Flashcards in Pathology Deck (144):
What is the basic pathophysiology of T2DM?
1. Insulin receptors become less sensitive to insulin
2. Less glucose enters cells
What causes insulin resistance?
Ectopic fat accumulation
Increased FFA circulation
Reduced glycogen synthesis
How does insulin resistance affect β-cells?
- Lipotoxicity (Increased FFA + triglycerides)
These reduce β-cell function
What kind of obesity is associated with increased risk of T2DM and CVS disease?
What is central obesity associated with?
- High BP
- High triglycerides
- Low HDL
- Insulin resistance
What is the thyroid gland mainly composed of?
- Surrounded by flat/cuboidal epithelial cells
- Thyroglobulin in centre (amorphic and pink)
Scattered C cells:
What do C cells look like?
Slightly larger than follicular cells
What function do C cells have?
- Reduces serum calcium
What does TSH do?
1. Binds to TSH-receptor on epithelial cells
2. G-proteins activated:
- GTP -> GDP
- Production of cAMP
> Increased production/release of T3 + T4
What two forms do T3 and T4 circulate in?
When T3 and T4 bind to target cell receptors, what happens?
1. Complex translocates to nucelus
2. Binds to thyroud response elements on target genes
3. Transcription increases
4. Increased basal metabolic rate
What is the most common cause of hyperthyroidism?
What is the male:female ratio for Grave's disease?
What is the peak age range for Grave's disease?
What autoantibodies are present in Grave's disease?
What autoantibody is relatively specific in Grave's?
Anti-TSH receptor (Thyroid stimulating)
What autoantibody may explain hypothyroid episodes?
TSH binding inhibitor Ig
What is the triad of features in Grave's disease?
Hyperthyroidism with diffuse thyroid enlargement
- Fibroblasts express TSH receptors
What is the most common cause of hypothyroidism?
Hashimoto's Thyroiditis (Autoimmune)
What are some associations for Hashimoto's?
Middle aged women
Other autoimmune disease
HLA-DR3 + HLA-DR5
What age do people get Hashimoto's Thyroiditis?
45-60 years old
What has been shown in twin studies for Hashimoto's?
Autoantibodies are present in asymptomatic siblings
What do polymorphisms in CTLA-4 cause?
Dysregulation of T cell responses
Reduced protein level and function:
- Increased risk of autoimmune disease
What does PTPN-22 normaly do?
Inhibits T cell function
What autoantibodies are present in Hashimoto's Thyroiditis and what happens when they're bound?
Anti-Thyroglobulin and Anti-Peroxidase
- Ab-dependent cell mediated cytotoxicity
What cells may mediate thyroid epithelium destruction?
CD8 positive cells
What is the process of cytokine mediated cell death?
- Recruits macrophages -> Damages follicles
What is Hashitoxicosis?
When Hashimoto's Thyroiditis is preceded by transient hyperfunction
What does Hashimoto's predispose to?
Other autoimmune disease
B-cell non-Hodgkin's Lymphoma in affected gland
What is a goitre?
Any thyroid enlargement
In what populations is there an increased incidence of diffuse goitre?
How else can diffuse goitre arise?
Ingesting substances which reduce T3/T4 production
- Cretinism (in kids)
How does diffuse goitre usually present?
- T3/T4 normal
- TSH raised
How does a Multi-Nodular Goitre arise?
Long-standing simple goitre:
- Recurrent hyperplasia + involution
- Impressive enlargement
What is a differential of multi-nodular goitre?
What is the pathogenesis of multi-nodular goitre?
Follicle rupture -> Haemorrhage -> Scarring -> Calcification
What mass effects can multi-nodular goitre have?
How does an autonomous multi-nodular goitre present?
What is the most common cause of a goitre?
- Lack of intake
- Lack of bioavailability
What type of neoplasm appears a discrete solitary mass encapsulated by a surrounding collagen cuff?
What is a thyroid adenoma difficult to distinguish from?
Dominant nodule in MNG
If a thyroid adenoma secretes thyroid hormones, is it classed as TSH-dependent or TSH-independent?
What mutations can cause a thyroid adenoma?
What mutations are seen in functional thyroid adenomas?
TSHR signalling pathway:
What people are at greatest risk of thyroid carcinomas?
Ionising radiation predisposes to what type of thyroid cancer?
Iodine deficiency predisposes to what type of thyroid cancer?
What genetic features are seen in papillary cancer?
Active MAP kinase pathway:
- Rearrange RET/NTKR1
- BRAF point mutation
What genetic features are seen in follicular cancer?
