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
Which is the most abundant cell type in the anterior pituitary?
somatotrophs (50%)
Secrete growth hormone in response to growth hormone releasing hormone from the hypothalamus
Which is the least abundant cell type in the anterior pituitary?
Thyrotrophs (5%)
Describe the regulation of prolactin release
prolactin is under negative control; dopamine inhibits prolactin production (because it is only needed in the
context of pregnancy/breastfeeding)
High oestrogenic states overcome inhibition by dopamine
Somatotroph axis
Hypothalamus alters its activity in response to external/environmental factors (stress, exercise, sleep, hypoglycaemia) –> secretes GHRH
Pituitary ssecretes growth hormone. secretion is pulsatile, mainly overnight
Effects are direct of mediated by insulin-like growth factor 1
growth hormone and IGF-1 are both involved in negative
feedback loop
Somatostatin released by the hypothalamus also inhibits growth hormone production by the anterior pituitary
Clinical disorders of the posterior pituitary gland
1) Cranial diabetes insipidus - insufficient ADH
2) SIADH - syndome of inappropriate ADH secretion -> causes hyponatremia and hypo-osmolality
Clinical disorders of the anterior pituitary gland
1) pituitary tumours - can result in overproduction or under function
2) Hypopituitarism - pituitary failure
Diabetes insipidus
lack of ADH and inability to reabsorb water
Results in passage of large volumes (>3 L/day, sometimes >10L) of dilute urine
Clinical features:
o Polyuria, polydipsia, nocturia
o Low urine osmolality and high plasma osmolality (inability to concentrate urine)
AVPR2
ADH receptor
basolateral membrane of kidney
GPCR
Binding causes PKA activation
Types of diabetes insipidus
1) cranial DI - ADH deficiency
- Can be idiopathic or genetic (mutation in ADH gene)
2) nephrogenic DI - ADH resistance
- genetic, usually a mutation in AVPR2 gene, or secondary to drugs
Diagnosis of DI
Water deprivation test
- first ask patient to keep a diary of urine production to
determine genuine polyuria
Deprive patients of fluid for 8h
Measure plasma and urine osmolality every 2-4h
Then give synthetic ADH and reassess urine osmolality. Will correct cranial DI but not nephrogenic DI (due to resistance rather than deficiency)
Treatment of DI
desmopressin = ADH analogue without vasoconstrictor effects
works for Cranial DI but not nephrogenic (maybe in high doses)
incidentaloma
asymptomatic non-functioning pituitary tumour
What is the most common Secretory pituitary adenoma?
prolactinoma (usually a microadenoma <1cm)
Clinical features result from suppression of gonadotrophic hormones, because prolactin inhibits GnRH secretion
hypogonadrotrophic hypogonadism (negative feedback on gonadotropins)
o Galactorrhoea
o Menstrual disturbance and subfertility in women
o Rare in men, presents with reduced libido/erectile dysfunction
Managed with Dopamine agonists (cabergoline)
Acromegaly
Excessive production of GH (and IGF-1) in adults (causes ‘gigantism’ in children)
o Growth plates have fused, and therefore cannot cause increase in height
o Cartilage, muscles and tendons can still grow
Usually due to a GH producing macroadenoma of the pituitary
Can be diagnosed with a glucose suppression test - glucose normally suppresses GH
Hypopituitarism
Failure of (usually anterior) pituitary function
Can affect a single hormonal axis (FSH/LH most commonly) or all hormones (panhypopituitarism)
Leads to secondary gonadal/thyroid/adrenal failure
Need multiple hormone replacement (give cortisol first if all axes affected)
o Lack of cortisol is life threatening
Caused by tumours, radiotherapy, surgery, infarction, etc.
What are the actions of growth hormone an cortisol on blood glucose?
increase blood glucose
counter-regulatory hormones for insulin - do the opposite
Describe the state of thyroid follicular cells when active/suppressed
Active = columnar cells, depleted colloid Suppressed = squamous cells, colloid acumulates
Describe thyroid hormone biosynthesis
orally ingested iodine is reduced to iodide in the GIT and absorbed.
