SUGER Flashcards
what are the layers of the glomerulus barrier?
- podocytes
- glomerular basement membrane
- fenestrated capillary endothelium
where does filtration of the blood take place?
glomerulus
which cell type in the glomerulus is responsibe for filtration of blood?
enodothelial cells
what is the name of the network of capillaries within the bowman’s capsule where blood filtration occurs?
glomerulus capillaries
what makes up the juxtoglomerular apparatus?
macula densa (from distal tubules)
juxtaglomerular cells (from afferent arteriole)
what do the juxtaglomerular cells from the afferent arteriole secrete?
renin in response to low BP
what is the average rate of urine flow?
1 ml/min
what % of cardiac output goes to the kidneys?
20%
brain 15%, muscles 20%, liver 25%
what gives rise to interlobular arteries?
arcuate arteries
what gives rise to the interlobular veins?
vasa recta
what is glomerular filtration?
passage of fluid from the blood into bowman space to form filtrate.
distal tubule responsible for secretion and reabsorbtion
what 5 factors determin glomerular filtration rate?
- pressure
- size of molecule
- charge
- rate of blood flow
- protein binding
which pressure forced favour filtration and which oppose filtration?
molecules up to what size can pass freely through glomerulus?
eg?
up to 10kDa
e.g. glucose, uric acid, potassium, creatinine
NOT plasma proteins (unless pathology!)
why can’t albumin, phosphate anf sulfate pass through the glomerulus?
the GMB is negatively charged so repells these negative anions
what happens to GFR when afferent resistance is increased?
reduced blood flow to glomerulus, reduced pressure in glomerulus, reduced GFR
what happens to GFR when efferent resistance is increased?
blood unable to exit. build up of blood in glomerulus, increased pressure, increased GFR
up to a point - then paradoxically this reverses (ACEi)
why cant albumin pass into the nephron tubule?
it has a weight of 66kDa and is negatively charged so cannot pass.
what protein might be find in the urine of a healthy individual?
no protein in urine of healthy individual
except Tamm Horsfall protein which is produced by the tubule
How is GFR calculated?
in practice, GFR is not measured directly. how is it normally calculated?
why is creatine normally used as a marker for GFR?
freely filtered
not secreted or absorbed (mostly)
not metabolised
what is the “gold standard” of a GFR marker?
inulin
- freely filtered]
- not secreted/absorbed
- not metabolised
time consuming though
what is a normal GFR?
125ml/min
what could affect a persons creatine levels?
dietary protein (+)
medications (+)
creatinine supplements (+)
age/gender/weight/ethnicity (-)
seven (!) things that regulate glomerular filtration
- renal autoregulation
- neural regulation
- hormone
- intrarenal baroreceptors
- extracellular fluid volume
- blood colliod osmotic pressure
- inflammatory mediators
what are the two mechanisms of renal autoregulation of GFR?
myogenic mechanism
tubuloglomerular feedback
how does the myogenic mechanism protect the GFR from high bp?
the myogenic mechanism is the intrinsic ability og renal arteriold to contrict/dilate
high BP
⇩
stretches blood vessel wall
⇩
opens stretch-activated cation channels
⇩
membrane depolarises
⇩
voltage gated channel open
⇩
calcium flows in
⇩
smooth muscle contraction
⇩
increase vascular resistance
⇩
minimises GFR chnages
only PREglomerular resistance vessels
can only protect up to a point.
how does the tubuloglomerular feedback influence afferent arteriolar resistance?
how does neural regulation affect GFR?
sympathetic nervous system - vasoconstricts afferent arterioles
what are the two mechanisms of hormone regulation of the GFR?
RAAS - renin released from JGA due to low bp/Na
and
ANP - from atria due to blood volume - vasodilation of afferent arteriole
how to intrarenal baroreceptors regulate GFR?
change diameter of afferent arterioles
how can extracellular fluid volume affect GFR?
changes in blood volum will affect hydrostatic pressure in glomerulus
how can blood colloid osmotic pressure affect GFR?
onctoic pressure of exerted by proteins
name some inflammatory mediators that affect the GFR
porstaglandins, NO, bradykinin histamine, cytokines
Name three homrones that reduce the GFR
norepinephrine
epinephrine
endothelin
which hormone prevents the decrease of GFR?
Angiotensin II
which two hormones increase the GFR?
enodothelial-derived nitric oxide
prostaglandins
how do NSAIDs affect GFR?
vasoconstricts afferent arteriole
how do ACEi affect GFR?
vasodilation of efferent arterioles
presentation of nephrotic syndrome
triad: oedema proteinuria low albumin
what is the most common cause of nephrotic syndrom in adults?
membranous pathology - thickening of GMB
which hormone regulates the diamter of the afferent and efferent arterioles to control the GFR?
renin
what is filtration fraction?
GFR/renal plasma flow
what is “clearance”?
the volume of plasma from which a substance is comletely removed by the kideny per unit time.
what is the definition of “rare” in disease?
1 in 2000 (europe)
what is the incidence of ADPKD?
1 in 500-1000
what is the second most common site of cysts in ADPKD?
the liver
what is an important extrarenal manifestation of ADKP, aside from cysts elsewhere?
intracranial aneurysms (8%)
what are the 2 genetic factors that cause ADPKD? which is “more serious”
Polycystin-1 and Polycystin-2
kidney will live longer in in PKD2 (80yr) than in PK1 (NT = 68/ T=56 yr)
what kind of tumour is often found in tuberous sclerosis?
AML tumour: AngioMyoLipoma - blood, muscle, fat
= cysts, adenomas on face, hypopigmentation
which gene most often causes tuberous sclerosis?
TSC2 (70-90%)
TSC prevalance = 1/1000
What causes androgen insensitivity syndrome?
presentation?
46 XY indivual with androgen receptor deficiency, tissues dont respond to androgens
Partial AIS - testosterone has some effect - apparant at birth
Complete AIS - no testosterone. Genitalia appear feamle, undiagnosed until puberty - no uterus
AMH still produced, mullerian duct regresses - no uterus
What is Acidemia?
Low blood pH
What is Alkalemia?
High blood pH
broadly, what are two factors that can affect blood pH?
Respiratory (CO2)
and
Metabollic (Inrinsic from metabolites, extrinsic from diet, buffers)
What is the Henderson-Hasselback Equation?
where is bicarb recyled?
in the kidneys
where is H+ secreted?
kidneys
Stewart’s strong ion difference is an alternative to the Henderson-Hasselbach equation…what does it look at?
why is is not used very often?
looks at what is driving thr changes in pH.
but more calculations = more analytical errors.
in an ABG, what is a the standard bicarbonate a measure/calculation of?
bicarbonate levels if patients’ CO2 was normal.
- bicarb is affected by both resp and metabolic
what does a negative base excess in and ABG indicate?
Negtative base excess = acidosis
Base excess = alkalosis
Causes of metabolic Acidosis?
Failure of H+ excretion - renal, hypoaldosterone, renal tubular acidosis.
Excess H+ - lactic acidosis, ketoacidosis, ingest acids.