Mutations in PI3K/AKT
What genetic features are seen in anaplastic cancer?
MAP kinase mutations
p53 + -catenin mutations
What genetic features are seen in medullary cancer?
MEN2 (Germline RET mutations)
What is the structure of a papillary thyroid carcinoma?
- Can be multifocal
- Often cystic
- May be calcified
What worsens the prognosis of a papillary thyroid cancer?
What is the structure of a follicular thyroid carcinoma?
Usually a single nodule:
- Enlarges slowly
May surround capsule
Where do medullary thyroid carcinomas arise from?
- Can secrete calcitonin
What can medullary thyroid carcinomas be related to?
MEN2A or MEN2B:
- Often presenting in younger patients
How do familial medullary thyroid cancers appear?
C cell hyperplasia
What are medullary thyroid carcinomas composed of?
What deposits are seen in medullary thyroid cancer?
Amyloid (abnormally folded calcitonin)
What effects do medullary thyroid cancers have?
- Airway obstruction
- Diarrhoea (VIP production)
- Cushing's (ACTH production)
What is the most undifferentiated and aggressive thyroid carcinoma?
What are the parathyroid glands composed of? What do they look like and what do they secrete?
- Moderate cytoplasma
- Bland, round, central nuclei
What are the supporting cells in the parathyroid gland? What do they look like?
- Acidophilic cytoplasm
What is parathyroid hyperplasia associated with?
MEN1 and MEN2A
How does a parathyroid adenoma appear?
Single gland -> 0.5-5grams
Other glands are atrophic
Microscopically represents normal glands
Fibrous CT capsule:
- Adjacent rim of compressed tissue
What happens in secondary hyperthyroidism?
- Results in compensatory overactivity
What are signs of secondary hyperthyroidism?
Low calcium intake
Vitamin D deficiency
What happens in tertiary hyperparathyroidism?
Associated with hypercalcaemia
What are the signs of hyperparathyroidism?
Stones (Kidney and Gallstones)
Groans (Constipation/Peptic ulcer/Pancreatitis)
- Aortic/Mitral calcification
What specific bone problem can hyperparathyroidism cause?
Osteitis Fibrosa Cystica
What can DiGeorge syndrome cause? What is the mutation seen?
Congenital absence of thyroid and parathyroid glands:
What is familial hypoparathyroidism associated with?
Primary adrenal insufficiency (Addison's)
What are signs of hypoparathyroidism?
- Neuromuscular irritability
- Chvostek's and Trousseau's Signs
Basal ganglia calcification
What is the adenohypophysis and where is it derived from?
Derived from Rathke's Pouch
What is the neurohypophysis and where is it derived from?
Extension of neural tissue:
- Modified glial cells
- Axonal processes
What hormones are secreted by the anterior pituitary?
-TSH, ACTH, FSH, LH
What hormones are secreted by the posterior pituitary?
How is the anterior pituitary composed histologically?
- Somatotrophs -> GH (50%)
- Mammotrophs -> PRL (20%)
- Corticotrophs -> ACTH (20%)
- Thyrotrophs -> TSH (5%)
- Gonadotrophs -> FSH/LH (5%)
Are the axons forming the posterior pituitary myelinated or not?
What can cause anterior pituitary hyperfunction?
What can cause anterior pituitary hypofunction?
Ischaemic necrosis (Sheehan Syndrome)
Tumours extending into sella
What conditions affect the posterior pituitary?
- Lack of ADH secretion
- Ectopic secretion (tumour)
- Primary pituitary disorder
What percentage of intra-cranial tumours are pituitary adenomas?
What disorder is pituitary adenoma associated with? What is this condition called?
MEN1 -> Wermer Syndrome
What size is a microadenoma and what size is a macroadenoma?
Micro is 1cm
How do we classify pituitary adenomas?
By cell type/hormone produced
Are all pituitary adenomas functional?
- 25-30% are hypofunctional/non-functional
True or false; if a pituitary adenoma is functional, hormones can be secreted at a subclinical level?
What subset of pituitary adenomas are aggressive?
Those with p53 mutations and many mitotic figures
What can large pituitary adenomas cause?
Infarct -> Panhypopituitarism
What does a PRL-secreting pituitary adenoma cause?
What does a GH-secreting pituitary adenoma cause?
GH -> Increased IGF
Stimulates growth of:
- Connective tissue
What does a ACTH-secreting pituitary adenoma cause?
True or false; Pituitary hypofunction is usually panhypopituitarism?
What tumours can cause pituitary hypofunction?
