3E Flashcards
What is Addison’s disease?
chronic adrenal insufficiency due to destruction of the adrenal cortex
UK prevalence is about 4/100,000
What is the main aetiology of Addison’s disease in affluent countries?
autoimmune adrenalitis
What is the main aetiology of Addison’s disease in developing countries?
tuberculosis
Explain why a patient with Addison’s disease may have a low baseline cortisol level and not respond to a synacthen test.
In the case of infection, the patient will be using cortisol at a greater rate than usual. If the patient fails to increase their cortisol dosage to account for this, it will result in reduced basal cortisol levels.
The patient fails to respond to synacthen because the Addison’s disease has caused significant adrenal atrophy.
How is the short synathen test performed?
take a basal serum cortisol reading
administer 250 micrograms of synacthen intravenously at time 0
measure blood cortisol at 30 and 60 minutes
in healthy individuals, basal plasma cortisol should exceed 170nmol/l and rise to at least 580nmol/l on stimulation.
Patients with insufficient adrenal function are unable to raise their serum cortisol in response to synacthen.
What often separates the kidney and adrenal gland?
a thin layer of adipose tissue. Appears as a light gap on MRI
Name the three zones of the adrenal gland and the hormone produced in each zone
Z. glomerulosa - aldosterone/mineralocorticoids
Z. fasciculata - cortisol/glucocorticoids
Z. reticularis - adrenal androgens
NB: cortisol and adrenal androgens are thought to be produced by both the fasciculata and reticularis
Which autoantibodies are commonly found with IDDM?
ICA (islet cell antibody)
I-A2 (insulinoma associated antigen 2)
GAD 65 (glutamic acid decarboxylase 65)
Others:
AII (insulin autoantibody)
ZnT8 (zinc transporter)
Define MODY (Maturity-onset Diabetes of the Young)
hereditary forms of diabetes mellitus caused by mutations in an autosomal dominant gene disrupting insulin production
embryology of the adrenal glands
cortex - mesodermal. derived from urogenital ridge
medulla - neural crest cells
Which area of the adrenal cortex is the largest?
zona fasciculata (forms 80% of cortex)
Lipid rich layer
Phaeochromocytoma
tumour of adrenal medulla
causes secondary hypertension
What are the effects of Glucagon & Adrenaline on enzymes regulating gluconeogenesis?
stimulate gluconeogenesis in the liver:
- stimulate glucose 6 phophatase
- stimulate PEPCK
- inhibit glucokinase
Which Tissues are dependent on a constant supply of glucose?
1) brain - fatty acids cannot cross blood-brain barrier
2) RBC - no mitochondria
3) Testes - testis blood barrier prevents entry of FA
4) Retina
Glucagon receptor
Found on hepatocytes
GPCR
binding activates cAMP dependent protein kinase A
Insulin receptor
Fuond on adipocytes, striated muscle and liver
tyrosine kinase receptor
binding causes autophosphorylation of intracellular tyrosine residues. This activates protein kinase B (akt)
What are the effects of Glucagon & Adrenaline on enzymes regulating glycogen synthesis/breakdown?
stimulate glycogenolysis in the liver:
- stimulate G6Pase
- stimulate glycogen phosphorylase
- inhibit glucokinase
- inhibit glycogen synthase
Glucagon has no direct effect on muscle or adipose tissue because they have no glucagon receptors
NA - stimulates glycogen phosphorylase in muscle
what is the effect of Insulin on enzymes regulating glycogen synthesis/breakdown?
Insulin stimulates glycogenesis (glycogen synthesis)
- stimulates GK/HK
- stimulate glycogen synthase
- inhibits G6Pase (liver)
- inhibits glycogen phosphorylase
what is the effect of Insulin on enzymes regulating gluconeogenesis?
Insulin inhibits gluconeogenesis:
- inhibits PEPCK
- inhibits G6Pase
What are the Principal actions of Insulin on the liver?
Stimulates:
1) glycolysis
2) glycogen synthesis
3) fatty acid synthesis
Inhibits:
1) gluconeogenesis (PEPCK & G6Pase)
2) glycogen breakdown
What are the Principal actions of Insulin on striated muscle?
1) increased glut 4 mobilisation to the membrane (increased glucose uptake)
2) glycogen synthesis
3) fatty acid synthesis
Inhibits glycogen breakdown
What are the Principal actions of Insulin on adipose tissue?
1) increased glut 4 mobilisation to the membrane (increased glucose uptake)
2) increased FA synthesis (LPL and ACC stimulated)
3) inhibits lipolysis (breakdown of cAMP prevents HSL activation)
What is the effect of adrenaline on adipose tissue?
stimulates lipolysis by upregulating hormone sensitive lipase
which molecule directly inhibits PFK1 activity?
