Pathology - Endo

Question 0

Where does the posterior pituitary originate?

What are its’ products?

Answer 0

The neurohypophysis originates as an extension of the hypothalamus.

The axon terminals located in the neurohypophysis store oxytocin and vasopressin.

Question 1

Name the 5 basic anterior pituitary cells types and their products:

Answer 1

Somatotrophs: GH
Lactotrophs: Prl
Corticotrophs: ACTH, POMC, MSH, Endorphins, Lipotropin
Thyrotrophs: TSH
Gondadotrophs: FSH, LH

Question 2

What is the most common cause of hyperpituitarism?

Answer 2

Anterior pituitary adenomas.

Question 3

What are the local mass effects caused by pituitary tumours?

What may cause an abrupt clinical presentation of a pituitary mass?

Answer 3

Local mass effects include diplopia, optic nerve compression, bitemporal hemianopia, and increased ICP with headache, nausea, and vomiting.

Pituitary apoplexy (haemorrhage into an adenoma) may cause abrupt onset of symptoms.

Question 4

What is the prevalence of pituitary tumours? What is the peak incidence?

What are the most common cell types involved in a pituitary adenoma?

What is the most common combination?

Answer 4

The overall population prevalence of pituitary tumours is 14%, the peak incidence is between 35-60 years.

Prolactinomas are the most common functional pituitary tumours (30%)

GH producing tumours are the second most common.

A combination of the above is the most common combination.

Question 5

Describe the symptoms suggestive of a prolactinoma:

Answer 5

Amenorrhea
Galactorrhea
Loss of libido
Infertility

Question 6

What is lactotroph hyperplasia?

Answer 6

Besides adenomas, pathological hyperprolactinaemia may be caused by lactotroph hyperplasia, which occurs when the normal inhibitory effect of dopamine is removed.

This may be caused by trauma, damage to the dopaminergic neurons, or drugs that block dopamine synthesis.

Question 7

Describe the symptoms suggestive of a GH producing adenoma:

Answer 7

The effects depend on age.

Prior to epiphyseal plate closure: gigantism
After epiphyseal plate closure: acromegaly.

GH excess is also associated with gonadal dysfunction, DM, weakness, HTN, arthritis, CHF, and increased GI cancers.

Question 8

Describe the symptoms suggestive of a ACTH cell adenoma:

Answer 8

Cushing’s disease.

Nelson’s syndrome occurs after removal of the adrenals, which removes the negative feedback for growth, thus creating a large destructive tumour.

Question 9

Diagnosis of a pituitary carcinoma requires?

Answer 9

Demonstration of metastases.

Question 10

What are the two most common supra stellar tumours?

Answer 10

Gliomas and Craniopharyngiomas

The latter are Rathke pouch remnants and are slow growing with a bimodal age distribution.

Question 11

Describe the regulation of Insulin release:

Answer 11

A rise in glucose leads to increased uptake into B-cells through GLUT2. As glucose is metabolised, intracellular ATP increases. This inhibits the activity of an ATP-sensitive K+ channel, leading in turn to membrane depolarisation, influx of calcium, and release of Insulin from pre-formed stores.

Question 12

What is the principle function of Insulin?

Answer 12

Insulin increases glucose transport into target cells, primarily skeletal muscle and adipocytes.

GLUCOSE UPTAKE INTO OTHER CELL TYPES IS INSULIN INDEPENDENT.

Question 13

What is the most important genetic association in type 1 diabetes mellitus?

Answer 13

~50% of susceptibility is attributable to the class II MHC (HLA) locus.

90-95% of whites with type 1 DM have HLA-DR3 or HLA-D4 haplotypes, and an associated DQ8 haplotype incurs the greatest risk.

Question 14

What are the three major initiatives by which diabetes causes complications?

Answer 14

Formation of Advanced Glycation End products (AGEs)

Activation of Protein Kinase C

Intracellular Hyperglycaemia and Disturbances in Polyol pathways.

Question 15

What are AGEs?

How to AGEs cause the complications of diabetes?

Answer 15

AGEs are formed by interactions between AAs and glucose derived metabolites.

They bind to R(eceptor)AGE expressed on vascular wall and inflammatory cells and mediate inflammatory cytokines release.

Question 16

How does diabetes increase Protein Kinase C release?

What damage does this cause?

Answer 16

Intracellular hyperglycaemia stimulates de novo synthesis of diacylglycerol, which in turn activates Protein Kinase C.

PKC increased production of VEGF, TGF-B, Endothelin (and reduced NO), and pro-inflammatory cytokines.

