Pathology - Endo Flashcards
Where does the posterior pituitary originate?
What are its’ products?
The neurohypophysis originates as an extension of the hypothalamus.
The axon terminals located in the neurohypophysis store oxytocin and vasopressin.
Name the 5 basic anterior pituitary cells types and their products:
Somatotrophs: GH Lactotrophs: Prl Corticotrophs: ACTH, POMC, MSH, Endorphins, Lipotropin Thyrotrophs: TSH Gondadotrophs: FSH, LH
What is the most common cause of hyperpituitarism?
Anterior pituitary adenomas.
What are the local mass effects caused by pituitary tumours?
What may cause an abrupt clinical presentation of a pituitary mass?
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.
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?
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.
Describe the symptoms suggestive of a prolactinoma:
Amenorrhea
Galactorrhea
Loss of libido
Infertility
What is lactotroph hyperplasia?
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.
Describe the symptoms suggestive of a GH producing adenoma:
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.
Describe the symptoms suggestive of a ACTH cell adenoma:
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.
Diagnosis of a pituitary carcinoma requires?
Demonstration of metastases.
What are the two most common supra stellar tumours?
Gliomas and Craniopharyngiomas
The latter are Rathke pouch remnants and are slow growing with a bimodal age distribution.
Describe the regulation of Insulin release:
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.
What is the principle function of Insulin?
Insulin increases glucose transport into target cells, primarily skeletal muscle and adipocytes.
GLUCOSE UPTAKE INTO OTHER CELL TYPES IS INSULIN INDEPENDENT.
What is the most important genetic association in type 1 diabetes mellitus?
~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.
What are the three major initiatives by which diabetes causes complications?
Formation of Advanced Glycation End products (AGEs)
Activation of Protein Kinase C
Intracellular Hyperglycaemia and Disturbances in Polyol pathways.
What are AGEs?
How to AGEs cause the complications of diabetes?
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.
How does diabetes increase Protein Kinase C release?
What damage does this cause?
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.
How does intracellular hyperglycaemia cause the complications of diabetes?
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.
What are the adrenal hyperfunction syndromes?
Cushing syndrome (excess glucocorticoids) Hyperaldosteronism (excess mineralocorticioids) Androgenital syndromes (excess androgens)
What are the causes of Cushing syndrome?
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.
What is Cushing disease?
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.
What proportion of endogenous Cushing syndrome is caused by ectopic ACTH producing tumours?
Who is at risk of these?
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.
What proportion of endogenous Cushing disease is made by primary adrenal neoplasms?
Adenoma (10%) and carcinoma (5%) are the most common causes of ACTH independent Cushing syndrome.
Describe the Dexamethasone suppression test and how the results should be interpreted:
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.
What is the eponymous morphological change seen in the pituitary with elevated glucocorticoid levels?
Crooke hyaline change.
Describe the causes of primary hyperaldosteronism:
Primary idiopathic hyperaldosteronism: accounts for 60%
Adrenocortical neoplasm: 35% of cases
Glucocorticoid-remidiable hyperaldosteronism: rare
What is Conn syndrome?
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.
What are the causes of secondary hyperaldosteronism?
Congestive heart failure
Decreased renal perfusion
Pregnancy
Renal artery stenosis
Which gene mutation causes 21-Hydroxylase deficiency?
CYP21A
What reactions are catalysed by 21-Hydroxylase?
Conversion of Progesterone to 11-Deoxycorticosterone and thus Aldosterone.
Conversion of 17-Hydroxyprogesterone to 11-Deoxycortisol and thus Cortisol.
Describe the 3 syndromes that may manifest as a result of CYP21A mutation:
Salt wasting syndrome
Simple virilizing adrenogenital syndrome without salt wasting
Non-classic (late onset) adrenal virilism.
What are the causes of primary acute adrenocortical insufficiency?
Adrenal crisis in patients with chronic insufficiency
Rapid withdrawal of steroids
Massive adrenal haemorrhage.
What is Addison disease?
What are the causes of Addison disease?
How does it manifest?
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.
What causes autoimmune adrenalitis?
What is APS?
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.
How is secondary adrenocortical insufficiency distinguished from primary?
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.
Most adrenal cortical neoplasms are sporadic. Which two genetic syndromes have a predilection for adrenal cortical carcinoma?
Beckwith-Weidemann syndrome (imprinting disorder)
Li-Fraumeni syndrome (p53 mutations)
Functional adrenocortical adenomas tend to be associated with….
Functional adrenocortical carcinomas tend to be…
Hyperaldosteronism and Cushing’s
Virilizing.
Describe pheochromocytomas:
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.
Which familial syndromes are associated with pheochromocytomas?
MEN2A and MEN2B
vHL
NF-1
Sturge-Webber
What are the MEN syndromes?
The multiple endocrine neoplasia syndromes are a group of genetically inherited diseases resulting in proliferative lesions of multiple endocrine organs.
What are the features of MEN tumours that distinguish them from their sporadic counterparts?
Tumours occur at a younger age
Tumours are more aggressive and recur more frequently
Multiple organs and multifocal
Preceded by asymptomatic endrocrine hyperplasia.
What is the MEN1 gene?
Where is it located and what does it code for?
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.
Which tumours are associated with MEN1?
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
How is MEN2 subclassified?
MEN-2A
MEN-2B
Familial medullary thyroid cancer.
What is the RET gene?
Where is it? What are the effects of RET mutations (with examples)?
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.
Which tumours are associated with MEN-2A?
Pheochromocytomas in 40-50%
Medullary thyroid cancer in 100%!!!!!
Parathyroid hyperplasia in 10-20%
Which tumours are associated with MEN-2B?
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.
What is Familial medullary thyroid cancer?
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.
What is the role of screening in MEN syndromes?
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.
