-toxic) goiter leading up to this
point may have resulted from either "endemic"
goiter (seen in parts of the world where dietary
deficiency of iodine may occur) or the uncommon
"nonendemic" or sporadic goiter. Inborn errors
of thyroid hormone biosynthesis leading to goiter
are extremely uncommon.
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Aetiology Pathogenesis

• Aetiology
• Lack of iodine
• Rare inherited enzyme defects in T4 or T3
  synthesis
• Hypercalcaemia ? interfers with hormone
  production
• Drugs that induce hypothyroidism
• Sulphonylureas
• Lithium
• Amiodarone
• rescorcinol

• Pathogenesis
• Aetiology
• ?
• impaired synthesis of T4 or T3
• ?
• compensatory ? TSH
• ?
• hyperplasia hypertrophy of follicular cells
• ?
• enlargement of gland
• ?
• bigger smaller bigger with hormone
  fluctuations
• ?
• multinodular

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Clinical Features

• Mass effects of large gland
• Airway obstruction
• Dysphagia
• Calcification
• May mask neoplastic disease
• Toxic (hyperfunctioning) nodule may develop
• Hyperthyroidism
• Plummer syndrome (no opthalmology)

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Graves Diseaseorgan-specific autoimmune disease
of the thyroid gland

• Clinical triad
• Thyrotoxicosis (hyperfunctioning diffuse thyroid
  enlargement)
• Infiltrative ophthalmology ? 40 cases
• Infiltrative dermopathy ? pretibial myxoedema
  (minority of cases)
• Epidemiology
• 20-40 yrs ? peak incidence
• Woman gt men (71)
• Genetic predisposition
• Strong association with HLA-DR3

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Pathogenesis

• Auto-antibodies to TSH receptors ? IgG-LATS
• (causes infiltrative ophthalmology)
• ?
• Bind to TSH-receptors in thyroid gland
• ?
• Stimulate release of thyroid hormone by mimicking
  TSH action
• ?
• Release of T4 or T3
• (Thyroid hyperplasia)
• ?
• ? Sympathetics
• (causes wide-staring gaze)
• ?
• Hormone release increases deposition of
  mucopolysaccharides in connective tissue
• ?
• Pretibial myxoedema dermopathy
• deposition behind eyeball (exopthalmos proptosis)

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Morphology

• Macroscopic
• Moderately enlarged
• Firm
• Beefy-red (increased blood flow)
• Microscopic
• Hyperplasia of the acinar epithelium
• Reduced stored colloid
• Local accumulations of lymphocytes with follicle
  formation

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A diffusely enlarged thyroid gland associated
with hyperthyroidism is known as Grave's disease.
At low power here, note the prominent infoldings
of the hyperplastic epithelium. In this
autoimmune disease the action of TSI's
predominates over that of TGI's.
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Clinical Features

• Clinical triad
• Diffuse, smooth enlargement of thyroid
• Bruit ? increased blood flow through gland
• Ophthalmology
• Wide staring gaze exopthalmos
• Lid lag ? weak extraoccular muscles
• Corneal injury
• Dermopathy ? pretibial myxoedema
• Localised areas of thickening hyperpigmentation
  of skin
• Over ant aspect of feet lower legs
• Diagnosis
• ? T4 or T3 ?TSH
• ? radioactive iodine uptake

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Thyroiditisinflammation of the thyroid

• Non-specific Lymphocytic Thyroiditis
• Associated with HLA-DR5 ? suspected autoimmunity
• Multifocal lymphocytic inflammatory infiltrate in
  parenchyma
• Gland normal or symmetrically enlarged
• Mostly incidental finding (asymptomatic)
• May present with transient hyperthyroidism ?
  inlam damage to follicles ? hormone leaking ?
  thyrotoxicosis
• Hashimotos Thyroiditis ?Chronic lymphocytic
  thyroiditis
• Subacute (Granulomatous) Thyroiditis
• De Quervain thyroiditis
• Often preceded by URT-I (possible viral origin)
• Follicle disruption ? extrusion of colloid ?
  granuloma
• Neutrophilic infiltrate
• Acute onset ? neck pain fever malaise thyroid
  enlargement
• Transient hyperthyroidism
• ? ESR, WBC, T4 or T3
• Self-limiting ? 6-8 weeks

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Hashimotos Thyroiditisautoimmune inflammatory
disorder of the thyroid(chronic lymphocytic
thyroiditis)

• Epidemiology
• Associated with other immune disorders (e.g. SLE)
• 45-65 yrs ? peak incidence
• Females gt males (101)
• Morphology
• Diffuse symmetrical enlargement
• Capsule intact
• Mononuclear inflam infiltrate
• Well developed germinal centres
• Small follicles
• Fibrosis of gland ? may atrophy