Question 17

How does intracellular hyperglycaemia cause the complications of diabetes?

Answer 17

The products of intracellular glucose metabolism create an increased osmotic load which leads to water influx and cellular injury.

Reductions in NADPH, which is taken up by the metabolism do increased intracellular glucose, also lead to reduced glutathione regeneration and therefore increased susceptibility to oxidative stress.

Question 18

What are the adrenal hyperfunction syndromes?

Answer 18

Cushing syndrome (excess glucocorticoids)
Hyperaldosteronism (excess mineralocorticioids)
Androgenital syndromes (excess androgens)

Question 19

What are the causes of Cushing syndrome?

Answer 19

Administration of excess corticoids

Primary hypothalamic-pituitary disorders with ACTH hypersecretion

Cortisol hypersecretion by adrenal adenoma, carcinoma, or nodular hyperplasia

Ectopic ACTH production by a non-endocrine neoplasm.

Question 20

What is Cushing disease?

Answer 20

Pituitary ACTH hypersecretion causes Cushing disease.

There is a 4:1 female preponderance and it accounts for 70% of cases of endogenous hypercortisolism.

Most are caused by an ACTH secreting pituitary tumour.

Question 21

What proportion of endogenous Cushing syndrome is caused by ectopic ACTH producing tumours?

Who is at risk of these?

Answer 21

Ectopic ACTH producing tumours accounts for 10% of endogenous Cushing syndrome.

They occur most commonly in men 40-60 and are associated with SCLC and other NE tumours.

Question 22

What proportion of endogenous Cushing disease is made by primary adrenal neoplasms?

Answer 22

Adenoma (10%) and carcinoma (5%) are the most common causes of ACTH independent Cushing syndrome.

Question 23

Describe the Dexamethasone suppression test and how the results should be interpreted:

Answer 23

Low (1-2mg) and high (8mg) doses can be given.

The principle is that exogenous steroid will exert negative feedback on the pituitary in a normal homeostatic system. A normal individual’s serum ACTH will be suppressed by both low and high dose Dexamethasone.

In Cushing disease serum ACTH will be increased and is not suppressed by low dose but is suppressed by high dose Dexamethasone.

Ectopic ACTH produced by tumours will have high ACTH before and after both types of suppression.

Primary adrenal neoplasms will have low serum ACTH and will not respond to either mode of suppression.

Question 24

What is the eponymous morphological change seen in the pituitary with elevated glucocorticoid levels?

Answer 24

Crooke hyaline change.

Question 25

Describe the causes of primary hyperaldosteronism:

Answer 25

Primary idiopathic hyperaldosteronism: accounts for 60%

Adrenocortical neoplasm: 35% of cases

Glucocorticoid-remidiable hyperaldosteronism: rare

Question 26

What is Conn syndrome?

Answer 26

Primary hyperaldosteronism caused by an aldosterone secreting tumour.

2:1 female preponderance. Typically arises in middle age.

Manifests as hypertension, hypokalaemia, hypermatraemia, metabolic alkalosis, and low plasma renin.

Question 27

What are the causes of secondary hyperaldosteronism?

Answer 27

Congestive heart failure
Decreased renal perfusion
Pregnancy
Renal artery stenosis

Question 28

Which gene mutation causes 21-Hydroxylase deficiency?

Answer 28

CYP21A

Question 29

What reactions are catalysed by 21-Hydroxylase?

Answer 29

Conversion of Progesterone to 11-Deoxycorticosterone and thus Aldosterone.

Conversion of 17-Hydroxyprogesterone to 11-Deoxycortisol and thus Cortisol.

Question 30

Describe the 3 syndromes that may manifest as a result of CYP21A mutation:

Answer 30

Salt wasting syndrome

Simple virilizing adrenogenital syndrome without salt wasting

Non-classic (late onset) adrenal virilism.

Question 31

What are the causes of primary acute adrenocortical insufficiency?

Answer 31

Adrenal crisis in patients with chronic insufficiency

Rapid withdrawal of steroids

Massive adrenal haemorrhage.

Question 32

What is Addison disease?

What are the causes of Addison disease?

How does it manifest?

Answer 32

An uncommon condition associated with the destruction of at least 90% of the adrenal cortex.

Causes include autoimmune adrenalitis (60-70%), infectious processes, metastatic neoplasms, and rare genetic condition like adrenal hypoplasia congenita.

Manifests as insidious onset weakness, fatigue, anorexia, hyperkalaemia, hyponatraemia, hypotension, and cutaneous pigmentation.

Question 33

What causes autoimmune adrenalitis?