Basolateral sodium-iodide pump transports iodide from the blood into follicular cells. The iodide diffuses to the apical membrane, where it is antiported with chloride by pendrin. Iodide is oxidised to I+ by thyroid peroxidase.
I+ combines with tyrosine residues in thyroglobulin (organification of thyroglobulin) forming mono or di-iodinated thyronine, which combine to form T3/T4.
Describe thyroid hormone release
1) Stimulation by TSH causes follicle cells to remove thyroglobulin from the follicles by endocytosis.
2) Lysosomes in the cell fuse with the vesicles, and lysosomal enzymes break down thyroglobulin, releasing free T3 and T4 into the cytoplasm. amino acids are recycled and used to synthesise more thyroglobulin.
3) T3 and T4 diffuse across the basement membrane and into the bloodstream.
4) Most of the T3 and T4 are bound to thyroid-binding globulins (TBGs), and some are bound to transthyretin or albumin.
Thyroglobulin
Polypeptide backbone for the synthesis and storage of thyroid hormones.
Iodinated glycoprotein with many tyrosine residues
What is important to remember in Secondary hypothyroidism?
this is due to pituitary gland failure
other HP axes may be affect as well -> critical to check cortisol!
Complications of Surgery for Graves’ Disease
haemorrhage - bleeding following surgery can lead to compression of the trachea and respiratory interruption.
RLN nerve palsy
hypocalcaemia
hypothyroidism
Goitre
Swelling in the neck resulting from an enlarged thyroid gland.
Which nerves must be preserved during neck surgery to ensure no voice hoarseness post operatively?
RLN and external branch of the superior laryngeal nerve
RLN lies in the groove between the oesophagus and the trachea and is closely associated with the inferior thyroid artery. Easily damaged by division, stretching or compression
What symptoms are seen with unilateral RLN damage?
hoarseness
What symptoms are seen with bilateral RLN damage?
complete voice loss and severe airway narrowing
which muscle is supplied by the superior laryngeal nerve?
cricothyroid muscle
closely associated with superior thyroid arteries and may be damaged when vessles are ligated
What symptoms are seen with superior laryngeal nerve damage?
weakness of phonation and impaired alteration of pitch due to loss of tension on vocal cords (usually achieved by action of cricothyroid muscle)
How many parathyroid glands are there and why are they at risk in thyroid surgery?
4 glands, 2 on each side
Usually embedded in posterior part of the thyroid gland and can be inadvertently excised
What is the effect of low PTH on calcium and bone?
hypocalcaemia, but little effect on bone.
Low serum calcium ca lead to tetany, tremor and convulsions
Where are the enzymes involved in steroid hormone synthesis located?
mitochondria and SER
Describe the blood supply of the adrenal glands
superior adrenal artery - branch of inferior phrenic artery
middle adrenal artery - branch of AA
inferior adrenal artery - branch of renal artery
- The blood reaches the outer surface of the gland before entering and supplying each layer (centrepetal blood flow).
- At the centre, it flows into the medullary vein.
What regulates prduction of Adrenal Androgens?
ACTH
•Adrenal Androgens = DHEA, DHEA-S, androstenedione
Which enzyme catalyses the first enzymatic step in steroid hormone synthesis and where is it located?
Step 1 = conversion of cholesterol -> pregnenolone
catalysed by cholesterol side chain cleavage enzyme (P450scc)
located on inner mitochondrial membrane
What is the rate-limiting step in steroid hormone synthesis?
Rate-limiting step is the transport of free cholesterol
from cytoplasm into mitochondria.
Carried out by Steroidogenic Acute Regulatory Protein (StAR)
Where does the conversion of cholesterol to pregnenolone take place?
mitochondria
Which domains are conserved in steroid receptors?
Domain C - DNA binding domain (Highly conserved) contains 2 zinc fingers which bind to specific sequences DNA (HREs)
Domain E - ligand binding domain.
Where are MR receptors found?
Mineralocorticoid Receptors (MR) Distal Nephron, Salivary glands, sweat glands, large intestine, Brain, vascular tissue, heart
Steroid Receptor Affinity
MR: aldosterone > cortisol
GR: aldosterone = cortisol
NB: Cortisol conc is much higher than aldosterone. Cortisol can bind to MR
Which mechanism to protects mineralocorticoid receptor from illicit occupation by glucocorticoids?