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Here is a low power microscopic view of a thyroid
with Hashimoto's thyroiditis, note the lymphoid
follicle at the right center. This is an
autoimmune disease and often antithyroglobulin
and antimicrosomal (thyroid peroxidase)
antibodies can be detected. Other autoimmune
diseases such as Addison's disease or pernicious
anemia may also be present. Both thyroid growth
immunoglobulins (TGI) and thyroid stimulating
immunoglobulins (TSI) are present, though
blocking antibodies to TSI mitigate their effect.
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This is an example of an immunofluorescence test
positive for anti-microsomal antibody, one of the
autoantibodies that can be seen with autoimmune
diseases of the thyroid. A major component of
the antimicrosomal antigen is thyroid peroxidase
(TPO) which is often measured serologically.
Note the bright green fluorescence in the
thyroid epithelial cells, whereas the colloid in
the center of the follicles is dark.
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Pathogenesis

• Activation of CD4 T-cells
• (associated with HLA-DR5 DR3)
• ?
• Induces formation of CD8 cytotoxic T-cells
  (killer cells) Abs
• ?
• Parenchymal destruction sensitisation of
  B-cells
• ?
• Secretion of anti-TSH-receptor Abs
• ?
• Block action of TSH
• ?
• Hypothyrodism

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Clinical Features

• Painless enlargement of thyroid
• Usually symmetrical diffuse
• Gradual development of hypothyroidism
• ? T4 or T3 ?TSH
• May be preceeded by transient thyrotoxicosis
  (hashitoxicosis) caused by follicular disruption
• Increased risk of B-cell lymphoma

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Neoplasms of Thyroid

• Solitary nodules
• Likely to be neoplastic (rather than multiple
  nodules)
• Solid nodules
• Likely to be neoplastic (rather than cystic
  nodules)
• Nodules in younger patients
• Increased neoplastic risk than older patients
• Nodules in males
• Increased neoplastic risk than females
• Nodules that do not uptake radioactive iodine
• May be cysts or solid tumours

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Follicular Adenomasbenign neoplasms derived from
follicular epithelial cells

• Gross morphology
• Solitary, spherical encapsulated
• May compress surrounding thyroid
• Haemorrhage calcification fibrosis cystic
  changes
• Histology
• Well differentiated follicles
• Similar to hyperplasia
• Clinical Features
• Painless nodules
• Local symptoms in larger masses
• Thyrotoxicosis ? toxic nodules
• Little evidence of malignant transformation

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Thyroid Carcinomas

• Papillary Ca
• Follicular Ca
• Medullary Ca
• Anaplastic Ca
• Lymphoma

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Parathyroid
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Hyperparathyroidism

• Primary
• Hypersecretion of PTH
• Due to adenoma of hyperplasia of parathyroid
  gland
• Secondary
• Physiological increase in PTH secretion in
  response to hypocalcaemia
• Tertiary
• Development of an autonomous hypersecreting
  adenoma in longstanding secondary
  hyperparathyroidism

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Primary HyperparathyroidismBones, Stones
Groans Disease

• Aetiology
• Parathyroid adenoma
• Primary hyperplasia of gland
• Parathyroid carcinoma (rare)
• Epidemiology
• 0.1 population
• Females gt males
• Elderly ? post-menopausal females
• Sporadic or associated with MEN syndromes
• Increased PTH
• Excessive bone reabsorption
• Renal stones
• Hypercalcaemia
• matastatic calcification
• hypophosphataemia

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Morphology

• Parathyroid adenoma
• Well circumscribed, soft, tan lesions
• Confined to single glands (others normal)
• Hyperplasia
• Mutinodular process
• Chief cell hyperplasia (diffuse or multinodular)
• Parathyroid Ca
• Firm or hard tumores with fibrous or infiltrative
  growth
• Chief cells predominate
• Skeletal changes
• Predominance of osteoclasts (errode bone matrix)
• Mobilization of calcium salts
• New bone trabeculae due to osteoclast activity
• Osteitis fibrosa cystica brown tumour
• Renal system

77
Parathyroid hyperplasia is shown here. Three and
one-half glands have been removed (only half the
gland at the lower left is present). Parathyroid
hyperplasia is the second most common form of
primary hyperparathyroidism, with parathyroid
carcinoma the least common form.
78
In parathyroid hyperplasia, there is little or no
adipose tissue, but any or all cell types
normally found in parathyroid are present. Note
the pink oxyphil cells here. This is actually
"secondary hyperparathyroidism" with enlarged
glands as a consequence of chronic renal failure
with impaired phosphate excretion. The increased
serum phosphate tends to drive serum calcium
down, which in turn drives the parathyroids to
secrete more parathyroidhormone.
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Clinical Features

• Hypercalcaemia (clinically silent)
• Increased serum PTH
• Hypophosphataemia
• Bone pain
• Osteoporosis
• Osteitis fibrosa cystica
• Kidney stones (nephrolithiasis)
• Mild metabolic acidosis
• Constipation nausea PUD gallstones
• Pancreatitis
• Muscular weakness hypotonia
• Polyuria secondary polydipsia

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Secondary Hyperparathyroidism