HCO3- loss - diarrohoea
clinical features of metabolic acidosis?
sighing respirations, tachypnoea
-compensatory hyperventilation
how can you investigate the causes of metabolic Acidosis?
using the anion gap - the difference between measured anions and cations.
what would a wide anion gap indicate?
metabolic acidosis - lactic acidosis, ketoacidosis, acid ingestions, renal failure
what would a narrow anion gap indicate?
metabolic acidosis - GI HCO3- loss, renal tubular acidosis
causes of metabolic alkalosis?
alkali ingestion
GI acid loss - vomiting
renal acid loss - hyperaldosteronism, hypokalaemia
compensatory hypOventilation - but this is limited by hypoxic drive.
compensatory renal bicarb excretion (removal)
causes of respiratory acidosis?
CO2 retention –> increased carbonic acid dissociation
Respiratory failure Type 1/Type 2
if Chronic - compensated by increased renal H+ excrretion (remove) and bicarb retention (keep)
in respiratory acidosis/alkalosis, when would renal metabollic compensation occur?
only if chronic
causes of respiaroty alkalosis?
CO2 depletion due to hyperventilation
Type 1 Resp failure, panic attacks
compensation - increased renal bicarb loss (if chronic)
what is this?
- pH = low = Acidic
- pCO2 = low = Alkaline
- HCO3- = low = Acidic
- Base excess = low = Acidic
= metabolic acidosis
with respiratory compensation.
- likely diabetic ketoacidosis
what is the likely cause of this?
- pH = high = alkaline
- pCO2 = low = alkaline
- HCO3- = normal
- Base excess = normal
= respiratory alkalosis
no renal compensation ∴ acute not chronic
likely cause Type 1 Respiratory failure - CO2 still low
what is the likely cause of this?
- pH = high = alkaline
- pCO2 = normal
- HCO3- = high = alkaline
- Base excess = hight = alkaline
= metabolic alkalosis, no resp compensation.
likely cause = vomitting in pregnancy
what is the likely cause of this?
- pH = low = acidic
- pCO2 = high = acidic
- HCO3 = high = alkaline
- Base excess = high = alkaline
= respiratory acidosis
with renal/metabolic compensation ∴ chronic
COPD
what is the likey cause of this?
- pH = low = acid
- pCO2 = high = acid
- HCO3- = low = acid
- Base excess = low = acid
MIXED metabollic and respiratory acidosis
pneumonia = type II resp failure
sepsis = lactic acidosis
what is the rate of renal blood flow?
1250ml/min
what is the rate of renal plasma flow?
700ml/min
what is the glomerular filtration rate?
125ml/min
what is the urnie flow rate?
1ml/min
disorder associated with glucose reabsorbtion in the proximal tubule?
renal glycosuria
what is the defect in renal glyosuria?
sodium glucose transporter (SGLT2)
- failure of glucose reabsoribtion - benign
clinical features of renal glycosuria?
incidental finding on testing, benign
SGLT2 inhibitors have now been established as a treatment for?
type 2 diabetes - remove sugar and help lose weight
reduced mortality
reduced CV mortality
reduced heart failure hospitalisation
what disorder is associated with Amino Acid reabsorbtion failure in the proximal tubule?
Aminoacidurias - e.g. cysturia
what is the defect in Aminoaciduria: cystinuria?
Renal basic amino acid transported (rBAT)
= faillure of cystine reabsorbtion - more cystine in urine - kidney stones
clinical features of Aminoaciduria: Cystinuria?
Renal colic, recuttent kidney stones
Treatment of Aminoaciduria: Cystinuria
- High fluid intake, lower cystine concentraion
- Alkalinise urine (cystine crystallised better in acidic urine)
- Chelation = prevents crystallising
- surgery to remove stones
what disease is associated with phosphate reabsorbtion disorders in the proximal tubule?
Hypophosphateaemic rickets (usually cross-linked)
(XLH)
what is the defect associated with hypophosphateaemic rickets?
complicated - but essentially a chain of things that lead to dcreased expression and activity of Phosphate transporters (NaPi-II) in proximal tubules
clinical features of hypophosphataemic rickets?
same as Vit D deficiency rickets: Bow legged deformaty, impaired growth
treatment for hypophosphataemic rickets?
phosphate replacement
which disorder is associated with problems with bicarbonate reabsorbtion in the proximal tubule?
proximal renal tubule acidosis
what is the defect that causes proximal (type 2) renal tubular acidosis?
Na/H antiporter defect
= failure of bicarb reabsorbtion
what are the clinical features of Proximal (type 2) renal tubular acidosis?
treatment?
acidosis, impaired growth
treatment = bicarbonate supplementation
what can a genertic defect in carbonic anhydrase cause?
a mix of proximal/distal renal tubular acidosis
(Bicarb reaborbtion failure)
treated with - acetazolamide which induces metabolic acidosis to allow for mor rapid compensation of respiratory alkalosis
what defect can cause a mix of proximal and distal renal tubular acidosis?
how can this be treated?
genetic defects in carbonic anhydrase.
inhibited by acetazolamide = induced metabolic acidosis to induce rapid compensatory alkalosis. (used to treat altitude sickness)
what syndrome is associated with multiplle reabsorbtion issues in the proximal tubule?
Fanconi syndrome
causes of fanconi syndrome?
genetics, myeloma, lead poisoning, cisplatin. - generalaised proximal tubular dysfunction (failure to generate sodium gradient by pump)
clinical features of fanconi syndrome
glycosuria, aminoaciduria, phosphaturic rickets, renal tubular acidoses
what is the function of the thick ascending limb in the loop of Henle?
Primary site of Na reabsorbtion.
Thick ascending limb is impermeable to water.
How is Na+ reabsorbed in the thick ascending loop of Henle?
active transport - Na+ / K+ ATPase pumps 3 Na+ out and 2 K+ in.
Low Intracellular conc of Na+ creates a negative charge. Na+ then moves into cell from lumen through the NKCC2 transporter - one Na+, one K+, two Cl- in.
Potassium moved back into lumen through ROMK transporter.
what are the overall effects of Na+ reabsorbtion in the thick ascending limb of the loop of henle?
- Na+ removed from lumen tubular lumen whilst retaining water (∴hypotonic soution arrived at the DCT)
- Na+ pumped into the interstitial space (∴hyperosmotic environment in kideny medulla)
- also magnesium, clacium, sodium and potassium paracellular reabsorbtion
What is Barrter’s syndrome?
a group of autosomal recessive conditions characterised by genetic mutations in the genes coding for the NKCC2 transporter, apical potassium channel or basolateral chloride ion channel.
NKCC2, ROMK, CICKa/b Barrtin
what is the mechanism of Barrter’s syndrome?
failure of sodium, potassium and chloride cotransport in thick ascending limb.