11 beta hydroxysteroid dehydrogenase
catalyses the conversion of Cortisol (active) to Cortisone (inactive) in selective tissues e.g kidney, allowing aldosterone to function normally
Action of ACTH
ACTH binds to GPCR and activates AC -> cAMP -> PKA
Stimulation of cholesterol delivery to the
mitochondria (rapid).
Increased transcription of genes coding for steroidogenic enzymes (long-term).
Action of Angiotensin II (aldosterone)
binds to GPCR and activates phospholipase C -> PIP2 cleavage -> IP3 and DAG
stimulates transcription of StAR and cholesterol uptake into mitochondria
Primary Aldosteronism
Conn’s syndrome
- HTN
- hypokalaemia
- hypernataemia
- low renin
- alkalosis (due to H+ excretion stimulated by aldosterone)
Causes: Aldosterone producing adenoma (unilateral)
Bilateral adrenal hyperplasia
Cushing’s Syndrome
Excess cortisol
- weight gain (central obesity)
- hyperglycaemia
- moon face
- high blood pressure
- red ruddy face, extra fat around neck
- striae
- proximal muscle wasting (presents as weakness)
Causes:
- ACTH producing adenoma (pituitary)
- Cortisol producing adenoma (adrenal)
- Iatrogenic
Management of primary adrenal insufficiency
hydrocortisone (cortisol replacement) and fludrocortisone (aldosterone replacement)
do not delay treatment, treat empirically
Differentiate clinically between primary and secondary adrenal insufficiency
Secondary insufficiency is similar to Addison’s EXCEPT:
o Skin pale (no elevated ACTH, therefore no pigmentation)
o No electrolyte abnormalities as aldosterone production is intact (regulated by RAAS)
Treat with hydrocortisone replacement (fludrocortisone unnecessary)
Cushing’s Disease
cushing’s syndrome caused by a pituitary adenoma
Diagnosis of Cushing’s syndrome
1) dexamethasone suppresion test to establish cortisol excess
2) measure ACTH.
- Low = ACTH-independent cause (e.g. adrenal adenoma)
- High = ACTH-dependent (ectopic tumour or cushing’s disease)
What is the most common cause of cortisol excess?
Iatrogenic - Due to prolonged high dose steroid therapy
Cushingoid appearance but low plasma cortisol
Chronic suppression of pituitary ACTH production and adrenal atrophy
What adrenal gland disorders cause HTN?
- phaeochromocytoma (increased afterload as NA vasoconstricts)
- primary aldosteronism (increased preload due to increased venous return)
Commonest secondary cause of hypertension
Conn’s syndrome (primary aldosteronism)
Clinical features of Conn’s
o Significant hypertension o Hypokalaemia (in up to 50%) o Alkalosis-> aldosterone increases H+ secretion in distal tubule
- renin supressed
- high aldosterone levels
Suppression testing
o Intravenous saline load -> should normally switch off RAAS
phaeochromocytoma hallmark symptoms
episodes of headache (HTN), palpitations, pallor and sweating (due to +++ NA)
Hyponatraemia
serum sodium <135 mmol/l
Almost always due to disorder of water balance, not sodium deficiency
Causes of hyponatraemia
1) SIADH
2) renal impairment
3) diuretic effect
Excess water retention dilutes plasma sodium concentration
SIADH diagnostic criteria
1) Hyponatraemia
2) urine osmolality > plasma osmolality
3) Urine sodium >20 mmol/l (inappropriate sodium excretion)
4) Absence of adrenal, thyroid, pituitary or renal insufficiency
5) no recent diuretic use
What is the effect of Hyponatraemia on the brain?
Plasma dilution decreases serum osmolality, resulting in a higher osmolality in the brain compared
to the serum.
This creates an abnormal pressure gradient and movement of water into the brain, which can cause
progressive cerebral oedema,
What is the risk of overly rapid correction of hyponatremia?
can cause central pontine myelinosis
withchronic hyponatremia, the brain compensates by decreasing the levels of osmolytes within the cells, so
that they can remain relatively isotonic with their surroundings and not absorb too much fluid.
