Pathology Flashcards
1
Q
What is the basic pathophysiology of T2DM?
A
- Insulin receptors become less sensitive to insulin
- Less glucose enters cells
- Hyperglycaemia
2
Q
What causes insulin resistance?
A
Ectopic fat accumulation
Increased FFA circulation
Increased CRP
Reduced glycogen synthesis
3
Q
How does insulin resistance affect β-cells?
A
Results in:
- Hyperglycaemia
- Lipotoxicity (Increased FFA + triglycerides)
These reduce β-cell function
4
Q
What kind of obesity is associated with increased risk of T2DM and CVS disease?
A
Central
5
Q
What is central obesity associated with?
A
Metabolic syndrome:
- High BP - High triglycerides - Low HDL - Insulin resistance
6
Q
What is the thyroid gland mainly composed of?
A
Follicles:
- Surrounded by flat/cuboidal epithelial cells
- Thyroglobulin in centre (amorphic and pink)
Scattered C cells:
- Parafollicular
7
Q
What do C cells look like?
A
Slightly larger than follicular cells
Clearer cytoplasm
8
Q
What function do C cells have?
A
Secrete calcitonin:
- Reduces serum calcium
9
Q
What does TSH do?
A
- Binds to TSH-receptor on epithelial cells
- G-proteins activated:
- GTP -> GDP
- Production of cAMP
> Increased production/release of T3 + T4
10
Q
What two forms do T3 and T4 circulate in?
A
Bound
Free
11
Q
When T3 and T4 bind to target cell receptors, what happens?
A
- Complex translocates to nucelus
- Binds to thyroud response elements on target genes
- Transcription increases
- Increased basal metabolic rate
12
Q
What is the most common cause of hyperthyroidism?
A
Grave’s disease
13
Q
What is the male:female ratio for Grave’s disease?
A
10:1
14
Q
What is the peak age range for Grave’s disease?
A
20-40
15
Q
What autoantibodies are present in Grave’s disease?
A
TSH receptor
Thyroid peroxisomes
Thyroglobulin
16
Q
What autoantibody is relatively specific in Grave’s?
A
Anti-TSH receptor (Thyroid stimulating)
17
Q
What autoantibody may explain hypothyroid episodes?
A
TSH binding inhibitor Ig
18
Q
What is the triad of features in Grave’s disease?
A
Hyperthyroidism with diffuse thyroid enlargement
Exophthalmos:
- Fibroblasts express TSH receptors
Pretibial myxoedema
19
Q
What is the most common cause of hypothyroidism?
A
Hashimoto’s Thyroiditis (Autoimmune)
20
Q
What are some associations for Hashimoto’s?
A
Middle aged women
Other autoimmune disease
HLA-DR3 + HLA-DR5
21
Q
What age do people get Hashimoto’s Thyroiditis?
A
45-60 years old
22
Q
What has been shown in twin studies for Hashimoto’s?
A
Autoantibodies are present in asymptomatic siblings
23
Q
What do polymorphisms in CTLA-4 cause?
A
Dysregulation of T cell responses
Reduced protein level and function:
- Increased risk of autoimmune disease
24
Q
What does PTPN-22 normaly do?
A
Inhibits T cell function
25
What autoantibodies are present in Hashimoto's Thyroiditis and what happens when they're bound?
Anti-Thyroglobulin and Anti-Peroxidase
When bound:
- Ab-dependent cell mediated cytotoxicity
26
What cells may mediate thyroid epithelium destruction?
CD8 positive cells
27
What is the process of cytokine mediated cell death?
IFNγ:
| - Recruits macrophages -> Damages follicles
28
What is Hashitoxicosis?
When Hashimoto's Thyroiditis is preceded by transient hyperfunction
29
What does Hashimoto's predispose to?
Other autoimmune disease
| B-cell non-Hodgkin's Lymphoma in affected gland
30
What is a goitre?
Any thyroid enlargement
31
In what populations is there an increased incidence of diffuse goitre?
Females
Pubescent
Young adults
32
How else can diffuse goitre arise?
Ingesting substances which reduce T3/T4 production
Dyshormonogenesis:
- Cretinism (in kids)
Mostly idiopathic
33
How does diffuse goitre usually present?
Euthyroid:
- T3/T4 normal
- TSH raised
Mass effects
34
How does a Multi-Nodular Goitre arise?
Long-standing simple goitre:
- Recurrent hyperplasia + involution
- Impressive enlargement
35
What is a differential of multi-nodular goitre?
Neoplasm
36
What is the pathogenesis of multi-nodular goitre?
Follicle rupture -> Haemorrhage -> Scarring -> Calcification
37
What mass effects can multi-nodular goitre have?