–> salt wasting –>hypokalaemic alkalosis due to volume contraction –> failure of coltage dependent calcium and magnesium absorbtion
symptoms of Barrter’s syndrome?
similar effects to loop diuretics:
hyponatraemia
hypokalaemia
metabolic alkalosis
prematurity, delayed growth, polyuria, polydipsia
what is the function of the distal tubule?
allow of “fine tuning” of sodium reabsorbtion, potassium and acid-base balance.
what is the function of the collecting duct?
mediates water reabsorbtion
name 4 distal tubule and collecting duct disorders
- Gitelman’s syndrome
- Distal (type 1) renal tubular acidosis
- Disorders resembling hyperaldosteronism
- Type 4 renal tubular acidosis
- Nephrogenic diabetes insipidus
of the three acid base regulation mechanisms the body has, what is the slowest but strongest?
renal regulation
what are the three types of chemical buffers?
Bicarbonate (ECF)
Phosphate (Urine ICF)
Protein (ICF) (Hb)
what two things can the kidney do to regulate acid-base balance?
HCO3- reabsorbtion
H+ excretion
which part of the nephron is not involved in acid-base regulation?
thin descending limb and thin ascending limb
where does HCO3- reabsorbtion take place?
early PCT (80%)
what facilitates the synthesis of H2CO3 from CO2 and H2O in the PCT cell?
what else does it do?
Carbonic Anhydrase.
synthesises H2CO3 from bicarb and H+ in the PCT lumen
how is bicarbonate reabsorbed into the capillery?
in the PCT, HCO3- is reabsorbed into the capillery with Na+ as cotrasnport.
later nephron, it is exhnaged for Cl-
During bicard reabsorbtion, how is H+ excreted into the lumen?
Na/H+ exchanger = secondary active transport
secondary to the Na/K/ATP pump pulling Na out of the cell
in HCO3- reabsorbtion, what is the net change in HCO3- and H+?
for every HCO3- reabsorbed into capillery, 1 H+ is excreted into PCT lumen.
BUT H+ binds to the HCO3+ already in the lumen so there is no net secretion of H+
what are the two methods that the kidneys can excrete H+?
via two urinary buffers:
* phosphate buffer
* ammonia
where in the nephron does H+ excretion take place?
alpha intercalated cells of the DCT and collecting ducts
how does H+ excretion via phosphate work?
H+ is excreted out of the lumen forcably using hydrogen-ATPase pumps on the lumen of late PCT alpha intercalated cells.
Excess luminal phosphate (only 85% of total phosphate is normally reabsorbed) can bind a large portion of hydrogen ions, buffering them as H2PO4– before excretion. This excretion of H+ ions increases blood pH.
how does H+ excretion via ammonia work?
glutamine is converted to glutamate and ammonium in the proximal convoluted tubule (PCT).
The ammonium dissociates to ammonia and H+ ions, allowing it to pass the through membrane and enter the lumen.
Once in the lumen, it reforms ammonium by picking up a luminal H+ ion. This allows hydrogen to be excreted as ammonium ions, increasing blood pH.
Furthermore, ammonia secreted at the PCT can be used further down to buffer and excrete H+ ions secreted by alpha-intercalated cells in the collecting duct. This is due to its ability to pass membranes and traverse the nephron.
outline the embryology of the pancreas.
when do exocrine functions begin?
when do endocrine functions begin?
at the junctiojof foregut and midgut, 2 pancreatic buds (dorsal and ventra) are genertated and eventually fuse.
exocrine functions begin at birth
endocrine functions begin from 10-15 weeks
exocrine activiry of the pancreas performed by what cells?
endocrine activity of the pancrease performed by what cells?
excocrine
- acinar cells = 99% of cells
- manufacture and secrete fluid and digestive enzymes - pancreatic juices into gut
endocrine
- iselt cells
- manufacture and release peptide hromones into portal vein
what are these cells? what is their function?
Islet cells of Langerhans
- site of insulin and glucagon secretion
what cells secrete insulin?
beta-cells of pancreatic iselts of Langerhans
what cells secrete glucagon?
alpha-cells of pancreatic iselts of Langerhans
what cells secrete somatostatin?
Delta cells in pancreatic islets of Langerhans
What is Insulin’s effect on:
* hepatic glucose output
* Glucose uptake
* lipolysis
* muscle breadown
- Supresses hepatic glucose output - ↓ glycogenolysis, ↓ glyconeogensis
- Increases glucose uptake to muscle and fat
- Suppressed lipolysis
- supressed breakdown on muscle (↓ketogenesis)
What is Glycogen’s effect on:
- hepatic glucose output
- Glucose uptake
- Peripheral release of gluconeogenic precursors
- lipolysis
- muscle breadown
- increases hepatic glucose output - ↑glycogenolysis, ↑glyconeogenesis
- reduces glucose uptake peripherally
- Stimulates peripheral release of gluconeogenic precursors (glycerol, AAs)
- Stimulates lipolysis
- Stimulates muscle glycogenolysis and breakdwon
what is insulin and what does it do?
polypeptide of 51 AAs.
- reduces glucose output by live, increases storage of glucose, fatty acids and AAs
what is glucagon and what does it do?
polypeptide of 29 AAs
- mobilises glucose, fatty acids and AAs from stores
How is insulin secreted by the 𝛃 cells?
- Glucose enters 𝛃-cell via GLUT2 glucose transporter
- Glucose metabolised in the cell, generating ATP
- The increase in ATP levels causes the cell’s potassium channels to close, leading to depolarization of the cell membrane
- Depolarisation opens voltage-gated calcium channels, calcium rushes in.
- The influx of calcium ions stimulates the beta cells to release insulin stored in small vesicles within the cell. These vesicles fuse with the cell membrane, releasing insulin into the bloodstream. Insulin is then transported throughout the body by the bloodstream.
what facilitates the movement of glucose into the 𝛃-cell through GLUT2 transporter?
glucokinase (= phosphorilator)
how can you tell if someone has been “killed” by insulin
when insulin is secreted from the cell, it is actually preleased as proinsulin which contains the A and B chains of insulin, and a C peptide.
Should be euqal amounts of insulin and C peptide, if C-peptide present, it is endogenous.
what are the two phases of Biphasic Insulin release
First phase repsonse (to high glucose) is rapid release of stored product
Second phase response is slower release of newly synthesised hormone
Explain insulin’s action in muscle and fat cells
- Insulin binds to insulin receptors on the surface of muscle and fat cells.
- This initiates intracellular signalling cascades that move the GLUT4 transporter proteins from intracellular vesicles to the cell membrane.
- GLUT4 then allows glucose to enter the cell
where can glucose sensors be found?
primary glucose sensors in pancreatic islets (𝛃-cells)
also medulla, hypothalamus and carotid bodies
also Input from senses and cells in gut wall
what is the short term glucose buffer of the body?
liver glycogen
what is the body’s short term response to hyperglycaemia?
make glycogen (glucose → glycogen = glycogenesis)
store the
what is the body’s short term response to hypoglycaemia?
Split glycogen (glycogen → gluocse = glycogenolysis)
what is the body’s long term effect to hyperglycaemia?
Make triglygeride (lipogenesis)
what is the body’s long term response to hypoglycaemia?
make glucose (gluconeogenesis) from AAs ansd Triglycerides
how does the route of getting glucose change insulin response?
insulin response is greater following oral glucose than intravenous glucose, despite similar plasma glucose concentrations.
this is due to INCRETIN = gut hormone stimulating insulin release
three mechanisms postprandial glucose levels are regulated by?