With correction of the hyponatremia withintravenous fluids, the extracellular tonicity increases, followed by
an increase in intracellular tonicity.
When the correction is too rapid, not enough time is allowed for the brain’s cells to adjust to the new
tonicity (by increasing the intracellular osmoles)
Water will leave the brain
Causes of HYPERNATRAEMIA
o Insensible/sweat losses (severe burns/sepsis)
o GI losses
o Diabetes Insipidus
o Osmotic diuresis due to hyperglycaemia (HHS/DKA)
Seen a lot in patients with dementia as they may have no intact thirst mechanisms
Clinical features of hypercalcaemia
Moans = depression/slowed down
Bones = bone pain, muscle weakness, osteopaenia
Stones = predisposed to nephrocalcinosis/nephrolithiasis
Abdominal Groans = vomiting, constipation
Causes of hypercalcaemia
1) primary hyperparathyroidism
2) ectopic PTHrP production (malignancy)
To differentiate between causes, measure the PTH
o If ↓ then malignancy is likely (PTHrP has negative feedback effect on PTH production)
o If ‘normal’ or ↑ then primary hyperparathyroidism
What is the effect of Glucocorticoids on vitamin D?
inhibit vit D production
What is the link between hyperventilation and calcium?
hyperventilation causes very mild and transient hypocalcaemia due to alkalosis –> tingling in hands
As the blood pH increases, blood transport proteins, such as albumin, become more ionized into anions. This causes the free calcium present in blood to bind more strongly with albumin.
Causes of hypocalcaemia
1) hypoparathyroidism
2) vitamin D deficiency
3) chronic renal failure - reduced ability to hydroxylate vitamin D
Ketone body formation
Occurs when there is an excess of acetyl CoA and not enough oxaloacetate for it to enter TCA
Acetyl CoA + acetyl CoA -> acetoacetate
can be convertate to acetone and betahydroxybutyrate
Macrovascular complications of DM
DM is associated with CHD, CVD, peripheral vascular disease
Hyperglycaemia causes excessive uptake of glucose into endothelial cells. Glucose is converted to sorbitol via the polyol pathway. This depletes NADPH and NO, and leads to oxidative stress and ROS formation.
Sorbitol is converted to fructose, which glycosylates proteins, leading to a buildup of advanced glycated end products (AGEs), which cause structural changes (e.g. basement membrane thickening)
ROS also stimulate increased transcription of pro-inflammatory mediators -> increased permeability causing LDL and monocyte infiltration -> ATHEROMA formation
tight glycaemic control has little effect, all CVD risk factors must be targeted
Microvascular complications of DM
Retinopathy
Neuropathy
Nephropathy
Two components:
1) capillary damage
Structurally and functionally abnormal small blood vessels receive increased blood flow and therefore increased BP. This leads to endothelial damage, causing leakage of albumin/other proteins
2) metabolic damage
Most tissues need insulin to take up glucose, but retina / kidney / nerves don’t
Hyperglycaemia causes excessive uptake of glucose into these cells. Glucose is converted to sorbitol via the polyol pathway. This depletes NADPH and NO, and leads to oxidative stress and ROS formation. CELL DAMAGE.
Sorbitol is converted to fructose, which glycosylates proteins, leading to a buildup of AGEs
Diabetic Retinopathy
1) Early stages (non-proliferative)
- hyperglycaemia causes damage to small blood vessels walls, causing microaneurysms
- these rupture and form dot haemorrhages
- protein exudate is left behind, forming hard exudate
- cotton wool spots result from microinfarcts
2) late stages (proliferative)
- damage to veins causes ischaemia
- VEGF is produced, stimulating angiogenesis -> proliferative retinopathy
- new blood vessels are fragile and easily rupture, causing vitreous haemorrhage
- failure to clear fluid causes macular oedema
Diabetic nephropathy
Hyperglycaemia causes damage to glomeruli - AGE cause GBM thickening and widening of filtration slits, causing proteinuria.
Kidney damage initially causes renal enlargement and hyperfiltration (afferent arteriole dilation and efferent arteriole constriction increases filtration pressure).
Systemic BP increases, and exacerbates disease progression. This leads to microalbuminuria, then macroalbuminuria.
progressive damage causes eventual decline in GFR, leading to end-stage kidney disease.