Cosmetic
Airway obstruction
Dysphagia
Vessel compression
38
How does an autonomous multi-nodular goitre present?
Hyperthyroid
39
What is the most common cause of a goitre?
Iodine deficiency:
- Lack of intake
- Lack of bioavailability
40
What type of neoplasm appears a discrete solitary mass encapsulated by a surrounding collagen cuff?
Thyroid adenoma
41
What is a thyroid adenoma difficult to distinguish from?
Dominant nodule in MNG
| Follicular carcinoma
42
If a thyroid adenoma secretes thyroid hormones, is it classed as TSH-dependent or TSH-independent?
TSH-independent
43
What mutations can cause a thyroid adenoma?
RAS
| PIK3CA
44
What mutations are seen in functional thyroid adenomas?
TSHR signalling pathway:
- TSHR
- G-proteins
45
What people are at greatest risk of thyroid carcinomas?
Females
| Early adulthood
46
Ionising radiation predisposes to what type of thyroid cancer?
Papillary
47
Iodine deficiency predisposes to what type of thyroid cancer?
Follicular
48
What genetic features are seen in papillary cancer?
Active MAP kinase pathway:
- Rearrange RET/NTKR1
- BRAF point mutation
49
What genetic features are seen in follicular cancer?
Mutations in PI3K/AKT
50
What genetic features are seen in anaplastic cancer?
MAP kinase mutations
PI3K/AKT mutations
p53 + -catenin mutations
51
What genetic features are seen in medullary cancer?
MEN2 (Germline RET mutations)
52
What is the structure of a papillary thyroid carcinoma?
Solitary nodule:
- Can be multifocal
- Often cystic
- May be calcified
53
What worsens the prognosis of a papillary thyroid cancer?
Age >40
Extra-thyroid extension
Distant metastases
54
What is the structure of a follicular thyroid carcinoma?
```
Usually a single nodule:
- Enlarges slowly
- Painless
- Non-functional
May surround capsule
```
55
Where do medullary thyroid carcinomas arise from?
C cells:
- Neuroendocrine
- Can secrete calcitonin
56
What can medullary thyroid carcinomas be related to?
MEN2A or MEN2B:
| - Often presenting in younger patients
57
How do familial medullary thyroid cancers appear?
Bilateral/Multicentric
| C cell hyperplasia
58
What are medullary thyroid carcinomas composed of?
```
Spindle/Polygonal cells
Arranged in:
- Nests
- Trabeculae
- Follicles
```
59
What deposits are seen in medullary thyroid cancer?
Amyloid (abnormally folded calcitonin)
60
What effects do medullary thyroid cancers have?
```
Mass:
- Dysphagia
- Hoarseness
- Airway obstruction
Paraneoplastic:
- Diarrhoea (VIP production)
- Cushing's (ACTH production)
```
61
What is the most undifferentiated and aggressive thyroid carcinoma?
Anaplastic
62
What are the parathyroid glands composed of? What do they look like and what do they secrete?
```
Chief cells:
- Round
- Moderate cytoplasma
- Bland, round, central nuclei
Secrete PTH
```
63
What are the supporting cells in the parathyroid gland? What do they look like?
Oxyphil cells:
- Larger
- Acidophilic cytoplasm
64
What is parathyroid hyperplasia associated with?
MEN1 and MEN2A
65
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
```
66
What happens in secondary hyperthyroidism?
Chronic hypocalcaemia:
| - Results in compensatory overactivity
67
What are signs of secondary hyperthyroidism?
Renal failure
Low calcium intake
Vitamin D deficiency
68
What happens in tertiary hyperparathyroidism?
Autonomous activity
| Associated with hypercalcaemia
69
What are the signs of hyperparathyroidism?
```
Bones
Stones (Kidney and Gallstones)
Groans (Constipation/Peptic ulcer/Pancreatitis)
Psychic overtones
CVS:
- Aortic/Mitral calcification
```
70
What specific bone problem can hyperparathyroidism cause?
Osteitis Fibrosa Cystica
71
What can DiGeorge syndrome cause? What is the mutation seen?
Congenital absence of thyroid and parathyroid glands:
- Hypoparathyroidism
Chromosome 22q11.2
72
What is familial hypoparathyroidism associated with?
Primary adrenal insufficiency (Addison's)
| Mucocutaneous candidiasis
73
What are signs of hypoparathyroidism?
```
Tetany:
- Neuromuscular irritability
- Chvostek's and Trousseau's Signs
Basal ganglia calcification
Parkinsonian
Increased ICP:
- Papilloedema
Cataracts
QT prolongation
```
74
What is the adenohypophysis and where is it derived from?
Anterior pituitary
| Derived from Rathke's Pouch
75
What is the neurohypophysis and where is it derived from?