- ↑ Insulin
↳ rising plasma glucose stimulates pancreatic 𝛃 islet cells to secrete insulin - ↓ Glucagon
↳Plasma glucose inhibits glucagon secretion by pancreatic 𝛂 cells - ↓Gastric emptying
↳slowing gastric emptying is a major determinant of postprandial glycaemic excursion
How does incretin promote weight loss?
slows gastric emptying
Where does glucose come from whem the body is fasting
in the fasting state, all glucose comes from the liver : Glycogenolyis and gluconeogenesis (3 carbon precursors to synthesise glucose)
glucose to braind and RBCs
[?]% of ingested glucose goes to the liver
[?]% of ingested glucose goes to the periphery?
40% to the liver
60% to the periphery, mostly muscles
what is a common mutation found in type 1 diabetes in the pancreatic beta cells?
Mutation of the Kir6.2 Potassium/ATP channel
- channel stays open for longer than it should and needs higher than usualy blood glucose levels to close them
- treatment - sulphonylureas which clost the channels
explain the pathogenesis of diabetic ketoacidosis
Body cannot make insulin:
* no insulin = no glucose uptake into cells = high BMs
* no glucose uptake into cells = liver creates more glucose = higher BMs
* no glucose uptake into cells = body starts breaking down fats
* fat breakdown = liver produces ketones = acidotic
the kidney develops from what embryological germ layer?
intermediate mesoderm
name the three overlapping kidney systems develop from the intermediate mesoderm
pronephros
mesonephros
metanephros
when does the pronephros develop and what is its function?
4/40 (disappears by 5/40)
Non functional
when does the mesonephros develop and what is its function?
4/40
part of it persists in males
whehn does the metanephros develop and what is its function?
5/40 - functional at 12/40.
this becomes the definitive kidney
From the mesopnepros, excretory tubules develop with a group of capillaries. what will each of these become? what happens after these have formed?
tubules = bowman’s capsule
capillaries = glomerulus
then collecting duct called mesopheric duct forms and gonad starts to develop
what is the fate of the mesonephros in females?
tubules and mesophrenic ducts degenerate
what is the fate of the mesonephros in males?
a few tubules and the mesophreni duct remain:
* mesophrenic duct = vas def
* tubules = ducts of testes
where does the kidney develop (from the?)
in the peliv region (from the metanephros)
in the development of the kidney from the metanephros, the collecting systems and excretory system develop…?
differently
Development of the collecting system 1:
Develops from the [a]
The [a] grows out from the [b]
Covered over by a ‘cap’ of [c]
Bud grows into the cap = [d]
Develops from the ureteric bud
The ureteric bud grows out from the mesonephric duct
Covered over by a ‘cap’ of metanephric tissue
Bud grows into the cap = renal pelvis
Development of the Collecting systems 2:
Bud splits into two parts = [a]
Continued subdivision and formation of tubules = [b], [c], [d], [e]
Bud splits into two parts = major calyces
Continued subdivision and formation of tubules = ureter, renal pelvis, major and minor calyces, collecting tubules
Development of the Excretory system:
Develops from [a]
Development promoted by the developing [b]
Development of each is dependent on the other
Metanephric tissue forms [c]
Vesicles become tubular and capillaries develop = [d]
Form [e]
Develops from metanephric cap
Development promoted by the developing collecting tubules
Development of each is dependent on the other
Metanephric tissue forms renal vesicles
Vesicles become tubular and capillaries develop = glomerulus
Form nephrons
the uteric bud forms which parts of the renal and urinary system?
- ureter
- Renal pelvis
- major and minor calcyces
- collecting tubules
the metanephric tissue forms which parts of the renal and urinary tissue
Nephrons
during the ascent of the kidneys in utero, what happens to the vessels?
if this doesnt happen what occurs
During ascent, new vessels are derived from more proximal parts of the aorta and lower vessels regress.
if regression does not occur = Accessory Renal Vessels
when does the kidney start to function?
12/40
what happens to fetal urine?
excreted into amniotic fluid
what is this an example of?
what is this an example of?
Pancake kdiney: Fusion of the upper and lower poles of the kidney.
what is this called?
crossed renal ectopia
what is the cloaca?
common cavity for urogenital system and the gut
what goes on to separates the cloaca?
urorectal septum.
divide cloaca into urogenital sinys and anal canal
the bladder develops from?
the urogenital sinus
the urogenital sinus gives rise to 3 parts:
Upper part = bladder
Middle / pelvic part = part of the male urethra
Phallic part = develops differently in males and females
if the urorectal septum fails to close it sinus this leads to?
hypospadius
what is this a case of and what has it resulted from?
exstrophy of bladder - rare
failure of anterior abdominal wall to close
the ureter develops from?
when?
the ureteric bud.
Ureter directly enters the bladder after the distal part of the mesonephric duct merges into the bladder wall.
what has this resulted from?
double ureter - ureter splits early in development
what can the development of two uteric buds (for one kidney) result in?
ecopic ureter
One enters bladder
Other enters bladder, urethra, vagina or epididymal region
all steroid hormones are synthesised from?
cholesterol
catecholamines are synthesised from?
tyrosine
eg dopamine
what is key for the synthesis of thyroid hormones?
iodine
what are the fastest acting hormones?
catecholamines
dopamine / adrenaline
what are the slowest acting hormones?
thyroid hormones
t3 / t4
what are the action times of peptide hormones?
mins - hours
Human growth, prolactin, insulin
what are the action times of steroids and pseudo steroids?
hours - days
cortisol, aldosterone
how does insulin effect?
peptide hormones - cell surface receptors
Insulin doesnt go into the cell.
involves cascade and translocation of GLUT4 which allows glucose into the cell.
how does cortisol effect?
steroid - intracellular
must get to cell nucleus
long 1/2 life and long mechanism of action
basic action of thyroid hormone?
basal metabolic rate, growth (including brain)
basic action of parathyroid hormone?
Calcium regulation
basic action of cortisol hormone?
glucose regulation, inflammation
low = addisons disease
basic action of aldosterone?
BP and Na regualtion
basic action of Catecholamines?
BP and stress
basic action of oestradiol?
mensturation
basic function of testosterone?
sexual functions.
male feautures
basic function of ANP?
Na+ regulation
basic function of insulin?
glucose regulation
basicl function of Vit D hormone?
Ca2+ regualtion
three ways to meausre hormone concentrations?
Bioassays
Immunoassays
Mass Spec
5 anterior pituitary hormones and their functions?
- ACTH - adrenal cortex regualtion
- TSH - thryoid regualtion
- GH - growth metabolism
- LH/FSH - Reproductive control
- PRL - breast milk
2 posterior pituitary hormones?
ADH - water regulation
Oxytocin - breast milk
draw out the HPT axis
what is this patient suufering with?
what other symptoms might be present?
thyrotoxicosis
-bulging eyes
-irritability and anxiety
- sweating
-goiter
what are these patients suffering with?
cushings disease - too much steroid due to pituitary tumor
what is this and what is it caused by?
acromegaly.
too much growth hormone.
a pituitary tumour can cause visual field defects because?
pressure on the optic chiasm
symptoms of hypothyroidism?