ATP
Which enzyme is activated by insulin in skeletal muscle after a meal?
Glycogen synthase
Mutations in which gene(s) account for the highest proportion (~50%) of the genetic risk of Type 1 diabetes?
HLAs
What is the baseline population risk of Type 1 diabetes in North America and Europe?
0.4%
what are the 3 features of DKA?
1) metabolic acidosis
2) ketosis
3) hyperglycaemia
State of cellular starvation in the midst of plenty
o Hyperglycaemia, but access to substrate for fuel is denied due to a lack of insulin
Characterised by uncontrolled catabolism as cells seek alternative sources of fuel
Explain how Diabetic ketoacidosis causes osmotic diuresis
o Glucose (and ketones) are freely filtered at glomerulus
o As blood glucose rises, the maximal reabsorption threshold of glucose is exceeded
o This means that there is an elevation of solute content in the tubules
o Increased solute concentration in tubular lumen generates an osmotic gradient
o This results in increased water loss in urine
HYPEROSMOLAR HYPERGLYCAEMIC STATE
Complication of diabetes mellitus in which high blood sugar results in high osmolarity without significant ketoacidosis
Occurs in Type 2 DM
o Insulin action is enough to suppress the production of ketones
o However, the low level of insulin action cannot suppress persistent hyperglycaemia and osmotic
diuresis
Which lobe of the pituitary is connected to the hypothalamus by blood vessels? what are the blood vessels called?
adenohypophysis, hypophysial portal veins
Which hormones travel to the pituitary gland via nerve fibres?
oxytocin
ADH
Which hormones are produced by the anterior pituitary?
1) growth hormone
2) LH/FSH
3) TSH
4) ACTH
5) Prolactin
where is melanocyte-stimulating hormone produced?
adenohypophysis (intermediate lobe)
What are the main effects of cortisol in the body?
1) METABOLIC
- stimulates gluconeogenesis
- glycogenesis
- lipolysis
- opposes insulin (raises blood glucose)
2) IMMUNOSUPPRESSION
- decreases lymphoid tissue (volume and activity)
- decreases antibodies and lymphocytes
- anti-inflammatory, blocks recruitment of eosinophils
3) SYSTEMIC
- increased apetite
- decreased vitamin D, therefore decreased calcium absorption
- increased bone resorption
- promotes effects of adrenaline -> increased BP/vascular tone
Explain how taking daily oral corticosteroids affects the normal production of hormones from all layers in the adrenal glands.
corticosteroid use increases serum cortisol, increasing negative feedback on the hypothalamus and anterior pituitary. This in turn decreases production of CRH and ACTH, causing understimulation of the adrenal glands, which atrophy.
Atrophy means that supplementation with glucocorticoids and possibly mineralocorticoids is a necessity
Explain the cause of pigmentation patches in primary hypoadrenalism.
in primary hypoadrenalism there is increased ACTH release from the anterior pituitary due to the lack of negative feedback. ACTH contains a sequence similar to melanocyte-stimulating hormone, which causes pigementation on the skin and buccal surfaces with excess ACTH
In which layer of the skin are melanocytes found?
stratum basale and underlying dermis.
Why does adrenal insufficiency cause hypoglycaemia?
cortisol normally increases gluconeogenesis and increases plasma glucose
What is fludrocortisone?
aldosterone replacement therapy
Which cells secrete insulin and which group of cells in the pancreas do they belong to?
beta cells belong to islets of langerhans
How do beta cells react to increasing concentrations of circulating glucose?
glucose enters beta cells via GLUT 2 receptors and is metabolised to ATP. ATP inhibits ATP-sensitive K+ channels, preventing K+ efflux. This depolarises the cell, opening voltage-gated calcium channels. Calcium influx stimulates insulin secretion.
What is the general structure of insulin in the blood stream?
two polypeptide chains linked by a disulphide bond
What protein can be used as a marker for insulin production?
C peptide
Describe the transduction of insulin signal in the effector cell.
Insulin receptor has alpha and beta subunits. binding of insulin causes autophosphorylation of the beta subunit, activating tyrosine kinase.
enzyme cascades are activated, including PIP3 kinase
glut 4 receptors are translocated to the cell membrane, allowing glucose entry
Which form of diabetes is usually an HLA-associated autoimmune disease?
type 1
What would be an appropriate adjustment to an insulin regimen during a period of intercurrent illness and why?
increase insulin. illness causes increase in cortisol, which counters the action of insulin
Which three ketones are produced in DKA?