Posterior pituitary
Extension of neural tissue:
- Modified glial cells
- Axonal processes
76
What hormones are secreted by the anterior pituitary?
```
Trophic:
-TSH, ACTH, FSH, LH
Non-trophic:
- GH
- PRL
```
77
What hormones are secreted by the posterior pituitary?
ADH
| Oxytocin
78
How is the anterior pituitary composed histologically?
```
Acidophils:
- Somatotrophs -> GH (50%)
- Mammotrophs -> PRL (20%)
Basophils:
- Corticotrophs -> ACTH (20%)
- Thyrotrophs -> TSH (5%)
- Gonadotrophs -> FSH/LH (5%)
Chromophobe
```
79
Are the axons forming the posterior pituitary myelinated or not?
No
80
What can cause anterior pituitary hyperfunction?
Adenoma
| Carcinoma
81
What can cause anterior pituitary hypofunction?
```
Surgery/Radiation
Haemorrhage (Apoplexy)
Ischaemic necrosis (Sheehan Syndrome)
Tumours extending into sella
Sarcoidosis
```
82
What conditions affect the posterior pituitary?
```
Diabetes insipidus:
- Lack of ADH secretion
SIADH:
- Ectopic secretion (tumour)
- Primary pituitary disorder
```
83
What percentage of intra-cranial tumours are pituitary adenomas?
10%
84
What disorder is pituitary adenoma associated with? What is this condition called?
MEN1 -> Wermer Syndrome
85
What size is a microadenoma and what size is a macroadenoma?
Micro is 1cm
86
How do we classify pituitary adenomas?
By cell type/hormone produced
87
Are all pituitary adenomas functional?
No:
| - 25-30% are hypofunctional/non-functional
88
True or false; if a pituitary adenoma is functional, hormones can be secreted at a subclinical level?
True
89
What subset of pituitary adenomas are aggressive?
Those with p53 mutations and many mitotic figures
90
What can large pituitary adenomas cause?
Bitemporal hemianopia
Pressure atrophy
Infarct -> Panhypopituitarism
91
What does a PRL-secreting pituitary adenoma cause?
Infertility
Decreased libido
Amenorrhoea
92
What does a GH-secreting pituitary adenoma cause?
```
GH -> Increased IGF
Stimulates growth of:
- Bone
- Cartilage
- Connective tissue
Gigantism/Acromegaly
```
93
What does a ACTH-secreting pituitary adenoma cause?
Cushing's
Usually Micro
BAH
94
True or false; Pituitary hypofunction is usually panhypopituitarism?
True
95
What tumours can cause pituitary hypofunction?
Rathke Cleft cysts
96
What causes of granulomas can cause pituitary hypofunction?
Sarcoidosis
| TB meningitis
97
How does a patient with apoplexy present?
```
Headache
Diplopia (CN iii pressure)
Hypopituitarism
CV collapse
Loss of consciousness
```
98
What hypothalamic tumours can cause pituitary hypofunction?
```
Benign:
- Craniopharyngioma
Malignant:
- Glioma
- Metastases
```
99
Where are craniopharyngiomas derived from?
Rathke's pouch
100
What are the features of craniopharyngiomas?
Slow growing
Often cystic
May calcify
101
Where do most craniopharyngiomas arise?
Suprasella
102
What ages are craniopharyngiomas most common?
Bimodal:
- 5-15 years
- 50-60 years
103
How do craniopharyngiomas present?
Headache
Visual disturbance
Reduced growth in children
104
What is central diabetes insipidus and what can cause it?
```
ADH deficiency
Caused by:
- Trauma
- Tumours
- Inflammation
```
105
What is nephrogenic diabetes insipidus?
Renal resistance to ADH
106
Where re the adrenal glands located?
Superomedial to the upper pole of the kidneys
107
What are the three zones of the adrenal cortex (from superficial to deep)? What are the functions of each?
Zona glomerulosa:
- Produces mineralocorticoids + aldosterone
Zona fasciculata:
- Produces glucocorticoids + cortisol
Zona reticularis:
- Produces sex steroids + glucocorticoids
108
What nerves innervate the adrenal medulla?
Pre-synaptic SNS fibres
109
What cells are in the adrenal medulla and what do they secrete?
```
Neuroendocrine/Chromaffin cells:
- Secrete catecholamines
> Adrenaline
> NA
> Small amount of dopamine
```
110
What other diseases can manifest in the adrenal gland?
Pituitary -> ACTH secretion
Shock/DIC
Conditions damaging gland
111
What three general pathologies can cause adrenal hyperfunction?
Hyperplasia
Adenoma
Carcinoma
112
What can cause acute and chronic adrenal hypofunction?