Weight gain
Fatigue
Dry skin
Coarse hair and hair loss
Fluid retention (including oedema, pleural effusions and ascites)
Heavy or irregular periods
Constipation
can be primary or secondary
weight of pituitary?
0.5g
blood supply to anterior pituitary?
the anterior pituitary has no arterial blood supply but recieves blood thorugh a poral venous circulation from the hypothalamus.
5 anterior pituitary hormones, their type and their function?
What stiumlates the relase (hypothalamus) of Thyroid Stimulating Hormone in the pituitary?
Thyrotropin releasing hormone
what stiumlates AdrenoCorticoTrophic Hormone release?
corticotropin releasing hormone
what stiumlates FSH release?
Gonadotropin releasing hormone
what stimulates LH release?
Gonadotropin releasing hormone
what stimulates growth hormon release?
Growth releasing hormone
the only anterior pituitary hormone that doesnt have negative feedback is?
prolactin
draw out the HPA - cortisol axis
ACTH acutley stimulates [?] release
cortisol
- about 20 mins behind
this graph depict the sleep/wake cycle.
what is the likely y axis?
cortisol levels - circadian rhythm
why is growth hormone difficult to measure?
pulsatile.
GH effect meidated by IGH1 in the liver = measured
what stimulates growth hormone?
what suppresses it?
stim = low glucose, exercise, sleep
suppress = hyperglycaemia
action of growth hormone?
linear growth in children (long bones)
- then sex hormones take over in puberty - axial
Stimulates:
- protein synthesis
- lipolysis
- gluocse metabolism
Regulation of body composistion
Psychological well-being
draw out the GHRH HP axis
draw out the thyroid stimulating hormone HPT axis
what is responsible for the negative feedback in the LH/FSH H-P-Ovary axis?
inhibin
draw out the GnRH, FSH/LH HPO axis (ovaries)
Draw out the HPG axis for testes
prolactin is synthesised in?
lactotrophs
what negaitively inhibits prolactin?
dopamine
draw out the prolactin axis
what are the embryological origins of the posterior and anterior pituitary?
Neural ectoderm –> Posterior Pituitary
Oral ectoderm –> Anterior Pituitary
what is the most commone cause of cushing’s disease?
cushings = high cortisol
high dose steroids, used to treat inflammation
two hormones of the posterior pituitary?
Vasopressin (ADH)
Oxytocin (milk and labour)
explain what happens to vasopressin levels during water defecit
Action of Vasopressin:
1. Vasopressin binds to [?]
2. Receptor activates [?]
3. Cell inserts [?] into apicle membrane
4. Water is absorbed by [?] into the [?]
Action of Vasopressin:
1. Vasopressin binds to V2 membrane receptor
2. Receptor activates cAMP secondary messenger system
3. Cell inserts aqauporin-2 into apicle membrane
4. Water is absorbed by osmosis into the blood
ADH keep it in the blood, out of urine
what regulates ADH release?
osmosreceptors
baroreceoptors
what is normaly measured when calculateing plasma osmolality?
Na+ (x2)
Glucose
Urea
name three things that could alter the relationship between plasma osmolality and vasopressing release
- drinking rapidly supresses vasopressin release and thirst
- pregnancy decreases the osmotic threshold for vasopressin release
- plasma vasopressin concentrations increase with age
what is AVP-D and AVP-R?
Vasopressin deficiency = cranial
Vasopressing Resistance = nephrogenic (diabetes insipidus)
causes of AVP deficiency?
idiopathic
tumours
trauma]infections - TB
familial (rare)
how is VPD/VPR measured?
hypertonic saline stimulation
- meausre copeptin
causes of AVP Resistance?
diabetes mellitus
duges
chronic renal failure
what is SIADH
what are its symptoms?
Syndrome of inappropriate antidiuretic hormone secretion
Too much AVP = low blood conc, low osmolaity, low plasma sodium
high urine conc
euvolaemia
outline the essential criteria for SIADH
- Hyponatraemia
- Plasma hypoosmolality
- High urine osmolality
- High Na in urine
- euvolaemia - no clinical signs or hyper/hypovolaemia
what should you be cautious of in treating hypernatraemia secondary to SIADH?
<12mmol/l incerease in Na+ per 24 hours
otherwise risk of central pontine myelinolysis.
what are the three layers of skin?
Epidermis
Dermis
Subcutis
three things that allow skin to be waterproof?
- tight junctions between cells in stratum granulosum
- epidermal lipids in statum corneum
- keratin in stratum corneum
waterproof in and out
why does skin wrinkle when wet
to improve grip
sympathetic vasoconstriction in dermis
what features of skin allow it to be a physical barrier?
stratified epithelium = resist abrasion
Fat in subcutis = shock absorber
outline the process of vitamin d synthesis and storage
7 dehydrocholesterol in plasma membranes of epidermal keratinocytes and dermal fibrobalsts converted to previtamin D3 (cholecalciferol) by UVB
Vitamin D is [a] so can be stored in [b]
[a] lipid soluble
[a] subcutis adipocytes
skin as a site of endocrine action-
* Androgens act on [?]
* Thyroid hormones act on [?]
- Androgens act on follicles and sebaceous
- Thyroid hormones act on keratinocytes, follicles, dermal fibroblasts, sebaceous glands, eccrine glands
effects of hypothyroidism on the skin?
epidermal - course, thin and scaly
dermis - myxoedema
hair and nail- dry and brittle
sweat glands - decreased sweating
4 hormones synthesised at the skin?
- Vitamin D
- 17𝛃- Hydroxysteroid dehydrogenase
- 5𝛂-reductase
- IGF binding protein 3
where is 17𝛃- Hydroxysteroid dehydrogenase and 5𝛂-reductase found?
17𝛃- Hydroxysteroid dehydrogenase - sebocytes
5𝛂-reductase - dermal adipocytes
function of 17𝛃- Hydroxysteroid dehydrogenase and 5𝛂-reductase?
convert dehydroepiandrosterone (DHEA) into androstenedione and 5 𝛂-dihydrotestosterone
where is insulin like growth factor binding protein 3 synthesised?
dermal fibroblasts
which type of UV light damages the skin
both!
UVA and UVB
how does UV light damage the skin?
- burns
- spresses langehans cells (immune)
- photo-aging
- DNA damage
Skin colour depends on [a] which is synthesised in [b] within [c] from [d].
Transported via [e] to adjacent keratinocytes.
[a] Melanin
[b] melanosomes
[c] melanocytes
[d] tyrosine
[e] dendrites
red hair containt more of which melanin
pheomelanin.
all skin types contain more of which melanin
eumelanin
melanin is prone to photodegradiation which may generate what?
ROS
what type of melanin increases the release of histamine?
pheomelanin
more/less melanin reduces ability to utilize light to make vitamin D
more
a range of peptides synthesised by [?] have antimicrobial properties
granular layer keratinocytes
where are Langerhans cells found?
what are they?
Epidermis
antigen-presenting and secrete cytokines
what immune cells are found within the dermis?