What is APS?

Answer 33

Mutations in the AIRE gene. This gene codes for a thymic transcription factor that regulates expression of thymic autoantigens which then trigger clonal deletion. Mutations in AIRE compromise tolerance.

Autoimmune polyendocrinopathy syndrome has two types; type 1 is associated with AIRE mutations and mucocutaneous infection and abnormalities with organ specific autoimmune disorders. Type 2 is just the latter.

Question 34

How is secondary adrenocortical insufficiency distinguished from primary?

Answer 34

Absence of hyperpigmentation

Near normal Aldosterone levels (as aldosterone production is largely independent of ACTH) thus…

Hyperkalaemia and hyponatraemia are not features of secondary adrenocortical insufficiency.

Question 35

Most adrenal cortical neoplasms are sporadic. Which two genetic syndromes have a predilection for adrenal cortical carcinoma?

Answer 35

Beckwith-Weidemann syndrome (imprinting disorder)

Li-Fraumeni syndrome (p53 mutations)

Question 36

Functional adrenocortical adenomas tend to be associated with….

Functional adrenocortical carcinomas tend to be…

Answer 36

Hyperaldosteronism and Cushing’s

Virilizing.

Question 37

Describe pheochromocytomas:

Answer 37

An uncommon (0.1-0.3%) cause of hypertension that arises from neoplasia of the chromatin cells of the adrenal medulla. Conveniently subscribes to a “rule of 10’s”:

10% arise in association with one of several familial syndromes

10% are extra-adrenal (organ of Zuckerkandl, carotid body)

10% of sporadic pheos are bilateral (50% in familial)

10% are NOT associated with hypertension

10% are biologically malignant.

Question 38

Which familial syndromes are associated with pheochromocytomas?

Answer 38

MEN2A and MEN2B
vHL
NF-1
Sturge-Webber

Question 39

What are the MEN syndromes?

Answer 39

The multiple endocrine neoplasia syndromes are a group of genetically inherited diseases resulting in proliferative lesions of multiple endocrine organs.

Question 40

What are the features of MEN tumours that distinguish them from their sporadic counterparts?

Answer 40

Tumours occur at a younger age
Tumours are more aggressive and recur more frequently
Multiple organs and multifocal
Preceded by asymptomatic endrocrine hyperplasia.

Question 41

What is the MEN1 gene?

Where is it located and what does it code for?

Answer 41

MEN1 is a gene located at 11q3. It codes for Menin, a product that localises to the nucleus.

It is a classic tumour suppressor gene in that both alleles are inactivated in the MEN1-associated tumours.

Question 42

Which tumours are associated with MEN1?

Answer 42

3 p’s (as well as thyroid, carcinoid, adrenocorticoid)

Parathyroid: 80-95% get primary hyperparathyroidism
Pancreas: Aggressive and multiple, leading cause of M&M
Pituitary: Prolactinomas and somatinomas

Question 43

How is MEN2 subclassified?

Answer 43

MEN-2A

MEN-2B

Familial medullary thyroid cancer.

Question 44

What is the RET gene?

Where is it? What are the effects of RET mutations (with examples)?

Answer 44

RET (rearranged during transfection) is proto-oncogene located on 10q11.2.

It codes for a tyrosine kinase that binds GDNF and transmits growth and differentiation signals.

Loss of function RET mutations cause intestinal aganglionosis and Hirschsprung’s. Gain of function RET mutations cause MEN-2A and MEN-2B.

Question 45

Which tumours are associated with MEN-2A?

Answer 45

Pheochromocytomas in 40-50%

Medullary thyroid cancer in 100%!!!!!

Parathyroid hyperplasia in 10-20%

Question 46

Which tumours are associated with MEN-2B?

Answer 46

Pheochromocytomas

Medullary thyroid cancer which is multifocal and more aggressive than in MEN-2A.

They do not develop hyperparathyroidism but do develop neuromas and ganglioneuromas and a Marfanoid habitus.

Question 47

What is Familial medullary thyroid cancer?

Answer 47

Familial medullary thyroid cancer is a variant of MEN-2A in which there is a strong predisposition to medullary thyroid cancer but not to the other cancers associated with MEN-2A or MEN-2B. It has a more indolent course than full blown MEN-2.

Question 48

What is the role of screening in MEN syndromes?

Answer 48

Not well established in MEN-1.

Important in MEN-2;
All kindred of patients with MEN-2 should be screened for RET mutations as 100% of patients with MEN-2 develop thyroid cancer and should therefore consider prophylactic thyroidectomy.