Neuropathy
Capillary damage, including occlusion in the vasa
nervorum causes reduced blood supply to the neural tissue. This results in impairments in nerve signalling that affect both sensory and motor function.
Sorbitol accumulation causes metabolic damage
Diabetic Foot
combination of peripheral neuropathy and peripheral vascular disease
Compromise of the blood supply + lack of sensation .
loss of sensation causes repetitive stress; unnoticed injuries and fractures, ulcer formation
-> reduced blood flow impairs healing, limits the access of phagocytic cells to the infected area
What does macrocytosis mean?
Macrocytosis is the enlargement of red blood cells with near-constant hemoglobin concentration
microcytosis = RBC are unusually small
What peritoneal fold connects the liver to the abdominal wall?
falciform ligament
Does the relatively high concentration of insulin within the blood entering the post-Islet exocrine pancreas influence activity of any other biomechanisms apart from uptake of glucose by cells of the body?
YES- INCREASED PRODUCTION OF INSULIN BY BETA CELLS IN THE ISLETS STIMULATES/ UPREGULATES SYNTHESIS OF EXOCRINE PANCREATIC DIGESTIVE
ENZYMES FOR RELEASE INTO THE DUODENUM VIA THE PANCREATIC DUCT
Why would a person with diabetes need to take
insulin even if they have not eaten?
To suppress glycogenolysis, lipolysis and gluconeogenesis
Illness can raise blood glucose levels (cortisol stimulates
gluconeogenesis – stress response), so people with diabetes may need
to increase their insulin dose.
How do patients with diabetes self-manage their
condition and why is this important?
- Insulin-dependent patients test blood glucose multiple times a day. May also test glucose and ketones in urine
- Awareness of diet, exercise, and other factors (e.g. menstrual cycle); adjust insulin dose accordingly.
- fixed dose insulin regime - diet/eating patterns much more restrictive
- non-insulin-dependent patients monitor blood (urine) glucose levels regularly
- T2DM: adherence to medication and lifestyle changes for other CV risk factors
T1DM: good blood glucose control helps minimise complications
• T2DM: healthy diet and exercise important to slow progress of diabetes and minimise complications
From which tissue does this capsule surrounding the pituitary develop?
MENINGES- CONTIINUOUS WITH DURA
Which substances do Corticotrophs secrete?
1) ACTH
2) MSH
3) β-lipotropin
4) β-endorphin.
Which enzyme, synthesized by the follicle cell, enables iodide to be converted to iodine?
THYROID PEROXIDASE
Synthesis of thyroid hormones involves both an exocrine and an endocrine stage. What are these?
exocrine - production and secretion of colloid into follicle lumen
endocrine - secretion of T3/T4 into blood capillaires
Describe the control of T3/T4 synthesis
The synthesis and breakdown of thryoglobulin is controlled by the hypothalamus and
adenohypophysis.
TSH reaching the thyroid gland via the circulation binds to its receptor (Thyrotropin receptor (TSHr)) stimulates the cAMP pathway.
Activation of TSHr stimulates thyroid follicular cells to synthesise and breakdown thyroglobulin from thyroid follicles and result in an increased release of thyroxine into the thyroid capillaries.
Summarise the function of calcitonin
LOWERS SERUM CALCIUM LEVELS- REDUCES RENAL CALCIUM REABSORPTION, promotes the absorption of calcium by bone and inhibits the action of osteoclasts.
three features of hypothyroidism seen on the face
Periorbital oedema
Coarsening of skin and facial features
puffy face (myxoedema)
hair loss/thinning
most common cause of secondary adrenal insufficiency
exogenous steroids
Negative feedback of endogenous steroids on CRH/ACTH -> no stimulus for adrenal gland, atrophy
Patients become steroid dependent
Implications:
o Unable to respond to stress (illness/surgery)
o Need extra doses of steroid when ill
o Cannot stop suddenly
o Gradual withdrawal of steroid therapy if >4-6 weeks
How do you screen for cortisol excess?
dexamethasone suppression test
How to differentiate between ectopic excess ACTH production vs pituitary excess production?