- Regulatory T cells
- Natural killer
- dendritic
- Macrophages
- Mast cells
keratinocytes secrete [?] and [?] that maintain populations of leucocytes in skin
cytokines
chemokines
when skin is challenged (immune) what happens? (x3)
- leucocytes migrate to dermis and lymph nodes and activate a T cell respones
- Keratinocytes proliferate and secrete cytokines
- leucocytes enter skin from the blood
what cells found within the skin allow it to function as a sensory organ?
Merkle cells - light touch (basal epidermis)
Pacinian corpuscles - pressure/vibration (dermis)
Meissner corpuscles - touch (dermis)
nerve endings - pain, itch, temp (dermis)
what is meant by endothermic homeotherms
heat generated through metabolism
vasoconstriction and vasodilation are under what kind of control?
all sympathetic!
vasoconstriction = sympathetic alpha-noradrenergic
vasodilation = sympathetic cholinergic
what muscles cause goosebumps?
innervation?
arrector pili muscles
sympathetic 𝛂1 - adrenergic fibres
functions of subcutaneous fat?
insulator
shock absorber, energy store.
label the arrows on the histological zones of the adrenal including what is made where
how does the fetal adrenal differ to the adult adrenal?
fetal zone —> zona reticularis
what does the adrenal glands develop from embryologically?
urogenital ridge 4/40
what is the precursor of all adrenal steroids?
cholesterol
describe the atomical structure of corticosteroids
cyclopentanoperhydrophenanthrene structure
- three cyclohexane rings (A, B, and C)
- single cyclopentane ring (D)
corticosteroids can pass through membranes because they are?
lipid soluble
Intracellular receptors —> alter gene indirectly/directly
what are the three classifications of steroids?
what is made in the zona glomerulosa?
what is the function?
what triggers its secretion?
mineralocorticoids - regulate body’s electrolytes via aldosterone
secretion triggered by renin
outline how mineralcorticoids are synthesised in the zona glomerula
what is synthesised in the Zona fasciculata?
what is its action?
glucocorticoids - sugar regulation and stress response. - acts on most tissues!
outline how glucocorticoids are synthesised.
what stimulates this syhtnesis
synthesis stoumlated by ACTH
what is synthesised in the zona reticularis?
weak androgens - sex hormones
outline how andorgens are synthesised in the zona reticularis
how are glucocorticoids transported around the body?
90% bound to Corticosteroid-Binding Globin
5% bound to albumin
5% “free”
only “free” = bioavailable.
Breakdown of CBG to free up more when needed
what regulates glucocorticoid synthesis?
ACTH
circadian rhythm, stress can also impact.
name two mineralcorticoids, which is more potent?
aldosterone and DOC
DOC has 3% activity of aldosterone
aldosterone acts where?
explain its action
distal convoluted tubule
* increases ENaC expression apically
* Increases Na/K/ATPase expression basolaterally
∴ INCREASES NA+ IN BLOOD, INCREASE K+ IN URINE
draw out RAAS
name to adrenal androgens, which is more potent?
Dehydroepiandrosterone (DHEA) most abundant adrenal steroid but very weak androgen
Androstenedione more androgenic but only 1/10th that of testosterone, but major source of androgens in women
- converted to testosterone in peripheral tissues.
REGULATED BY ACTH
what is synthesised in the adrenal medulla?
catecholamines
Adrenaline (80%) and Noradrenaline (20%)
what enzyme, present in the adrenal medulla, converts noradrenaline to adreniline?
Phenylethanolamine-N-methyl
Catecholamine synthesis is dependent on?
cortisol levels.
action of catecholamines
Catecholamines released during “flight or fight”
-gluconeogenesis in liver and muscle
-lipolysis in adipose tissue
-Tachycardia and cardiac contractility
-Redistribution of circulating volume
which gene determines how the bipotential gonads differentiate?
SRY gene
SRY + → male
SRY - → female
what does the presence of the SRY gene lead to the development of?
testes at 9/40
what does the absence of SRY gene lead to the development of?
ovaries 11/40
what migrates to the urogenital ridge in 6/40?
Primordial germ cells → oocytes and spermatogonia
What hormones will testes produce in reprodctive embryological development?
What do they produce, and what is their function?
Leydig cells = testosterone
= promotes Wolffian duct development
= dihydrotestosterone (DHT) = male external genitalia
Sertoli Cells = anti mullerian hormone = inhibits Mullarian duct development
What hormones will the ovaries produce in reproductive embryological development?
Follicular cells = Oestrogen = External Female Genitalia
Lack of testes = lack of anti mullerian hormone
what is the mesophrenic duct and what does it lead to the development of?
Mesophrenic = Wolffian = male structures
* ejaculatory duct
* epididymis
* prostate
* vas deferens
* seminal vesicle
what is the paramesophrenic duct?
what does it develop into?
paramesophrenic duct = Mullerian duct = female reporductive strcutures
* fallopian tuube
* uterus
* upper 2/3 of the vagina
what develops into the lower 1/3 of the vagina?
urogenital sinus (from cloaca) –> sinovaginal bulbs –> lower vagina
What hormone controls the development of external male genitalia? How is this hormone produced?
dihydrotestosterone (DHT)
5𝛂reductase converts testosterone to DHT
the genital tubercle becomes what in males and what in females?
males: Genital Tubercle –> Glans
females: Genital Tubercle –> clitoris
The genital fold develops into?
This goes on to develop into what in females and males?
genital fold –> Urethral fold
females: urethral fold –> labia minora
males: urethral fold –> fuse into penile urethra/shaft
what does the genital swelling differentiate into in males and females?
females –> labia majora
males —> scrotum
overview of what is made in each zone of adrenals.
What can Androgen insensitivity Syndrome lead to?
Androgen receptors not responding to androgens.
Clinical and biochemical phenotype
* Very high testosterone and dihydrotestosterone levels * Internal genitalia male (due to AMH production)
* External genitalia and external appearance female
* Gender identity female
=> Diagnosis often because of primary amenorrhoea
how do the body proportions of a newborn differ from that of an adult?
- Newborns:largerhead,smallermandible,shortneck, chest rounded, abdomen prominent, limbs short
- Adults:relative growth of limbs compared to trunk
in the Infancy-Childhood-Puberty Model, where does growth occur the fatsest?
Infancy - rapid until 2-3 years. determined by nutrition - long term growth faiulure if underfed in infancy
what does growth in the childhood component of the INFANCY-CHILDHOOD-PUBERTY MODEL depend on?
– switch from nutritional to hormonal dependence – height velocity slows 2-3 yrs to puberty
what does growth in the puberty component of the INFANCY-CHILDHOOD-PUBERTY MODEL depend on?
Growth Hormone and
sex hormones (oestrogen and testosterone)
how does growth end?
with fusion of epiphyses due to influence of oestrogens in boys and girls
* Boys convert testosterone to oestrogens in fatty tissues
on average how much taller are boys than girls?
12.5cm.
13.becuase girly start pubert 2-3 years before boys, with a shorted maxiumum growth spike
what are some determinants of growth?