Rathke Cleft cysts
What causes of granulomas can cause pituitary hypofunction?
How does a patient with apoplexy present?
Diplopia (CN iii pressure)
Loss of consciousness
What hypothalamic tumours can cause pituitary hypofunction?
Where are craniopharyngiomas derived from?
What are the features of craniopharyngiomas?
Where do most craniopharyngiomas arise?
What ages are craniopharyngiomas most common?
- 5-15 years
- 50-60 years
How do craniopharyngiomas present?
Reduced growth in children
What is central diabetes insipidus and what can cause it?
What is nephrogenic diabetes insipidus?
Renal resistance to ADH
Where re the adrenal glands located?
Superomedial to the upper pole of the kidneys
What are the three zones of the adrenal cortex (from superficial to deep)? What are the functions of each?
- Produces mineralocorticoids + aldosterone
- Produces glucocorticoids + cortisol
- Produces sex steroids + glucocorticoids
What nerves innervate the adrenal medulla?
Pre-synaptic SNS fibres
What cells are in the adrenal medulla and what do they secrete?
- Secrete catecholamines
> Small amount of dopamine
What other diseases can manifest in the adrenal gland?
Pituitary -> ACTH secretion
Conditions damaging gland
What three general pathologies can cause adrenal hyperfunction?
What can cause acute and chronic adrenal hypofunction?
> Haemorrhage after Neisseria meningitidis
What mode of inheritance is CAH?
What is the pathogenesis of CAH?
1) 21-hydroxylase deficiency
2) Reduced steroid synthesis:
- No cortisol or aldosterone production
3) Increased androgen production -> Virilisation
What does the decreased cortisol in CAH result in?
What can cause acquired adrenal hyperplasia?
- Pituitary adenoma -> Cushing's Disease
- Ectopic ACTH -> Small Cell LC
Bilateral adrenal enlargement
What are the types of adrenal enlargement?
Diffuse -> ACTH driven
Nodular -> ACTH-independent
What should you suspect if there is an adrenocortical tumour in children?
What can an adrenocortical carcinoma present with?
Fever (due to necrosis)
A well-circumscribed and encapsulated adrenocortico tumour. Approximately 2cm diameter, with a yellow-brown cut surface.
How can an adrenocortical carcinoma spread?
Vascular spread to liver, lungs and bone
Peritoneum and pleura
What features suggest an adrenocortical carcinoma?
Haemorrhage + necrosis
Frequent and atypical mitoses
What can adrenocortical adenomas resemble and how?
- Well differentiated
- Small nuceli
- Rare mitotic figures
What can cause a massive adrenal haemorrhage?
Disseminated Intravascular COagulation (DIC)
What are the three common causes of chronic adrenal insufficiency?
- Fungal (Histoplasma)
Metastases (Lung and breast)
How much of the adrenal gland needs to be destroyed for there to be symptoms?
What biochemical results are seen in Addison's?
What can cause an Addisonian crisis?
Where do adrenal medullar neuroblastomas arise?
40% from medulla
60% along sympathetic chain
What is the general composition of a medullar neuroblastoma?
May show maturation to ganglion cells
What features worsen the prognosis of a adrenal medulla neuroblastoma?
What cells is a phaeochromocytoma derived from?
Chromaffin cells in the adrenal medulla
What can a phaeochromocytoma cause?
Paroxysmal secondary hypertension:
- Stress/Exercise/Posture/Tumour palpation
Which of the following is not a complication of phaeochromocytomas:
How is phaeochromocytoma diagnosed biochemically?
Phaeochromocytomas are the 10% tumour. What does this mean?
10% are extra-adrenal:
- Organs of Zuckerkandl
- Carotid body
10% are bilateral
10% are malignant
10% are NOT associated with hypertension
What percentage of Phaeochromocytomas are familial? What are features of familial Phaeochromocytomas?
- Germline mutations
- Younger and bilateral
- 30% malignant if β-subunit of succinate dehydrogenase mutation
What features of a phaeochromocytoma suggest it is malignant?
How do phaeochromocytomas appear?
Yellow and red-brown
BUT can vary up to
Haemorrhagic and necrotic
What makes phaeochromocytomas appear brown?
- Oxidises catecholamines
What do tumour cells in a phaeochromocytoma form?
What syndrome are phaeochromocytomas a feature of?
MEN2A -> Sipple Syndrome
and also MEN2B
What causes MEN2A and what are they at risk of?
RET oncogene germline mutations -> 10q11.2
- Medullary thyroid cancer
- PTH hyperplasia