```
Acute:
- Waterhouse-Friderischsen
> Haemorrhage after Neisseria meningitidis
Chronic:
- Addison's
```
113
What mode of inheritance is CAH?
Autosomal recessive
114
What is the pathogenesis of CAH?
1) 21-hydroxylase deficiency
2) Reduced steroid synthesis:
- No cortisol or aldosterone production
3) Increased androgen production -> Virilisation
115
What does the decreased cortisol in CAH result in?
ACTH release
| Cortical hyperplasia
116
What can cause acquired adrenal hyperplasia?
Endogenous ACTH:
- Pituitary adenoma -> Cushing's Disease
- Ectopic ACTH -> Small Cell LC
Bilateral adrenal enlargement
117
What are the types of adrenal enlargement?
Diffuse -> ACTH driven
| Nodular -> ACTH-independent
118
What should you suspect if there is an adrenocortical tumour in children?
Li-Fraumeni syndrome
119
What can an adrenocortical carcinoma present with?
Fever (due to necrosis)
120
A well-circumscribed and encapsulated adrenocortico tumour. Approximately 2cm diameter, with a yellow-brown cut surface.
Adrenocortical adenoma
121
How can an adrenocortical carcinoma spread?
```
Locally:
- Retroperitneum
- Kidney
Vascular spread to liver, lungs and bone
Peritoneum and pleura
Regional LNs
```
122
What features suggest an adrenocortical carcinoma?
```
Large size:
- >50g
- >20cm
Haemorrhage + necrosis
Frequent and atypical mitoses
Capsular/Vascular invasion
```
123
What can adrenocortical adenomas resemble and how?
Cortical cells:
- Well differentiated
- Small nuceli
- Rare mitotic figures
124
What can cause a massive adrenal haemorrhage?
Newborn
Anticoagulants
Disseminated Intravascular COagulation (DIC)
Waterhouse-Friderichsen
125
What are the three common causes of chronic adrenal insufficiency?
```
Autoimmune destruction
Infection:
- TB
- Fungal (Histoplasma)
- HIV
Metastases (Lung and breast)
```
126
How much of the adrenal gland needs to be destroyed for there to be symptoms?
>90%
127
What biochemical results are seen in Addison's?
```
Hypoglycaemia
Hyperkalaemia
Hyponatraemia
Hypovolaemia
Hypotension
```
128
What can cause an Addisonian crisis?
Infection
| Surgery/Trauma
129
Where do adrenal medullar neuroblastomas arise?
40% from medulla
| 60% along sympathetic chain
130
What is the general composition of a medullar neuroblastoma?
Primitive cells
| May show maturation to ganglion cells
131
What features worsen the prognosis of a adrenal medulla neuroblastoma?
N-myc amplification
| Telomerase expression
132
What cells is a phaeochromocytoma derived from?
Chromaffin cells in the adrenal medulla
133
What can a phaeochromocytoma cause?
Paroxysmal secondary hypertension:
- Stress/Exercise/Posture/Tumour palpation
- Micturition
134
Which of the following is not a complication of phaeochromocytomas:
- CHF
- MI
- CVA
- PAD
- Arrhythmia
PAD
135
How is phaeochromocytoma diagnosed biochemically?
Urinary:
- Catecholamines
- Metabolites
136
Phaeochromocytomas are the 10% tumour. What does this mean?
```
10% are extra-adrenal:
- Paragangliomas
- Organs of Zuckerkandl
- Carotid body
10% are bilateral
10% are malignant
10% are NOT associated with hypertension
```
137
What percentage of Phaeochromocytomas are familial? What are features of familial Phaeochromocytomas?
25%:
- Germline mutations
- Younger and bilateral
- 30% malignant if β-subunit of succinate dehydrogenase mutation
138
What features of a phaeochromocytoma suggest it is malignant?
Large
| Necrotic
139
How do phaeochromocytomas appear?
Yellow and red-brown
BUT can vary up to
Haemorrhagic and necrotic
140
What makes phaeochromocytomas appear brown?
K2Cr2O7:
| - Oxidises catecholamines
141
What do tumour cells in a phaeochromocytoma form?
Nests (Zellballen)
142
What syndrome are phaeochromocytomas a feature of?
MEN2A -> Sipple Syndrome
| and also MEN2B
143
What causes MEN2A and what are they at risk of?
```
RET oncogene germline mutations -> 10q11.2
They have:
- Phaeochromocytomas
- Medullary thyroid cancer
- PTH hyperplasia
```
144
What causes MEN2B and what are they at risk of?
```
RET point mutations
They have:
- Phaeochromocytomas
- Medullar thyroid cancer
- Neuromas
- Ganglioneuromas
- Marfanoid habitus
```