- Parental phenotype and genotype * Quality and duration of pregnancy * Nutrition
- Specific system and organ integrity * Psycho-social environment
- Growth promoting hormones and factors
all growth disorders originate from or affect {?}
the growth plate - chondrogenesis
Disproportion can give clues to diagnosis
Short limbs –>
Short back & long legs –>
Disproportion can give clues to diagnosis
Short limb —> hypochondroplasia
Short back & long legs —> delayed puberty
outline the growth hormone axis
GHRH is regulated by?
food, sleep, steroids
what is the most abundant hormone?
Growth hormone
where is growth hormone synthesised?
by what cells?
somatotroph cells = 40-50% of total cells in anterior pituitary
when is growth hormone at max?
night (pulsatile)
what is growth hormones effect on glucose use. lipolysis and muslce mass?
decrease glucose use;
increase lipolysis andmusclemass
what stimulates growth hormone?
Exercise
Stress
Hypoglycaemia
Fasting
High protein meals
Perinatal development
Puberty
what supresses growth hormone?
Hypothyroidism
Hyperglycaemia
High carbohydrate meals
Glucocorticoid excess
Aging
what is puberty?
- Describes the physiological, morphological, and behavioural changes as the gonads switch from infantile to adult forms.
- Definitive signs:
– Girls - Menarche – first menstrual bleeding. – Boys - first ejaculation, often nocturnal.
– These do not signify fertilityv
what are the secondary sexual characteristics of female puberty and what hormones control them?
- Ovarian oestrogens regulate the growth of breast and female genitalia
- Ovarian and adrenal androgens control pubic and axillary hair
what are the secondary sexual characteristics of male puberty and what hormones control them?
- Testicular androgens
–External genitalia and pubic hair growth
–enlargement of larynx and laryngeal muscles = voice deepening
mean age of breast development in girls?
Breasts - 8.87 (african), 9.96 (white)
what is precocious puberty?
onset of secondary sexual characteristics before 8 yrs (girl), 9 yrs (boy)
* Menarche before 9 yrs may lead to short stature
what is characterised as delayed puberty?
Delayed puberty: absence of secondary sexual
characteristics by 14 yrs (girl), 16 yrs (boy)
* Delayed puberty leads to reduced peak bone mass and osteoporosis
outline the female HPG axis
outline the male HPG axis
Physical changes controlled by gonadal and adrenal
sex steroids is regulated by?
the gonadotrophins, LH and FSH
Hypothalamic regulation of GnRH is increased by?
and decreased by?
GnRH secretion
(+) Glutamate and kisspeptin
(-) GABA and opioids
what is adrenarche?
gradual “maturation” of the adrenal gland, development of pubic and axillary hair, body odour and acne
what percentage of cardiac output do the kidneys receive?
20-25%
= 1200ml/min of blood flow
where is the medulla and where is the cortex?
Cortex above dashed line
Medulla below dashed line
suprise histology slide
another suprise histology slide
label the part of the tubule
What does the proximal convoluted tubule absorb?
glucose
amino asids
phosphate
bicarb
how is bicarb reabosorbed in the PCT?
glucose is only absorbed where?
how?
PCT - only site of glucose reabsorbtion
Co-transported with Na via sodium glucose transporter 2 (SGLT2)
Defect → failure of glucose reabsorption (glucose in urine)
Loop of Henle generates a concentration gradient in the medulla via?
countercurrent system
What is absorbed in the thick ascending limb of the loop of Henle?
Na - active transport
What cells line the thin descending limb of the loop of henle?
What about the thin ascending and thic ascending?
thin descending - simple squamous
thin ascending - simple squamous
thick ascending - simple cuboidal or low columnar with prominant folding and no microvilli +++ mitochonndria for active transport
what occurs in the distal convoluted tubule?
Distal tubule and cortical collecting ducts allow “fine tuning” of sodium reabsorption, potassium and acid-base balance
the distal convoluted tubule is impermeable to?
to passive movement of water and sodium
the distal convoluted tubule can reabsorb approx 5% of Na…how?
Impermeable to passive movement of water and sodium
Uses NCCT co transporter to reabsorb 5% of sodium
what cells line the distal convoluted tubule?
Epithelial cells
- Simple cuboidal epithelium with tall microvilli
- Numerous mitochrondria
Basal striations
Tight junctions
how is salt and water abrobed in the DCT
what is the function of the collecting duct?
Collecting duct mediates water reabsorption and maintains acid base homeostasis
what are the two cells important in the collecting duct and what is their functions?
Principal cells - Na and water reabsorption and K excretion (simple cuboidal epithelium)
Intercalated cells (alfa and beta) – secrete H or HCO3
Essential for acid base homeostasis
how does ENaC and Aldosterone effect the principle cells of the collecting duct?
ENaC – specific sodium transporter , main site of Na regulation
Aldosterone – increases the number of open ENaC channels regulating Na absorption
how does the collecting duct reabsorb water?
Reabsorption of water due to action of ADH and aquaporins
ADH acts on tubule (principle cells
-Binds V2 receptor
-Activates adenylyl cyclase increasing cyclic AMP
-Vesicles containing aquaporin 2 channels deposit contents into apical membrane
ADH produced in hypothalamus, stored in posterior pituitary gland
SIADH caused by?
Excess ADH released
Excessive dilution of blood lowering sodium concentration
Fluid retention
Consequent reduced aldosterone further reducing sodium uptake
label which dieretic affect which part of the tubules and what they affect
The defect in Barrter’s syndrome is similar to which diuretic’s mechanism of action:
A. Chlorthialidone (thiazide like diuretic)
B. Furosemide (loop)
C. Spironolactone (mineralocorticoid receptor antagonist)
D. Acetazolamide (carbonic anhydrase inhibitor)
B. Furosemide (loop)
Which cell in the collecting duct functions in maintaining acid-base balance?
A. Intercalated cells
B. Enterochromaffin cells
C. Parietal cells
D. Principal cells
A. Intercalated cells
In renal tubular acidosis type 1 (distal), which of the following statements is true?
A. Bicarbonate reabsorption is impaired
B. Hydrogen ion secretion is impaired
C. Urinary pH is acidic (<5.5)
D. Aldosterone action is impaired
B. Hydrogen ion secretion is impaired
Amino acids are transported via specific transporters that are present in which region?
A. Proximal tubules
B. Loop of Henle
C. Distal tubules
D. Collecting ducts
A. Proximal tubules
About 80% of filtered bicarbonate is reabsorbed in proximal tubules, which enzymes are involved?
Na/K ATPase enzymes on basolateral surface
Na/K ATPase enzymes on luminal surface
Carbonic anhydrase enzymes
Thiazide diuretics inhibit the reabsorption of sodium and chloride by inhibiting the Na-Cl cotransporter present in…?
A. Proximal tubules
B. Loop of Henle
C. Distal tubules
D. Collecting ducts
C. Distal tubules
bloody supply to the thyroid?
where is the thyroid?
in the neck
25-30g, surrounded by thin fibrous capsule
the major cellular stuctures in the thyroid is/
follicles
-follicular cells
what do c cells in the thyroid produce?
calcitonin
outline the role of thyroid hormones
- Control of metabolism: energy generation and use
- Regulation of growth
- Multiple roles in development - up to 2yo = major in brain development
outline the HPT axis
outline thyroid hormone synthesis
5 steps
with underfunction of the thyroid, what would you expect TRH and TSH to be?