CRH stimulation test. no change in ACTH = ectopic source
IATROGENIC CUSHING’S SYNDROME
COMMONEST CAUSE OF CORTISOL EXCESS
Cushingoid appearance but low plasma cortisol
Due to prolonged high dose steroid therapy
Metabolic syndrome
cluster of conditions — increased blood pressure, high blood sugar, excess body fat around the waist, and abnormal cholesterol or triglyceride levels — that occur together, increasing your risk of heart disease, stroke and diabetes.
In a patient who presents with central weight gain, which is the best screening test to exclude cortisol excess?
Overnight dexamethasone suppression test.
Plasma cortisol should be undetectable in normal
circumstances
OR:
- Urinary free cortisol
- Late night salivary cortisol (Should be undetectable or very low in normal)
Explain how aldosterone influences Na, K and H
Aldosterone upregulates ENaC channels on the interstitial side and sodium-potassium ATPase channels on the basolateral side of renal tubular epithelial cells, resulting in [increased] resorption of sodium ions from the lumen in the collecting duct.
The increased negative charge in the luminal fluid causes increased potassium ion [secretion] from principle tubular cells and increased hydrogen ion secretion from tubular intercalated cells, aided by upregulation of the apical H+-ATPase and sodium-potassium ATPase channels by aldosterone and hypokalemia.
Overall, [more] potassium and hydrogen ions are lost in the urine.
What is the link between type 2 diabetes and obesity?
The mechanism linking obesity and type 2 Diabetes Mellitus is poorly understood.
Inflammation is an important mediator that links Type 2 DM with atherosclerosis. Type 2 Diabetes is associated with [higher] levels of pro-inflammatory cytokines such as CRP, IL6, and TNF α.
Hormones released by adipose tissue ([adipokines]) can also [promote] inflammation. The [distribution] pattern of body fat is also important, with [central] obesity a significant risk factor for both Type 2 diabetes and [cardiovascular] disease.
What is a clinical sign of hypoparathyroidism?
tetany due to hypocalcaemia
Most common causes of thyrotoxicosis
Autoimmune (Grave’s disease) 70%
Toxic multinodular goitre 20%
Toxic adenoma 5%
Thyroiditis 3% (Inflammatory, drug induced, post-pregnancy)
Graves’ disease
Autoimmune disorder
Seen most frequently in women (age 40-60y)
Thyroid antibodies often detectable
- TRAB (TSH receptor Ab) in 70-100%
- TPO in 70-80% (overlapping autoimmunity)
Symmetrical gland enlargement
Histologically = colloid depletion and columnar epithelial cells
Associated with other autoimmune diseases
- Type 1 DM, pernicious anaemia, vitiligo
Can be associated with eye disease
Signs/symptoms of hyperthyroidism
Irritability/hyperactivity Heat intolerance and sweating Weight loss with increased appetite Diarrhoea Amenorrhea/oligomenorrhea
Signs: Sinus tachycardia/AF Fine tremor Warm, moist skin Eye signs Goitre, pre tibial myxoedema
Graves’ Ophthalmopathy
due to oedema and inflammation of extra-ocular muscles
Occurs in 70% of graves patients
What additional investigations should be performed in a patient with high levels of T3/T4?
Thyroid autoantibodies (TRAB)
Radioiodine uptake scan (symmetrical in graves, will be localised to site of nodule/adenoma with toxic nodular goitre or adenoma)
Outline management options for hyperthyroidism
Anti thyroid therapy (carbimazole/PTU)
Beta blockers for symptomatic relief
Radioiodine therapy
Surgery
Patient presents with:
- TSH 28 (0.04-5)
- T4 6 (9-21)
Outline 3 causes of this pattern of thyroid hormone dysfunction.
1) Hashimoto’s thyroiditis (anti TPO antibody)
2) Severe iodine deficiency
3) Iatrogenic - Following radio iodine therapy or surgery, Amiodarone, lithium
4) Thyroiditis - Viral or post-partum, often temporary
What symptoms are typical in hypothyroidism?
Symptoms of hypothyroidism: Weight gain Depression Lethargy Constipation Cold intolerance Poor concentration Hoarseness Menorrhagia
What clinical signs can be seen in hypothyroidism?