1) acetoacetate
2) betahydroxybutyrate
3) acetone
Explain how insulin deficiency results in ketone production
deficiency of insulin causes excessive lipolysis. FA are broken down to acetyl CoA, which enters TCA. Excess acetyl CoA is converted to acetoacetyl CoA, which is metabolised by the liver to produce acetoacetate and betahydroxybutyrate. Production of ketones exceeds their metabolism
What is the normal anion gap?
<18 mmol/L
What anion gap is seen in DKA?
high anion gap due to addition of organic acids.
What does a normal anion gap indicate?
retention of HCl or loss of bicarbonate. Plasma bicarbonate decreases but electroneutrality is maintained by retaining chloride
What is the first line of treatment with DKA?
IV saline to correct dehydration. The life-threatening aspect is dehydration, not hyperglycaemia.
What endocrine emergency can occur in type 2 diabetes?
hyperglycaemic hyperosmolar state.
Onset tends to be insidious. Marker dehydration and hyperglycaemia but no ketosis/acidosis (no switch to ketone metabolism).
NB: patients are given heparin to prevent coaguation and hyperosmolar state increases the risk of coagulation.
What is the normal relationship of the upper lid to the cornea?
upper lid normally crosses the cornea so that the uppermost part of the iris is obscured
Name the thyroid hormones and indicate which is more potent
tri-iodithyronine = more potent
tetraiodothyronine (thyroxine)
Define basal metabolic rate
the calculated equivalent oxygen consumption or heat production by the body in a fasting subject at complete rest
outline two functions of thyroid follicular cells
1) transport iodide from the blood and trap it in the cytosol
2) synthesise thyroglobulin
3) resorption of thyroglobulin
4) release of thyroxine from follicles
Name the main protein that transports thyroid hormones in the plasma
thyroid binding globulin
Why does the thyroid gland move upwards on swallowing
larynx rises on swallowing
thyroid is attached to it by the pretracheal fascia
Name two components derived from the diet that are essential in thyroid hormone synthesis
1) iodine
2) tyrosine
Describe the regulation of thyroid hormone secretion
TRH is released from the hypothalamus in response to low T3/4 or low metabolic rate
TRH stimulates anterior pituitary to release TSH. TSH is released into circulation and stimulates thyroid follicular cells to secrete T3 and T4 into the blood strweam
Blood levels of T3/4 reach normal levels and inhibit TRH/TSH release
What results would you expect from the thyroid function tests to confirm a diagnosis of primary hyperthyroidism?
low TSH (undetectable) high T3/T4
Where is the pituitary gland located?
Lies beneath the third ventricle in a bony cavity of the sphenoid bone (sella turcica) in the base of the skull
Which part of the pituitary stains darker?
anterior
Embryology of the pituitary
neurohypophysis = downgrowth from diencephalon adenohypophysis = rathke's pouch (upgrowth from oral cavity)
chromophils
cells which take up stain
acidophils
lactotrophs and somatotrophs
pink cytoplasm and dark nuclei
basophils
corticotrophs, thyrotrophs, and gonadotrophs
darker cells with purple cytoplasm
chromophobes
resting/degranulated chromophils, stain weakly
non-secretory and serve as support cells or precursors to the acidophils and basophils.
Posterior Pituitary
contains non-myelinated axons which are the neurosecretory cells.
cell bodies are located in the hypothalamus.
Direct extension of the CNS
Not strictly speaking an endocrine organ
Secretes two hormones, which are stored in vesicles:
o ADH
o oxytocin - acts on the uterus.
Embryology of the thyroid gland
develops as an endodermal downgrowth (the ‘thyroglossal duct’) from the floor of the developing pharynx.
The foramen caecum at the back of the tongue marks the site of the downgrowth.
Hashimoto’s thyroiditis
Autoimmune reaction against thyroid antigens:
Anti-thyroid peroxidase
Anti-TSH receptor antibodies
Anti-thyroglobulin
o diffusely but asymmetrically enlarged
o Lymphocyte infiltration
o prominent fibrosis
o Oncocytic change in epithelium (Hürthle cells), fibrosis
o Paler, may resemble lymph node on section
Embryology of the parathyroid glands
o Upper pair from 4th branchial cleft - Descend with thyroid
o Lower pair from 3rd branchial cleft - Descend with thymus
What are the cell types found in the parathyroid glands?
1) chief cells - contain PTH granules, secrete PTH
2) Oxyphil cells - No secretory granules
3) water clear cells - chief cells with pools of glycogen in cytoplasm
Fat infiltration normal, increases with age to plateau in early adulthood