TSH high because trying to stiumlate more thyroid
which enzyme facilitates
tyrosine –> diiodotyrosine—> thyroxine?
what is the biologically active thyroid hormone?
T3
what is the most abundant thyroid hormone?
T4
how is T3 produced?
Produced by mono-deiodination of T4
Thyroid hormones are Produced by [a]
Synthesised from the [b] which requires [c]
[] [ is absorbed from bloodstream and concentrated in follicles
Produced by follicular thyroid cells
Synthesised from the thyroglobulin precursor
Iodine is absorbed from bloodstream and concentrated in follicles
if thyroglobulin detected, this might indicate?
cancer
[a] binds iodine to tyrosine residues in thyroglobulin molecules to form [b]
Thyroperoxidase binds iodine to tyrosine residues in thyroglobulin molecules to form MIT + DIT
MIT + DIT =
T3
DIT + DIT =
T4
name three thyroid hormone binding proteins
TBG
Transthyretin
Albumin
Free thyroid is what is measured clinically
Thyroid hormones are a different class of hormones.
They require a [a] to enter cell (dont use extracellular receptor)
But then, once in the cells, act like a steroid hormone which use [b]
[a] Transmembrane reporters
[b] nuclear receptors
thyroid hormone transport in the CNS depends on which transporters? (2)
MCT8
OATP1C1
What serum levels would you expect to find with primary hyperthyroidism
↓ Serum TSH
↑Serum free T4
↑Serum free T3
What serum levels would you expect to find with primary hypothyroidism
↑ Syrum TSH
↓Serum free T4
↓Serum free T3
different if pituitary is problem - secondary
hyperthyroidism prevalence?
incidence?
- prevalence: 2.7%
- incidence: 0.1%/yr (♀> ♂ )
Prevalence: ♀: 20/1000 ♂: 2/1000
hypothyroidism prevalence? incidence?
- prevalence:1.9%
- incidence: 0.4%/yr (♀> ♂ )
Prevalence 40/1000 females
5% of over 60’s
goitre prevalence and incidence?
- prevalence 24.4 %
- incidence: 0.2% (♀> ♂ )
name some causes of hyperthyroidism
- Graves’ hyperthyroidism - autoantibodies against TSHR
- Toxic nodular goitre (single or multinodular)
- Thyroiditis (silent, subacute): inflammation
cardiovascular symptoms of hyperthyroidism
Tachycardia (rapid heart rate)
AF (atrial fibrillation)
Shortness of breath
Ankle swelling
can be a CV Killer!
GI symptoms of hyperthyroidism
Weight loss
Diarrhoea
Increased appetite
neuro signs of hyperthyroidism
Tremor
Myopathy (muscle weakness)
Anxiety
“can be properly bonkers”
Eyes/skin signs of hyperthyroidism
Sore, gritty eyes
Double vision
Staring eyes
Pruritus (itching)
Feeling warm all the time
name some causes of hypothyroidism
Autoimmune – Hashimoto’s thyroiditis (TPO and Tg antibodies - genetic predisposition)
After treatment for hyperthyroidism
Subacute/silent thyroiditis
Iodine deficiency
Congenital (thyroid agenesis/enzyme defects)
CV signs of hypothyroidism
Bradycardia (slow heart rate)
Heart failure
Pericardial effusion
GI signs of hypothyroidism
Weight gain - only around 5kg
Constipation
skin signs of hypothyroidism
Myxoedema
Erythema ab igne
Vitiligo
neuro signs of hypothyroidism
Depression
Psychosis
Carpal tunnel syndrome - always check thyroid
how many parathyroid glands?
4
what does the parathyroid gland do?
Regulate calcium and
phosphate levels
Secrete parathyroid hormone
(PTH) in response to:
Low calcium or
High phosphate
action of PTH?
Increases calcium reabsorption in renal distal tubule
Increases intestinal calcium absorption (via activation of vitamin D)
Increases calcium release from bone (stimulates osteoclast activity)
Decrease phosphate reabsorption
what % of calcium is soluble?
what is it necessary for?
1%
which enzymes control Endocrine control of extracellular calcium homeostasis
Parathyroid hormone
Vitamin D
Calcitonin, FGF23
calcium absorbtion in the kidney depends on what hormones?
Parathyroid hormone
Vitamin D
FGF23
what are normal serum calcium levels?
2.1-2.6
what % of serum calcium is free?
50% of serum calcium ‘free’ (ionised)
50% bound to albumin (so cannot diffuse into cells)
what systems are involved in calcium homeostasis?
what happens during hypocalcaemia to maintain homeostasis?
what happens during hypocalcaemia to maintain homeostasis?
what happens to urinary phosphate and urinary calcium in hypocalcaemia?
What happen in the intestine?
Kidney: Reabsorb calcium, pee phosphate out (if not, kidney stones)
Intestine: Reabsorb calcium AND phosphate
PTH mainly binds to?
Binds to G protein coupled receptors mainly in kidney and osteoblasts
Primary hyperparathyroidsm causes?
Primary HPT:
parathyroid tumour (usually benign adenoma)
Causes hypercalcaemia and low serum phosphate
Loss of negative feedback from hypercalcaemia
(Treatment is surgery)
secondary hyperparathyroidism causes?
Secondary HPT:
renal disease (increased phosphate, decreased activation of vitamin D) = loss of negative feedback
(Treatment with phosphate binders or vitamin D analogues)
causes of tertiart hyperparathyroidism
Tertiary HPT:
long-standing secondary HPT leads to irreversible parathyroid hyperplasia. Usually seen when renal disease corrected e.g. by transplantation
(Treatment is surgery)
where is calcitonin produced?
when is it released?
What does it do?
Produced by thyroid c-cells (parafollicular)
Calcitonin released in hypercalcaemia
Inhibits bone resorption (by direct effect on osteoclasts)
Not essential to life (post thyroidectomy no calcium problems)
Two calcitonin genes products from a single gene and primary RNA transcript
what occurs during hypercalcaemia to maintain homeostasis?
uric acid is derived from?
purine
the enzyme involved in uric acid synthesis is?
xanthine oxidase
Purine intake is from?
diet (meats esp.)
nucleotide breakdown
body synhesis
what hormone promotes uric acid excretion
oestrogen
therefore gout rare in premeno women
what is gout caused by
too much uric acid
ususally due to reduced uric acid excretion
if untreated, gout can cause?
damage to joint
infections
nerve damage
what can reduce uric acid excretion
thiazide diuretics
reduced kidney function
metabolic syndrome
alcohol (also increases uric acid synthesis)
how doe the medication allopurinol treat gout?
inhibits xanthine oxidase
Lesch Nyhan syndrome is a rare inherited disease caused by high uric acid levels.
behavioural problems; biting fingers and lips (severe).
what causes it?
lack of HPRT.
(no backwards recycling or purines into nucleotides
∴ more uric acid)