Weight gain Bradycardia Dry skin Coarse, thin hair Anaemia Slow relaxing reflexes May have goitre
A 22 year old woman complains of suddenly feeling very tired over the past 3 days.
On further questioning she reports that she is going to
the toilet almost every hour and passing lots of urine.
She has no significant past medical history.
You suspect she may have diabetes mellitus.
List 3 further questions you would ask her in order to support your hypothesis that she has diabetes
Thirst, excessive fluid intake
Weight loss
Lethargy/recurrent infections
The patient is prescribed insulin therapy. You then
need to educate her about factors that can precipitate
hypoglycaemia. List 3 important factors of which she needs to be aware
Hypoglycaemia = Plasma glucose < 4 mmol/L
Main precipitants:
Exercise Alcohol Missed meal Error Sepsis Hypoadrenalism
She asks you what to look out for if she is becoming
hypoglycaemic. Give two clinical features she might
have in this situation
Autonomic: tremor sweating anxiety nausea
Neuroglycopenic: headache dizziness difficulty speaking confusion
Give 2 therapeutic methods of reducing the chance of
this patient developing diabetic nephropathy
GOOD GLYCAEMIC CONTROL
ACEi is treatment of choice to reduce risk of progression of nephropathy
NB: for neuropathy annual assessment of vibration and light touch
3 causes of cushing’s syndrome
1) cushing’s disease - pituitary adenoma
2) iatrogenic
3) ectopic ACTH-producing tumour (e.g. lung cancer)
4) adrenal adenoma/carcinoma
How would you distinguish between exogenous and endogenous excess steroid?
ENDOGENOUS SOURCE
- Increased urinary and plasma cortisol
EXOGENOUS SOURCE
- May look normal or ‘Cushingoid’
- Decreased urinary and plasma cortisol
List potential causes of hyponatraemia (4)
Any cause of SIADH (infection/malignancy/drugs)
Loss of salt and water (diarrhoea/vomiting)
Retention of water and salt (heart failure/liver cirrhosis)1) With hypovolaemia (Na/water loss)
- Loss of sodium via GI tract (vomiting/diarrhoea) or
kidneys (diuretics/renal tubular disorders)
2) With normovolaemia (water gain)
- Syndrome of Inappropriate ADH (SIADH)
- Glucocorticoid deficiency
3) With hypervolaemia (Na/water gain)
- Heart failure, hepatic cirrhosis, nephrotic syndrome
- Pathological fluid retention lowers plasma sodium
Hyponatraemia - What investigations should be performed? (4)
Plasma osmolality Urine osmolality Urine sodium TFT Short synacthen test/ early am cortisol
Management of hyponatraemia
Treat underlying cause
Fluid restrict
If acute or severe, consider IV hypertonic saline bolus
1) Severe and acute
- Unconscious or seizures
- Give infusion of hypertonic (3%) saline
- Can increase quickly
2) Less severe
- Try to establish cause- treat pneumonia
- Usually fluid restriction is correct management
- Increase slowly
- 2nd line treatment controversial -> Can consider AVPR2 antagonists (‘vaptans’)
action of thyroid hormones
Increase basal metabolic rate:
- upregulate metabolic enzymes -> upregulates all metabolic processes = CALORIGENIC EFFECT
- increased HR/BP to facilitate increased O2 delivery
- Increased rate/depth of respiration
- vasodilation to eliminate heat
- increased GI activity - motility/enzyme secretion/appetite
- increased breakdown of fats/proteins
causes of hyperthyroidism
Graves
Toxic adenomas (rarely thyroid carcinomas)
Multinodular goitre (abnormal swelling of the neck)
Thyroiditis
Excessive administration of thyroxine
causes of hypothyroidism
Hashimoto’s Thyroiditis (anti-TPO antibodies).
Thyroiditis (viral) - inflammation of thyroid gland due to a viral cause
Thyroidectomy
Following Radioactive Iodine therapy
Pituitary/Hypothalamic disease - secondary hypothyroidism
Severe Iodine Deficiency - ‘endemic goitre’
Radioactive iodine uptake scan
Usually ordered in the setting of thyrotoxicosis to help identify the underlying aetiology.
measures the amount of radioactive iodine (usually I-123) that is taken up by the thyroid gland.