• Aetiology ? any pathology that decreases calcium
• Renal failure
• ? phosphate excretion ? hyperphosphataemia ?
  hypocalcaemia
• ? alpha1-hydroxylase ? ? Vit D ? ? calcium
  absorption
• Decreased calcium intake
• Steatorrhoea
• Vit D deficiency
• Morphology
• Hyperplasia of parathyroid glands
• Increased chief cells
• Metastatic calcification
• Clinical
• Dominated by symptoms related to chronic renal
  failure
• Renal osteodystrophy
• Serum calium levels near normal
• Calcification ? blood vessels ? ischaemia
• Rare increased activity of parathyroid ? tertiaty
  hyperparathyroidism

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Hypoparathyroidism

• Aetiology
• Isiopathic
• Surgical ablation
• Congenital absence (diGeorge syndrome)
• Autoimmune hypoparathyroidism
• Clinical
• Hypocalcaemia
• Tetany convulsions parasthesiaes psychiatric
  disturbances
• Cardiac arrhythmias
• Raised intra-cranial pressure
• Hyperphosphataemia
• Very low PTH levels

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Endocrine Pancrease Diabetes Mellitus
83
Cells of islets of Langerhans

• a (alpha cells) ? Glucagon
• Promotes breakdown of glycogen (liver)
• Promotes gluconeogenesis from proteins
• ß (beta cells) ? Insulin
• Promotes glucose entry into cells
• Promotes glycogen synthesis (inhibits breakdown)
• Promotes lipogenesis from glucose (inhibits
  lipolysis)
• Promotes protein synthesis with GH
• Synthesis release stimulated by increased serum
  glucose
• d (delta cells) ? somatostatin
• Inhibits insulin glucagon secretion
• PP (polypetide cells) ? pancreatic polypetide
• Function in humans unknown

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Diabetes Mellitus

• Chronic disorder of CHO, fat protein metabolism
• Abnormal metabolic state in which there is
  glucose intolerance due to inadequate insulin
  action
• Diagnosis based on clinical demonstration of
  glucose intolerance (table 17.10)

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Classification

• Insulin Dependant Diabetes Mellitus
• Presents in childhood
• Typical catabolic effects
• Prone to develop ketoacidosis
• Lymphocytic infiltration of islets ? ß-cells
  destruction
• Aetiology
• Autoimmunity
• Genetic factors (HLA)
• Viral infection (trigger?)

• Non-Insulin Dependant Diabetes Mellitus
• Presents in adulthood
• Common in obese patients
• Not prone to ketoacidosis
• May develop a non-ketotic coma ? hyperosmolarity
  of the plasma
• Insulin secretion normal or increased ? reduction
  in number of cell surface receptors
• Aetiology
• Genetic factors

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• Secondary Diabetes
• Chronic pancreatitis
• Hormonal tumours
• Corticosteroid drugs
• Haemochromatosis
• Genetic disorders
• Surgical

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Pathology of Insulin Deficiency

• Actions of insulin catabolic ? promote laying
  down of tissue stores from circulating nutrients
• Consequences of insulin deficiency ? catabolic
  (breakdown energy stores)
• Major features of insulin deficiency
• Inability to utilize glucose
• Overproduction of glucose (hyperglycaemia)
• Diminished protein synthesis
• Increased lipolysis ? hyperlipidaemia ? rapid
  wasting weight loss
• Osmotic diuresis ? polyuria ? dehydration
  thirst
• Free fatty acids ? ketone bodies (e.g.
  acetoacetate acetone) ? H ions ? metabolic
  acidosis
• Ketosis acidosis hyperglycaemia
  hyperosmolity electrolyte imbalence ? diabetic
  ketoacidotic coma

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This is an insulitis of an islet of Langerhans in
a patient who will eventually develop type I
diabetes mellitus. The presence of the
lymphocytic infiltrates in this edematous islet
suggests an autoimmune mechanism for this
process. The destruction of the islets leads to
an absolute lack of insulin that characterizes
type I diabetes mellitus.
90
This islet of Langerhans demonstrates pink
hyalinization (with deposition of amyloid) in
many of the islet cells. This change is common
in the islets of patients with type II diabetes
mellitus.
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Clinical Features

• Insulin Dependant Diabetes Mellitus
• Children gt adults
• Normal weight (paradoxical weight loss with ?
  appetite)
• Decreased blood insulin
• Anti-islet-Abs
• Ketoacidosis common
• N/V difficult resiration
• Coma death
• Polydipsia polyurea polyphagia

• Non-Insulin Dependant Diabetes Mellitus
• Adults gt children
• Obesity common
• Normal or increased blood insulin
• No anti-islet-cell Abs
• Non-ketotic hyperosmolar coma
• May present with polydipsia polyuria
• Unexplained weakness or WL

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Complications

• Large Blood Vessels
• Accelerated ATH ? MI cerebrovascular dx
  ischaemic limbs
• Small blood vessels
• Endothelial cells basal lamina damage
• Retinopathy ? blindness
• Nephropathy
• Gangrene of extremeties
• Peripheral Nervous System
• Neuropathy
• Neutrophils
• Susceptibility to infections
• Pregnancy
• Pre-eclampia toxaemia large babies neonatal
  hypoglycaemia

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Multiple Endocrine Neoplasia
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